Evidence-Based Reviews

Akathisia: Is restlessness a primary condition or an adverse drug effect?

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Serotonin antagonists and agonists. Blockade of 5-HT2 receptors can attenuate D2 blockade and mitigate akathisia symp­toms. Mianserin, 15 mg/d, can be helpful, and ritanserin, 5 to 20 mg/d, produced about a 50% reduction in akathisia symp­toms in 10 patients taking neuroleptics.36 Neither is available in the United States, however.

Cyproheptadine, a potent 5-HT2A and 5-HT2C antagonist with anticholinergic and antihistaminic action, improved akathisia symptoms in an open trial of 17 patients with antipsychotic-induced akathisia.37 The recommended dose is 8 to 16 mg/d.

A study using the selective inverse ago­nist pimavanserin (not FDA-approved) decreased akathisia in healthy volunteers taking haloperidol.14,24,33

Zolmitriptan, a 5-HT1D agonist, also can be used38; one study found that 7.5 mg/d of zolmitriptan is as effective as propranolol.39

A 2010 study showed a statistically signifi­cant improvement in 8 patients taking trazo­done, compared with 5 patients on placebo, all of whom met criteria for at least mild akathisia. Trazodone’s antiakathitic effect is attributed to its 5-HT2A antagonism.25

Anticholinergics. Traditionally, benztropine, biperiden, diphenhydramine, and trihexy­phenidyl have been used for prevention and treatment of extrapyramidal side effects. A Cochrane review concluded, however, that data are insufficient to support use of anticho­linergics for akathisia.40 Although multiple case reports have shown anticholinergics to be effective in treating drug-induced akathi­sia,12,17,33 their association with cognitive side effects suggests a need for caution.18

Benzodiazepines. Through their sedative and anxiolytic properties, benzodiazepines are thought to partially alleviate akathisia symptoms. Two small trials found clonaz­epam helpful for akathisia symptoms2,20; and 1 case report revealed that a patient with akathisia improved after coadministration of clonazepam and baclofen.41

Anticonvulsants. Valproic acid has not been found to be useful in antipsychotic-induced tardive akathisia.42 However, a case report described a patient with schizophrenia whose akathisia symptoms improved after the dosage of gabapentin was increased.43 Last, carbamazepine was found to be effec­tive in reducing akathisia symptoms in 3 patients with schizophrenia who were resis­tant to beta blockers, anticholinergics, anti­histaminergics, and benzodiazepines.19

α-adrenergic agonists. In an open trial, akathisia symptoms in 6 patients improved with clonidine, 0.2 to 0.8 mg/d.17 Speculation is that strong α1 antagonism might help pre­vent akathisia, which could be why this con­dition is not associated with iloperidone.44

D2 agonists. Akathisia and restless legs syndrome have similar pathophysiology,1,2 and patients with akathisia could ben­efit from D2 agonists such as cabergoline, pramipexole, rotigotine, and ropinirole. One case study revealed that a patient with aripiprazole-induced akathisia improved with ropinirole.45 D2 agonists can precipi­tate or worsen psychosis, however, and would be a relative contraindication in patients with psychotic disorders.22

Bottom Line

Failure to detect drug-induced akathisia can increase morbidity and delay recovery in patients undergoing psychiatric care. Knowing what to look for and how to tailor treatment to the needs of a given patient is an essential component of good care.

Related Resources
• Ferrando SJ, Eisendrath SJ. Adverse neuropsychiatric effects of dopamine antagonist medications. Misdiagnosis in the medical setting. Psychosomatics. 1991;32(4):426-432.
• Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004;26(3):265-270.

Drug Brand Names

Aripiprazole • Abilify Haloperidol • Haldol
Baclofen • Lioresal Iloperidone • Fanapt
Benztropine • Cogentin Lurasidone • Latuda
Biperiden • Akineton Mirtazapine • Remeron
Buspirone • BuSpar Pramipexole • Mirapex
Cabergoline • Dostinex Propranolol • Inderal
Carbamazepine • Tegretol Quetiapine • Seroquel
Clonazepam • Klonopin Ropinirole • Requip
Clonidine • Catapres Rotigotine • Neupro
Clozapine • Clozaril Trazodone • Desyrel, Oleptro
Cyproheptadine • Periactin Trihexyphenidyl • Artane
Diphenhydramine • Benadryl Valproic acid • Depakene
Gabapentin • Neurontin Zolmitriptan • Zomig

Mandy Evans, MD, assisted with editing the manuscript of this article.

Dr. Forcen reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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