Background

Antipsychotics and other common psychoactive medications can cause neuropsychiatric complications such as akathisia. Akathisia is an extrapyramidal symptom characterized by an uncomfortable sensation of internal restlessness and 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’) have a higher propensity for producing EPS because of strong binding to dopamine receptors (D2).  Newer (‘atypical,’ or second generation antipsychotics) have a lower risk of EPS, in part due to blockage of serotonin receptors (1). Continued untreated akathisia is risk factor for developing chronic akathisia, but currently it is not known if a single episode of akathisia increases the risk for developing chronic EPS.

Incidence and Risk Factors  The incidence of akathisia with strong dopamine blockers such as haloperidol is 30% and 5-15% with drugs 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 of akathisia 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 of akathisia in hospice patients is unknown (1).

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. The following language may be helpful, “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 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, identifying the causative agent and removing it is the most effective treatment strategy.

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 an antipsychotic is needed, rotate to an antipsychotic with a lower risk of EPS.
   • Chlorpromazine has a lower risk of EPS compared with other older antipsychotics such as haloperidol 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 (5,8).
   • Quetiapine has the lowest D2 receptor affinity and is often effective in the elderly at low doses (12.5-25 mg PO BID) due to a 40% lower drug clearance.  It has been found to be the least likely to cause EPS effects of all of the widely available newer antipsychotics (8). Only available orally.
   • Olanzapine has been shown to have slightly less incidence of akathisia compared to risperidone or aripiprazole. Limited comparative data exists, but this agent could be considered if unable to tolerate the above. Olanzapine has the advantage of being available as an orally dissolving tab and IM. Usual effective doses are 2.5-5 mg a once day.(8)
4. If discontinuation or rotation to another antipsychotic is not possible, adjunctive medications can be added to help prevent or reduce the akathisia (4,7,8). This practice is largely empiric, and no treatment has been clearly shown to be superior. Limited controlled trial data support the efficacy of mirtazapine and propranolol (8,9).
   • Serotonin antagonists: mirtazapine 15 mg PO at bedtime,
   • Nonselective beta-blockers: propranolol 10 mg PO TID titrated to maximum of 80 mg/day
   • Anticholinergics:  diphenhydramine 25-50 mg PO/SC/IM/IV q6 hours; benztropine 2 mg PO/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

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. White C, Jackson N. Acute akathisia in palliative care. Eur J Pall Care. 2005; 12:5-7.
5. Twycross R, Wilcock, A. Antipsychotics. In: Hospice and Palliative Care Formulary USA. 2nd ed. 2008. UK: Palliativedrugs.com Ltd.
6. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiat. 1989; 154:672-676.
7. Bratti IM, et al. Chronic restlessness with antipsychotics. Am J Psychiat. 2007; 164:1648-1654.
8. Poyurovsky M. Acute antipsychotic-induced akathisia revisited. Br J Psychiatry. 2010; 196(2):89–91.
9. 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.

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. Re-copy-edited in September 2015.