Acute drug-induced movement disorders …

Joseph H Friedman MD

Movement Disorders

Updated 03.06.2024
Released 07.16.1993
Expires For CME 03.06.2027

Acute drug-induced movement disorders

Author: Joseph H Friedman MD

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Editor: Robert Fekete MD

Acute drug-induced movement disorders

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Introduction

Overview

Acute drug-induced movement disorders are primarily due to neuroleptics, but other psychoactive medications and nonpsychiatric medications may produce them as well, both at toxic as well as at therapeutic or even subtherapeutic levels. Although it is generally believed that drug-induced movement disorders are much less common in the era of atypical antipsychotic drugs, there are few data to support this contention. Both acute and nonacute neuroleptic-induced movement disorders still do occur; therefore, neurologists and psychiatrists must be able to recognize and treat them. Although vesicular mono-amine transporter type 2 (VMAT2) medications are now available to treat tardive syndromes, not much else has changed in the development or treatment of medication induced movement disorders (24). Akathisia may be mistaken for other conditions, including restless legs, increased psychosis, anxiety, or internal tremor, and it should be included on the differential diagnostic list for restlessness or agitation. These problems are occasionally seen with antiemetics and, more commonly, with antipsychotics (eg, chlorpromazine) used for migraines or depression (eg, aripiprazole, brexpiprazole olanzapine). Akathisia may also be seen with VMAT2 inhibitors used to treat hyperkinetic movement disorders, such as chorea or tardive syndromes. Although these drugs do not cause tardive syndromes, they have been associated with acute dystonic reactions and akathisia. Acute dystonic reactions occur with some, but not all, of the newer antipsychotic medications. Acute akathisia is harder to characterize because of the subjective nature of the symptoms. Neuroleptic malignant syndrome occurs with all antipsychotics, including clozapine and the other second-generation antipsychotics. The SSRIs may cause akathisia or, with overdose or in combination with nonspecific monoamine oxidase-inhibiting drugs, serotonin syndrome, which can be difficult to distinguish from neuroleptic malignant syndrome.

Key points

	• Extrapyramidal side effects may be seen with all first- and second-generation antipsychotic drugs.
	• Acute akathisia and acute dystonic reactions are usually the first extrapyramidal side effects to develop, primarily shortly after initiation of an antipsychotic or a dose increase, and generally before parkinsonism develops.
	• Akathisia may be difficult to diagnose because of its subjective nature and overlap with anxiety and psychosis but is a very important cause for noncompliance and increases risk of suicide. It may also account for agitation in patients who have impaired communication.
	• VMAT2 inhibitors may cause akathisia and, rarely, acute dystonic reactions.

Historical note and terminology

The term “acute drug-induced movement disorders” refers primarily to acute dystonic reactions and akathisia. These syndromes were first described as adverse drug effects in the mid-1950s (81; 17) and were recognized as being similar to the dystonic and akathisic syndromes seen in postencephalitic parkinsonism. Akathisia had been recognized even before the encephalitis epidemic, the term having been coined at the turn of the century to describe psychiatric patients unable to remain seated and thought to suffer from a form of hysteria (36). The syndrome we currently call akathisia had been described in the 19th century in idiopathic Parkinson disease (09). The term “akathisia” was taken up by neurologists after the epidemic of postencephalitic parkinsonism, which was frequently associated with akathisia (90).

These syndromes are thought to have become considerably less common in the current era of atypical antipsychotic drugs but have not been well studied. Parkinsonism and tardive syndromes have been widely thought to have been reduced with the introduction of the atypical antipsychotics, but data on this are conflicting (16; 61).

Clinical manifestations

Presentation and course

Akathisia and acute dystonic reactions may develop within minutes of drug intake (40). More commonly, acute dystonia occurs before akathisia, generally within hours to days of drug initiation or dose increase. Ninety-five percent of acute dystonic reactions occur within 4 days of drug initiation (06).

Acute dystonic reactions are involuntary sustained muscle contractions causing an abnormal posture that usually lasts for about 20 to 30 minutes at a time and is often painful; the contractions remit and recur a variable number of times before resolving entirely (33; 13). The cranial and cervical muscles are most commonly involved. The head may be turned, flexed, or extended. Jaw, tongue, and muscles of facial expression may be involved in isolation or together. Patients with tongue involvement frequently describe it as feeling swollen, most likely the subjective sensation of involuntary tongue contractions and not the result of actual swelling (personal observation). Oculogyric crisis (described previously only with postencephalitic parkinsonism), in which the eyes deviate conjugately up and to one side, may occur in concert with other dystonic reactions or by itself. Pisa syndrome is an uncommon form of dystonia that causes truncal flexion towards either side (83). Pure truncal flexion is called camptocormia. The Pisa syndrome may occur as a tardive syndrome or as an acute dystonic reaction. It has been observed in Parkinson disease and has been associated with several non-neuroleptic medications.

Akathisia is more difficult to recognize (86). It is an inability to remain still due to a sense of inner restlessness (02). People are gripped by a compulsion to move, as if a "foreign force" (45) has taken over, making them unable to remain in one place. When seated, the patient will rock in place or change positions, often standing every few seconds, and will appear fidgety. While standing, the patient will typically march in place or shift weight from side to side (11). If observed outside of a formal evaluation, akathisic patients move continuously and find it difficult to watch television, engage in conversations, or sleep because of difficulty remaining still. When mild, it may be perceived by the patient or observer as anxiety (45; 29). It may be impossible to distinguish akathisia from psychosis when the patient is uncommunicative due to psychosis (85; 86) or dementia. Akathisia may persist for long periods if neuroleptics are continued (56). Akathisia is an uncomfortable sensation and, when severe, patients may consider it a greater problem than the psychosis being treated (personal observation). As a result, it is associated with higher measures of suicidality than similarly treated patients without this problem. Acute movement disorders induced by antiemetics and antipsychotics, when not used for psychosis, are less likely to be recognized than when antipsychotics are used for schizophrenia (89).

Clozapine may cause asterixis, presumably even causing falls due to knees buckling, but how quickly this may develop is unknown (30).

Drugs of abuse may also cause acute movement disorders. Cocaine is known to cause chorea and dystonia via dopamine reuptake inhibition (20). Amphetamine use can result in punding, which is a repetitive purposeless stereotyped behavior such as excessive hair brushing (26).

Prognosis and complications

Acute dystonic reactions consistently resolve when the offending drug is stopped, and consistently respond to anticholinergics or diphenhydramine. After the acute episode resolves, patients should continue taking the anti-dystonia medication orally for the next couple of days to prevent recurrence, but data on treatment are lacking.

Akathisia has a more complex prognosis. In most cases, akathisia resolves if the medication is stopped, but it may take longer. It may persist if the neuroleptic is continued, unlike acute dystonia, which is self-limited. Akathisia can even evolve into a tardive syndrome. Although akathisia is believed to be a common reason for medication noncompliance among the psychotic, it is not known if akathisia precludes a good antipsychotic response. When akathisia is recognized, the prognosis is good. The akathisia is treated directly or the offending neuroleptic is stopped, and (if possible) a new one of a different chemical family and of lower potency is started. Prognosis is obviously much worse for patients whose akathisia is unrecognized or who are treated in institutions against their wills, or with depot injections. Interestingly, akathisia may be prognostic of a poor antipsychotic response (53).

Clinical vignette

Vignette 1. An 80-year-old man, without any known neurologic problems, was admitted to the hospital for evaluation of severe abdominal pain. On his first night he became confused and tried to climb out of the bed. He was given an intramuscular injection of haloperidol 1 mg. A few hours later he became mildly agitated, climbed out of bed again, and was given another injection of the haloperidol. Over the next 3 days this continued while his abdominal problem, undiagnosed, resolved. He was discharged from the hospital on haloperidol 2 mg daily, which no one stopped. He was evaluated 3 months later and was severely parkinsonian and akathisic. He apologized to me repeatedly as he stood up from his chair every minute or so, explaining that he was unable to sit still. His haloperidol was stopped, and his akathisia resolved within 3 months. At that time, his parkinsonism improved but was still present.

Vignette 2. When asked if he had seen much akathisia when he used an intravenous cocktail that included metoclopramide, one neurologist/headache specialist responded that he had never observed it. He noted, however, that occasionally patients became extremely anxious and refused to remain in the clinic for the usual observation period; these patients had unrecognized akathisia (44).

Biological basis

Etiology and pathogenesis

By definition, these syndromes are drug induced. Most commonly, they are caused by dopamine receptor blocking drugs. Dopamine depleting drugs such as alpha-methylparatyrosine, used to treat hypertension, which block the synthesis of catecholamines, can also cause acute dystonia (59). Akathisia has been well described as an adverse effect of the selective serotonin reuptake inhibiting antidepressants, yet these drugs induce parkinsonism or acute dystonia only rarely (35; 52). In a large retrospective chart review, nine patients of 1875 taking citalopram developed acute dystonic reactions (63). Certain antimalarials also have been reported to rarely induce dystonia, as does the antiepileptic, tiagabine (92). One case of bupropion-induced acute dystonic reaction has also been documented (19), which is surprising because the drug has mild dopaminergic properties. Levodopa frequently causes recurrent dystonia in Parkinson disease patients, but these usually involve a foot, are also associated with choreoathetoid movements, and resolve when levodopa is discontinued. Wilson disease may cause acute dystonia in children (23), and a variety of other disorders may very rarely cause acute dystonic spells in adults or children (08). Akathisia has been reported to affect about 7% of people treated with tetrabenazine for hyperkinetic movement disorders (46). It also has been reported to cause acute dystonia (12).

Only limited data support the theoretical explanations for either acute dystonia or akathisia. Acute dystonia can be induced in animals with injections directly into the brain using cholinergic agonists (14) or sigma opiate receptor blockers (87). All theories are based on the clinical observation that dopaminergic receptor blockade induces both acute dystonia and akathisia, but dopamine depleting drugs do as well. Two major theories to explain acute dystonia center on a dopamine imbalance: either too little or too much (55; 56; 13), or possibly variant dopamine receptors (49). Neuroleptics induce compensatory dopamine release, which presumably overstimulates the unblocked receptors in a manner similar to excess levodopa causing dystonia in Parkinson disease. A third theory holds that an acute insufficiency of dopamine stimulation causes dystonia, explaining the relationship to high doses and high potency neuroleptic drugs, the effectiveness of anticholinergics in treating the syndrome, and the early onset of the dystonia. A puzzling feature of the atypical antipsychotics has been their relative freedom from extrapyramidal side effects despite their antagonism for D2 receptors. One hypothesis for this feature, which may also be a contributing explanation for the development of acute dystonia, is the speed of dissociation of these drugs from the D2 receptor (41). Thus, rates of dissociation may have something to do with parkinsonism and the more acute side effects. However, aripiprazole, a partial dopamine D2 agonist, has been implicated in causing acute dystonic reactions in several case reports (94; 65). An interesting observation that complicates our understanding is that haloperidol, when given intravenously, is less likely to cause either of these problems than when given orally, even at high doses (60); however, IM haloperidol causes more acute movement disorders than oral haloperidol. Yet a large prospective study of intravenous metoclopramide given for the treatment of headache reported akathisia, but that was reduced by slowing the infusion from 2 to 15 minutes (74). Various studies have suggested a predisposition for the development of akathisia with low serum iron or ferritin, but other published work does not corroborate this notion (38).

A single PET study has shown a correlation between high binding of D1 and D2 specific dopamine receptor binding ligands in the putamen in normal and schizophrenic subjects with akathisia (25). An alternative theory suggests that akathisia may in part be the result of acute mesocortical dopamine insufficiency (35). How the selective serotonin reuptake inhibitor antidepressants cause akathisia is unknown. There may be subtypes of depression that are more likely to be associated with such a response (50), and there may be differences among the selective serotonin reuptake inhibitors and their affinity for the 5HT2C receptor. The effect may be the result of an indirect effect on dopamine.

There are no compelling theories to explain either akathisia or dystonia that integrate data regarding responses to treatment with medications of widely different types, the epidemiology of the syndromes, and the occurrence of both syndromes in postencephalitic parkinsonism.

Three cases of recurrent oculogyric crises were reported to occur despite withdrawal from the offending dopamine-blocking drug (77), blurring the distinction between acute and tardive dystonia (27).

Epidemiology

Acute dystonia is more common in males and the young in general, with peak incidence under 15 years of age (48). It decreases with age (03), becoming rare after 40 years of age. In a prospective study of 200 neuroleptic naive patients admitted to a psychiatric hospital, 45% developed acute dystonic reaction, without gender preference, on low doses of haloperidol (58). Another prospective study of 660 previously treated outpatients found acute dystonic reaction in only 8% of haloperidol-treated patients (84). In children, generalized dystonic reactions and oculogyric crises predominate, whereas adults tend to suffer isolated neck and cranial dystonias. A report describing acute dystonic reactions occurring in three young brothers when given metoclopramide for gastroenteritis (79) raises the question of a genetic predisposition. Akathisia seems to have no age or gender predilections (51; 76). Both are more common with high-potency neuroleptics, high doses of drugs, and depot injections (56). Estimates for the occurrence of akathisia are variable, ranging from under 10% in early studies to 70% (01), with a figure of 20% generally accepted (13) depending on criteria used (76). A review of akathisia incidence associated with the newest second-generation antipsychotics in subjects of controlled clinical trials found that exposure to each of the drugs was significantly increased compared to those assigned to placebo, and these subjects had all been on neuroleptics shortly before enrolling in the trials (18). Akathisia usually develops over days to weeks, following a time course similar to, but somewhat faster than, drug-induced parkinsonism (56). Ninety percent of cases develop within 73 days of the beginning of treatment, but some develop within minutes, especially after intravenous administration of a neuroleptic (25). In a study of migraine treatment with intravenous metoclopramide in nonpsychiatric patients, akathisia developed in 33 of 356 patients, mostly women, within minutes (29). There was no relationship to dose. Onset of akathisia after 3 months of a stable neuroleptic dose may be considered tardive akathisia (75).

An interesting anesthesiology study reported on extrapyramidal side effects in 45,766 patients who were given a single dose of perphenazine (4 mg or 8 mg) to prevent postoperative nausea (37). Only five cases of akathisia and one of acute dystonic reaction were noted in this retrospective chart review, an event rate of 1.3 per 100,000 patients.

Abnormalities of iron stores in the brain has been suggested as a risk factor for developing akathisia, but data supporting this hypothesis are weak (78).

Even the newer second generation antipsychotics may cause acute akathisia (47).

Prevention

The best prophylaxis against both acute dystonic reactions and akathisia is to avoid the drugs that cause them. The atypical antipsychotics either do not cause these side effects or do so at a significantly lower rate than the previous generation of antipsychotic drugs. It is important to note that this “second generation” of antipsychotics has not been shown to be more effective than the previous generation, with the exception of clozapine, but there are data suggesting fewer acute extrapyramidal side effects such as acute dystonia and akathisia (15). Ziprasidone has been increasingly, but still uncommonly, reported to cause acute dystonic reactions (88; 95), as have the other atypicals except for quetiapine and clozapine. Akathisia has also been associated with aripiprazole and risperidone (42; 67).

Prophylaxis against acute dystonia with antiparkinson medication has been studied and found to be helpful (43; 80; 91; 10; 13; 03). Use of low-potency neuroleptics, which have prominent anticholinergic activity, also reduce the incidence. However, the anticholinergics have potent side effects including dry mouth, constipation, blurred vision, memory impairment, urinary retention, and sexual dysfunction. The utility of amantadine in prophylaxis of acute dystonia has not been studied. Prophylaxis probably should be reserved for those at most risk and discontinued after a few weeks, when the risk falls.

Although akathisia is common, high quality studies of prophylaxis are lacking. A Cochrane review found no reliable data on this (73), and a metaanalysis found a single placebo controlled trial reporting benefit for diphenhydramine for akathisia against metoclopramide (62).

The suggestion that giving a neuroleptic intravenously rather than orally might reduce the likelihood of extrapyramidal side effects was not borne out in a study in which over 40% of migraineurs who received intravenous haloperidol experienced uncomfortable restlessness (60; 31).

Differential diagnosis

Acute dystonic reactions are easy to recognize. Unfortunately, factitious cases, involving medicated patients familiar with the syndrome, can be impossible to distinguish from real cases. These patients mimic the disorder for secondary gain. Naturally occurring dystonic syndromes such as torticollis, writer's cramp, and blepharospasm can look like dystonic reactions but are slower in onset, occur typically in nonpsychiatric patients, involve no precipitating medications, and do not resolve.

Blepharospasm

Repetitive episodes of spasmodic eye closure are sustained for several seconds. (Contributed by Dr. Joseph Jankovic.)

Tonic focal seizures, paroxysmal dystonias, and muscle spasm due to bony injury or subluxation (especially in the cases of atlantoaxial subluxation simulating torticollis or a subluxated jaw looking like jaw dystonia) can look like acute dystonia but should be easily distinguishable based on history and duration of the episodes. Hypocalcemia with carpopedal spasm may also need to be considered, as well as cephalic tetanus and drug intoxication (39). An interesting chart review found that acute dystonic reactions in children were misdiagnosed in the majority of cases (22; 93). The initial diagnoses had been conversion disorder, meningitis, epileptic seizure, mandibular subluxation, tetanus, and unknown brain pathology (22).

Akathisia may be confused with mania, stimulant drug intoxication, drug withdrawal, or an agitated emotional state (86; 51). One must be wary of missing akathisia, as it may be the cause for a paradoxical worsening of behavior in response to antipsychotic treatment (85; 86; 07). Equally important is the consideration of akathisia as a driving force for agitation in demented patients who receive antipsychotic drugs for psychiatric aspects of their dementias or for agitated behavior in children and adolescents (32). A summary of an international meeting on agitation noted that the majority or participants considered antipsychotics their first-line drug treatment when the etiology of the agitation was unknown (57). Therefore, worsening of agitation should be a warning sign. If the response to an antipsychotic is worsened behavior, akathisia must be considered. Because the patients are often unable to communicate, a high index of suspicion must be maintained. Restless legs (Ekbom syndrome) is not associated with dopamine blockade although it is relieved by L-DOPA and dopamine agonists. Patients develop uncomfortable sensations in their legs that are relieved by walking (51). These sensations occur primarily at night and interfere with falling asleep but do not occur to a significant degree during the day. This syndrome has been associated with iron deficiency in some cases. Finally, tardive dyskinesia or "pseudo akathisia" can cause a constellation of fidgety looking choreic movement in which patients look restless but are not (11).

Management

Drug treatment. Acute dystonia is easily treated with intramuscular or intravenous benztropine, diphenhydramine or diazepam, or resolves by itself whether the precipitating drug is discontinued or not. Prophylaxis with anticholinergics or diphenhydramine lowers the risk but increases adverse effects. When prophylaxis is used it can be reduced after 1 to 2 weeks.

Akathisia treatment is less straightforward. Several double-blind studies have demonstrated the benefits of low dose beta-blockers. Propranolol, a beta 1 and beta 2 lipophilic antagonist, has been the most studied and has been compared to betaxolol, a central beta 1 antagonist (21) as well as nadolol, atenolol, sotalol, metoprolol and pindolol (02). Unfortunately the number of patients involved in these studies has been small, leading to contradictory results. Propranolol appears to work as well or better than any other beta-blocker at doses as low as 10 to 20 mg three times daily. There is no answer yet as to whether the beta 1 or beta 2 receptor is more important. Selective blockers of each have been found to alleviate akathisia, once the blood-brain barrier is crossed (28).

Anticholinergics have long been used for akathisia and appear to work best in cases associated with parkinsonism (11). A Cochrane Review (54) found “no reliable evidence to support or refute the use of anticholinergics for people suffering from akathisia.” Benzodiazepines, clonidine, an alpha 2 partial agonist, amantadine, ritanserin, and mianserin (69), both 5HT2 antagonists, as well as other drugs have also been reported to improve akathisia. One report cites cyproheptadine as a potential therapy (04). It should be noted that some review articles on treating akathisia fail to distinguish between acute and tardive akathisia, which have very different treatments (72).

An open-label study described a beneficial effect of nicotine patches in neuroleptic-induced akathisia (05). If confirmed, this result would potentially explain the high cigarette use among psychiatric in-patients but would add a cholinergic agonist (nicotine) to the cholinergic (muscarinic) antagonists as a potential therapy. Another open-label report describes a positive, but brief (3-day), trial of the 5-HT 1D receptor agonist, zolmitriptan, 2.5 mg three times daily (34).

A prospective randomized controlled trial reported that midazolam, a rapid-acting benzodiazepine, reduced akathisia, within 5 minutes, significantly faster than diphenhydramine, although with greater sedation (64). Another report requiring duplication found benefit from trazodone 100 mg every night in a double blind, placebo controlled, crossover trial involving only 13 subjects (82). Mirtazapine (15 mg) has also been proposed, with only limited data (68).

A meta-analysis supported the use of mirtazapine, an antidepressant anxiolytic that increases norepinephrine secretion while blocking 5HT2A receptors, for acute akathisia (70). However, this was based on only two double-blind placebo-controlled trials in which 15 mg was given in the morning. Only 20% of the patients went into complete remission, and the drug took about 3 days to work.

A consensus of experts recommended that for pediatric cases of acute dystonic reactions, diphenhydramine and anticholinergics are the best first choices, and that anticholinergics, propranolol, clonazepam, and mirtazapine are the first-line choices for acute akathisia (71).

The best approach depends on the situation. If the psychosis is improving, the akathisia should be treated with anticholinergics if parkinsonism is present. If parkinsonism is not present, propranolol should be used. If anxiety is complicating the picture, a benzodiazepine is recommended. If psychosis persists and akathisia is present, then use of a neuroleptic of a different family and lower potency, or the dopamine-depleting drug tetrabenazine, if possible, is indicated (40). Other “second line” drugs that have been advocated include cyproheptadine, mirtazapine, trazodone, ritanserin, mianserin (34).

References

01: Adler LA, Angrist B, Reiter S, Rotrosen J. Neuroleptic-induced akathisia: a review. Psychopharmacology 1989;97:1-11. PMID 2565586
02: Adler LA, Angrist B, Rotrosen J. Acute neuroleptic-induced akathisia. In: Lang AE, Weiner WJ, editors. Drug-induced movement disorders. Mt. Kisco (NY): Futura Publishing, 1992:85-119.
03: Aguilar EJ, Keshavan MS, Martinez-Quiles MD, Hernandez J, Gomez-Beneyto M, Schooler NR. Predictors of acute dystonia in first-episode psychotic patients. Am J Psychiatry 1994;51:1819-21. PMID 7977894
04: Aizenberg D, Hermesh H, Zemishlany Z, et al. Cyproheptadine treatment in neuroleptic-induced akathisia. Br J Psychiatry 1995;167:483-6. PMID 8829717
05: Anfang MK, Pope HG Jr. Treatment of neuroleptic-induced akathisia with nicotine patches. Psychopharmacology (Berl) 1997;134:153-6. PMID 9399378
06: Ayd FJ. A survey of drug induced extrapyramidal reactions. JAMA 1961;175:1054-60. PMID 13685365
07: Barnes TR. A rating scale for drug induced akathisia. Br J Psychiatry 1989;154:672-6. PMID 2574607
08: Barow E, Schneider SA, Bhatia KP, Ganos C. Oculogyric crises: etiology, pathophysiology and therapeutic approaches. Park Rel Disord 2017;36:3-9. PMID 27964831
09: Bing R. Textbook of nervous diseases. Haymaker W, trans. St. Louis: Mosby, 1939.
10: Boyer WF, Bakalar NH, Lake CR. Anticholinergic prophylaxis of acute haloperidol-induced acute dystonic reactions. J Clin Psycholpharmacol 1987;7:164-6. PMID 3597801
11: Braude WM, Barnes TR, Gore SM. Clinical characteristics of akathisia: a systematic investigation of acute psychiatric inpatient admissions. Br J Psychiatry 1983;143:139-50. PMID 6137254
12: Burke RE, Reches A, Traub MM, Ilson J, Swash M, Fahn S. Tetrabenazine induces acute dystonic reactions. Ann Neurol 1985;17(2):200-2. PMID 3977303
13: Casey DE. Neuroleptic-induced acute dystonia. In: Lang AE, Weiner WJ, editors. Drug-induced movement disorders. Mt Kisco (NY): Futura Publishing, 1992:21-40.
14: Cools AR, Janssen HJ, Broekkamp CL. The differential role of the caudate nucleus and the linear raphe nucleus in the initiation and the maintenance of morphine-induced behaviour in cats. Arch Int Pharmacodyn Ther 1974;210:163-74. PMID 4474848
15: Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60(6):553-64. PMID 12796218
16: Dayalu P, Chou KL. Antipsychotic-induced extrapyramidal symptoms and their management. Expert Opin Pharmacother 2008;9:1451-62. PMID 18518777
17: Delay J, Deniker P. Drug-induced extrapyramidal syndromes. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Vol. 6. Disease of the basal ganglia. New York: Wiley, 1968:248-66.
18: Demyttenaere K, Detraux J, Racagni G, Vansteelandt K. Medication-induced akathisia with newly approved antipsychotics in patients with a severe mental illness: A systematic review and meta-analysis. CNS Drugs 2019;33(6):549-66. PMID 31065941
19: Detweiler MB, Harpold GJ. Bupropion-induced acute dystonia. Ann Pharmacother 2002;36(2):251-4. PMID 11847943
20: Duma SR, Fung VS. Drug-induced movement disorders. Aust Prescr 2019;42(2):56-61. PMID 31048939
21: Dumon JP, Catreau J, Lanvin F, Dupuis BA. Randomized, double-blind, crossover, placebo-controlled comparison of propranolol and betaxolol in the treatment of neuroleptic-induced akathisia. Am J Psychiatry 1992;149:647-50. PMID 1349458
22: El C, Celikkaya ME. Varied clinical presentations of acute dystonic reactions due to meotoclopramide. Pediatr Emerg Care 2019;35(5):369-72. PMID 30908432
23: Erol I, Alehan F, Ozcay F, et al. Neurologic complications of liver transplantation in pediatric patients with the hepatic form of Wilson’s disease. J Child Neurol 2008;23:293-300. PMID 18079318
24: Factor SA, Burkhard PR, Caroff S, et al. Recent developments in drug-induced movement disorders: a mixed picture. Lancet Neurol 2019;18(9):880-90. PMID 31279747
25: Farde L. Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans--a PET study with [11C]SCH 23390 and [11C]raclopride. Psychopharmacology (Berl) 1992;107(1):23-9. PMID 1534178
26: Fasano A, Petrovic I. Insights into pathophysiology of punding reveal possible treatment strategies. Mol Psychiatry 2010;15(6):560-73. PMID 20489735
27: FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neurology 1989;39(11):1434-7. PMID 2573005
28: Fleischhacker WW, Roth SD, Kane JM. The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol 1990;10(1):12-21. PMID 1968470
29: Friedman BW, Mulvey L, Esses D, et al. Metoclopramide for acute migraine: a dose-finding randomized clinical trial. Ann Emerg Med 2011;57(5):475-82.e1. PMID 21227540
30: Friedman JH. Asterixis is markedly increased in patients taking clozapine. Clin Neuropharm 2023;46(2):87. PMID 36790372
31: Gaffigan ME, Bruner DI, Wason C, Pritchard A, Frumkin K. A randomized controlled trial of intravenous haloperidol vs. intravenous metoclopramide for acute migraine therapy in the emergency department. J Emerg Med 2015;49(3):326-34. PMID 26048068
32: Garcia-Delgar B, Morer A, Varela E, et al. Activation in children and adolescents treated with serotonin reuptake inhibitors: a weighty reason? J Clin Psychopharmacol 2018;38(5):475-80. PMID 30063503
33: Gibb WR, Lees AG. The clinical phenomenon of akathisia. J Neurol Neurosurg Psychiatry 1986;49:861-6. PMID 2875132
34: Gross-Isseroff R, Magen A, Shiloh R, et al. The 5-HT1D receptor agonist zolmitriptan for neuroleptic-induced akathisia: an open label preliminary study. Intl Clin Psychopharmacol 2005;20:23-5. PMID 15602112
35: Hamilton MS, Opler LA. Akathisia, suicidality, and fluoxetine. Am J Psychiatry 1992;53:401-6. PMID 1364815
36: Haskovec L. Akathisia. Arch Bohemes Med Clin 1902;3:193-200.
37: Henao JP, Peperzak KA, Lichvar AB, et al. Extrapyramidal symptoms following administration of oral perphenazine 4 or 8 mg: An 11 year retrospective analysis. Eur J Anaesthesiol 2014;31(4):231-5. PMID 24503705
38: Hofmann M, Seifritz E, Botschev C, et al. Serum iron and ferritin in acute neuroleptic akathisia. Psychiatry Res 2000;93:201-7. PMID 10760378
39: Humphreys A, Tanner AR. Acute dystonic reaction or tetanus. An unusual complication of a "Whizz" overdose. Hum Exp Toxicol 1994;13(Suppl 5):311-2. PMID 8043311
40: Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother 2016;17(18):2461-70. PMID 27819145
41: Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics.: A new hypothesis. Am J Psychiatry 2001;158(3):360-9. PMID 11229973
42: Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized double blind, placebo-controlled 26 week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 2006;67:626-37. PMID 16669728
43: Keeper GA, Clappison VJ, Casey DE. Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983;40:1113-7. PMID 6138011
44: Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: neuroleptics, antihistamine, and others. Headache 2012;52(2):292-306. PMID 22309235
45: Kendler KS. A medical student's experience with akathisia. N Engl J Med 1976;133:454-5.
46: Kenney C, Hunter C, Jankovic J. Long term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007;22:193-7. PMID 17133512
47: Kishi T, Sakuma K, Saito T, Nakagawa A, Kato M, Iwata N. Comparison of brexpiprazole, aripiprazole and placebo for Japanese major depressive disorder: A systematic review and network meta-analysis. Neuropschopharmacol Rep 2024;44(1):165-75. PMID 38219278
48: Knight ME, Roberts RJ. Phenothiazine and butyrophenone intoxication in children. Pediatr Clin North Am 1986;33(2):299-309. PMID 2870459
49: Koning JP, Vehof J, Burger H, et al; Genetic Risk and Outcome in Psychosis (GROUP) investigators. Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients. Psychopharmacology (Berl) 2012;219(3):727-36. PMID 21750899
50: Lane RM. SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol 1998;12:192-214. PMID 9694033
51: Lang AE. Akathisia and the restless leg syndrome. In: Jankovic J, Tolosa E, editors. Parkinson's disease and movement disorders, II. Baltimore: Williams and Wilkins, 1993:349-64.
52: Leo RJ. Movement disorders associated with serotonin selective reuptake inhibitors. J Clin Psychiatry 1996;57:449-54. PMID 8909330
53: Levinson DF, Simpson GM, Lo ES, et al. Fluphenazine plasma levels, dosage, efficacy, and side effects. Am J Psychiatry 1995;152:765-71. PMID 7726317
54: Lima AR, Weiser KV, Bacaltchuk J, Barnes TR. Anticholinergics for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2004;(1):CD003727. PMID 14974032
55: Marsden CD, Jenner P. The pathophysiology of extrapyramidal side effects of neuroleptic drugs. Psychol Med 1980;10:55-72. PMID 6104342
56: Marsden CD, Mindham RH, Mackay AV. Extrapyramidal movement disorders produced by antipsychotic drugs. In: Bradley PB, editor. Psychopharmacology and treatment of schizophrenia. Oxford University Press, 1986.
57: Martinez-Raga J, Amore M, Di Sciasco G, et al. 1st International Experts’ Meeting on Agitation: Conclusions regarding the current and ideal management paradigm of agitation. Front Psychiatry 2018; 9:54. PMID 29535649
58: Mazurek M, Rosebush PI. Circadian pattern of acute, neuroleptic induced dystonic reactions. Am J Psychiatry 1996;153:708-10. PMID 8615420
59: McCann UD, Penetar DM, Belenky G. Acute dystonic reactions in normal humans caused by catecholamine depletion. Clin Neuropharmacol 1990;13:565-8. PMID 1980430
60: Menza MA, Murray GB, Holmes VF, Rafuls WA. Decreased extrapyramidal symptoms with intravenous haloperidol. J Clin Psychiatry 1987;48(7):278-80. PMID 3597329
61: Miller DD, Caroff SN, Davis SM, et al. Extrapyramidal side-effects of antipsychotics in a randomized trial. Brit J Psychiatry 2008;193:279-88. PMID 18827289
62: Mokharti, A, Yip O, Alain J, Berthelot S. Prophylactic administration of diphenhydramine to reduce neuroleptic side effects in the acute care setting: a systematic review and meta-analysis. J Emerg Med 2021;60(2):165-74. PMID 33131965
63: Moosavi SM, Ahmadi M, Monajemi MB. Acute dystonia due to citalopram treatment: a case series. Glob J Health Sci 2014;6(6):395-9. PMID 25363102
64: Parlak I, Erdur B, Parlak M, et al. Midazolam vs diphenhydramine for the treatment of metoclopramide induced akathisia: a randomized controlled trial. Acad Emerg Med 2007b;14:715-21. PMID 17545174
65: Pena MS, Yaltho TC, Jankovic J. Tardive dyskinesia and other movement disorders secondary to aripiprazole. Mov Disord 2011;26(1):147-52. PMID 20818603
66: Piecuch S, Thomas U, Shah BR. Acute dystonic reactions that fail to respond to diphenhydramine: think of PCP. J Emerg Med 1999;17(3):527. PMID 10338254
67: Potkin JG, Gharabawi GM, Greenspan AJ, et al. A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia and experiencing an acute exacerbation requiring hospitalization. Schiz Res 2006;85:254-65. PMID 16797162
68: Poyurovsky M, Bergman J, Pashinian A, Weizman A. Beneficial effect of low-dose mirtazapine in acute aripiprazole induced akathisia. Int Clin Pyschpharmacol 2014;29(5):296-8. PMID 24667488
69: Poyurovsky M, Shardorodsky M, Fuchs C, et al. Treatment of neuroleptic induced akathisia with the 5-HT2 antagonist mianserin. Double-blind, placebo-controlled study. Br J Psychiatry 1999;174:238-42. PMID 10448449
70: Praharaj SK, Kongasseri S, Behere RV, Sharma PS. Mirtazapine for antipsychotic-induced acute akathisia: a systematic review and meta-analysis of randomized placebo-controlled trials. Ther Adv in Psychopharmacol 2015;5(5):307-13. PMID 26557987
71: Pringsheim T, Doja A, Belanger S, Patten S; Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group. Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatr Child Health 2011;16(9):590-8. PMID 23115503
72: Pringsheim T, Gardner D, Addington D, et al. The assessment and treatment of antipsychotic-induced akathisia. Can J Psychiatry 2018;706743718760288. PMID 29685069
73: Rathbone J, Soares-Weither K. Anticholinergics for neuroleptic-induced acute akathisia. Coch Database Syst Rev 2006(4):CD003727. PMID 17054182
74: Regan LA, Hoffman RS, Nelson LS. Slower infusion of metoclopramide decreases the rate of akathisia. Am J Emerg Med 2009;27(4):475-80. PMID 19555621
75: Sachdev P. The epidemiology of drug-induced akathisia: part l. Acute akathisia. Schizophr Bull 1995;21(3):431-49. PMID 7481574
76: Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry 1994;51:963-74. PMID 7979885
77: Schneider SA, Udani V, Sankhla CS, Bhatia KP. Recurrent acute dystonic reaction and oculogyric crisis despite withdrawal of dopamine receptor blocking drugs. Mov Disord 2009;24(8):1226-9. PMID 19412963
78: Schoretsanitis G, Nikolakopoulou A, Guinart D, Correll CU, Kane JM. Iron homeostasis alterations and risk for akathisia. Eur Neuropsychopharmacol 2020;35:1-11. PMID 32444336
79: Silfeler I, Arica V, Arica S, Dogan M. Development of acute dystonia in three brothers due to metoclopramide. J Res Med Sci 2012;17(3):308-9. PMID 23267386
80: Sramek JJ, Simpson GM, Morrison RL, Herser JF. Anticholinergic agents for prophylaxis of neuroleptic-induced dystonic reactions: a prospective study. J Clin Psychiatry 1986;47:305-9. PMID 2872206
81: Steck H. Le syndrome extra-pyramidal et di-encephalique au cours des traitements au Larqactil et au Serpasil. Ann Med Psychol (Paris) 1954;112:737-43. PMID 14362101
82: Stryjer R, Rosenzcwaig S, Bar F, Ulman AM, Weizman A, Spivak B. Trazodone for the treatment of neuroleptic induced acute akathisia: a placebo controlled, double blind, crossover study. Clin Neuropharm 2010;33:219-22. PMID 20838215
83: Suzuki T, Matsuzaka H. Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management. CNS Drugs 2002;16:165-74. PMID 11888337
84: Tollefson GD, Beasley CM Jr, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457-65. PMID 9090331
85: Van Putten T. Why do schizophrenic patients refuse to take their drugs. Arch Gen Psychiatry 1974;31:67-72. PMID 4151750
86: Van Putten T. The many faces of akathisia. Compr Psychiatry 1975;16(1):43-7. PMID 234073
87: Walker M, Matsumoto MA, Bowen WD, Gans DL, Jones KD, Walker FO. Evidence for a role of haloperidol sensitive sigma "opiate" receptors in the motor effects of antipsychotic drugs. Neurology 1988;38(6):961-5. PMID 2897093
88: Weinstein SK, Adler CM, Strakowski SM. Ziprasidone induced acute dystonic reactions in patients with bipolar disorder. J Clin Psychiatry 2006;27:327-8. PMID 16566635
89: Wijemanne S, Jankovic J, Evans RW. Movement disorders from the use of metoclopramide and other antiemetics in the treatment of migraine. Headache 2016;56(1):153-61. PMID 26573884
90: Wilson SAK. Neurology. Baltimore: Williams and Wilkens, 1941.
91: Winslow RS, Stillner V, Coons DJ, Robinson MW. Prevention of acute dystonic reactions in patients beginning with high-potency neuroleptics. Am J Psychiatry 1986;143:706-10. PMID 2872822
92: Wolanczyk T, Grabowska-Grzyb A. Transient dystonias in three patients treated with tiagabine. Epilepsia 2001;42:944-6. PMID 11488897
93: Yarar C, Yakut A, Carman KB, et al. Metoclopramide-induced acute dystonia: data from a pediatric emergency unit. Pediatr Emerg Care 2021;37(9):e528-33. PMID 32118836
94: Young MC, Shah N, Cantrell FL, Clark RF. Risk assessment of isolated aripiprazole exposures and toxicities: a retrospective study. Clin Toxicol (Phila) 2009;47(6):580-3. PMID 19586356
95: Yumru M, Savas HA, Selek S, Savas E. Acute dystonia after initial doses of ziprasidone: a case report. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:745-7. PMID 16580766

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Joseph H Friedman MD

Dr. Friedman, Chief, Division of Movement Disorders, Department of Neurology, at the Warren Alpert Medical School of Brown University and Stanley Aronson Chair in Neurodegenerative Disorders at Butler Hospital received consultant fees from EPI-Q.
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Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
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Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, >2:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Acute dystonia: 333.7

Acute akathisia: 333.99
ICD-10: Idiopathic nonfamilial dystonia: G24.2

Other specified extrapyramidal and movement disorders: G25.8

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Acute drug-induced movement disorders

Associated Disorders

Oculogyric crisis
Parkinsonism

Differential Diagnosis

torticollis
writer’s cramp
blepharospasm
tonic focal seizures
paroxysmal dystonias
- muscle spasm due to bony injury
- subluxation
- atlantoaxial subluxation
- subluxated jaw
- hypocalcemia with carpopedal spasm
- cephalic tetanus
- drug intoxication
- mania
- stimulant drug intoxication
- drug withdrawal
- agitated emotional state
- restless legs
- Ekbom syndrome
- tardive dyskinesia
- pseudo-akathisia

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- Neuroleptic malignant syndrome
- Parkinson disease
- Stereotypies

Clinical Categories

Movement Disorders

Acute drug-induced movement disorders …

Acute drug-induced movement disorders

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

Acute drug-induced movement disorders

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Hemifacial spasm

Wilson disease

Neuroacanthocytosis

Restless legs syndrome

Dementia in Parkinson disease

ALS-like disorders of the Western Pacific

Sleep-related leg cramps

Sleep and cerebral degenerative disorders

This is an article preview.
Start a Free Account
to access the full version.