Background for Fast Fact #282     Antipsychotics and other common psychoactive medications prescribed in serious illness care can cause neuropsychiatric complications such as akathisia. Akathisia is an extrapyramidal symptom characterized by an uncomfortable sensation of internal restlessness and a need to move.  This Fast Fact discusses risk factors, pathophysiology, presentations, and management of akathisia.

Extrapyramidal symptoms (EPS)     EPS encompass several acute/reversible and chronic/irreversible side effects of psychoactive medications. They are believed to be caused by blockade of dopamine receptors (D2) or depletion of dopamine in the basal ganglia. Acute EPS include akathisia and dystonias. Chronic EPS include tardive dyskinesia and focal perioral tremor.  Older (‘typical’ or ‘first generation antipsychotics’) like haloperidol, chlorpromazine, or prochlorperazine, have a higher propensity for producing EPS because of strong binding to dopamine receptors (D2).  Newer (‘atypical,’ or second-generation antipsychotics) like risperidone, quetiapine, or olanzapine have a lower risk of EPS, in part due to blockage of serotonin receptors (1). Untreated akathisia is a risk factor for chronic akathisia, but it is not known if a single episode of akathisia increases the risk for developing chronic EPS.

Incidence and risk factors    The incidence with haloperidol (recognized as a strong dopamine blocker) is 30% and 5-15% with antipsychotics with weaker blocking (1). Elevated risk occurs with higher potency D2 binding, parenteral administration, and rapid dose escalation (1). Haloperidol has a particularly high risk due to its strong affinity for D2 receptors. Additional drugs known to cause akathisia include metoclopramide, prochlorperazine, promethazine, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors (3). Prevalence in hospice patients is unknown but there are several case reports describing it in this patient population (1,4,5).

Clinical presentation   Look for patients continuously needing to be repositioned in bed, or inability to stay still during a visit; pacing, shifting or rubbing legs back and forth in bed; restlessness and dissatisfaction with the room environment that they are in. Patient descriptions of the feeling include “locked in,” “a need to constantly move,” and a “glass coffin” in the published literature (5). The following questions may help clinicians better identify it, “Do you feel like that when you are down you want to be up, when you are up you want to be down?” “You want something, but just don’t know what it is?” ”Do you feel you have “ants in the pants?” 

Differential diagnosis    Akathisia can resemble other conditions. Restless legs syndrome (see Fast Fact #217) is characterized by patients’ inability to keep their lower extremities still at times of rest or sleep. It can be differentiated from akathisia usually by its circadian pattern with worsening at night (which akathisia typically lacks). Restless legs syndrome is chronic in nature (as opposed to akathisia which is typically an acute reaction to a new or increased drug dose). Delirium can manifest as restless agitation but has a definite cognitive and attentional disturbance that is not present with akathisia. Mania usually has a verbal component with racing thoughts and pressured speech, not solely the uncontrollable urge to move. Debilitated patients may also describe frustration about their reduced mobility, but do they not have the uncontrollable urge to move.

Treatment     Once the diagnosis is made, the first and most vital step is to identify the causative agent. 

1. If the akathisia is causing severe distress to a patient, immediately try to reduce symptoms by administering diphenhydramine or benztropine (doses below).
2. Discontinue or lower the dose of the medication or medications thought to be causing the akathisia.
3. If continued antipsychotic therapy is still needed, rotate to an antipsychotic with a lower EPS risk.
   • Chlorpromazine has a lower risk of EPS compared with other older antipsychotics and can be administered IM, IV, PR, or PO. Oral bioavailability is low, and higher doses may be needed. Usual effective dose ranges from 25 mg-150 mg q6 hours prn (6,7).
   • Quetiapine has the lowest D2 receptor affinity and is often used at low doses (12.5-25 mg PO BID) in older patients due to a 40% lower drug clearance.  It may be the least likely to cause EPS effects of all the widely available antipsychotics (8,9). It is only available orally.
   • Olanzapine has been shown to have slightly less incidence of akathisia compared to risperidone or aripiprazole. Limited comparative data exists though. Available as an orally dissolving tab and IM. Usual effective doses are 2.5-5 mg once a day (8,9).
4. If discontinuation or rotation to another antipsychotic is not possible, adjunctive medications may prevent or reduce the akathisia (4-11). This practice is largely empiric, and no treatment has been clearly shown to be superior (8,9). While anticholinergics are often first considered, they are limited by their side effect profile especially in patients older than 65.  Mirtazapine has been identified for its favorable efficacy to tolerability profile in a systematic review (11).
   • Anticholinergics:  diphenhydramine 25-50 mg PO/SC/IM/IV q6 hours; benztropine 2 mg PO/day; procyclidine 2.5 mg PO 3 times daily after meals.
   • Serotonin antagonists: mirtazapine 15 mg PO at bedtime.
   • Nonselective beta-blockers: propranolol 10 mg PO TID titrated to maximum of 80 mg/day.
   • Benzodiazepines: lorazepam 0.5-1 mg PO/SC/IM/IV q8 hours; clonazepam 0.25-0.5 mg PO BID.
   • Adrenergic blockers: clonidine 0.1-0.4 mg PO BID.
   • Vitamin B6.

References 

1. Levine M, Burns M. Antipsychotic Agents. In: Shannon M (Ed), Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 4th ed. 2007.Philadelphia: Elsevier.
2. Kane J, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiat. 2009; 70: 627-643.
3. Jackson N, Doherty J, Coulter S. Neuropsychiatric complications of commonly used palliative care drugs. Postgrad Med. 2008; 84:121-126.
4. Gattera JA, Charles BG, Williams GM, et al.  A retrospective study of risk factors of akathisia in terminally ill paitents. J Pain Symptom Manag 1994; 9(7):454-61.
5. Murphy D, Maher S, Kennedy G, et al.  Case series of akathisia in palliative medicine: patient perspective and efficacy of procyclidine in diagnosis and management. Am J Hosp Palliat Care 2024; Oct 1.
6. White C, Jackson N. Acute akathisia in palliative care. Eur J Pall Care. 2005; 12:5-7.
7. Twycross R, Wilcock, A. Antipsychotics. In: Hospice and Palliative Care Formulary USA. 2nd ed. 2008. UK: Palliativedrugs.com Ltd.
8. Bratti IM, et al. Chronic restlessness with antipsychotics. Am J Psychiat. 2007; 164:1648-1654.
9. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry. 2010; 196(2):89–91.
10. Poyurovsky M, Pashinian A, Weizman R, Fuchs C, Weizman A. Low dose mirtazapine: A new option in the treatment of antipsychotic induced akathisia. A randomized, double blind, placebo and propranolol controlled trial. Biol Psychiatry. 2006;59:1071–7.
11. Gerolymos C, Barazer R, Keon Yon D, et al.  Drug efficacy in the treatment of antipsychotic-induced akathisia. JAMA Netw Open 2024; 7(3):e241527.

Authors’ Affiliations: Napa Valley Hospice and Adult Day Services; Lancaster General Health.
Conflicts of Interest Statement: The authors have disclosed no relevant conflicts of interest.
Version History:  First published June 2014; reviewed and updated in September 2015; reviewed and updated again in April 2025.