Managing antipsychotic-induced extrapyramidal symptoms

Medication-induced extrapyramidal symptoms (EPS) are motor-related adverse reactions most commonly associated with antipsychotic medications.1 Given how commonly antipsychotics are used for a variety of indications, it is important for pharmacists to actively screen and monitor patients for EPS, and recommend management strategies as appropriate.EPS rates and risk factorsReported rates of antipsychotic-induced EPS vary widely in the literature, dependent on the duration of treatment and follow up, and agents examined. In the landmark CATIE trial, the rate of discontinuation of antipsychotic medications due to EPS ranged from 2%–8%, depending on the agent.2 Other literature quotes EPS rates as high as 61.6% in patients institutionalized with schizophrenia treated with first-generation antipsychotics.3 Because EPS is theorized to be caused by excessive dopamine blockade, first-generation antipsychotics are associated with higher rates of EPS compared to second-generation antipsychotics due to their stronger dopamine antagonism.1,4 Even among the same generation of antipsychotics, there are significant differences in risk; olanzapine, quetiapine, clozapine and aripiprazole are less frequently associated with EPS.4,5 Additional risk factors for developing EPS include high antipsychotic dose, longer duration of treatment, a history of EPS, concurrent substance use, age and polypharmacy.1,4,6Types of EPSExtrapyramidal symptoms are diverse, and can be categorized into dystonia, akathisia, Parkinsonism and tardive dyskinesia, with each requiring specific treatments.4 Neuroleptic malignant syndrome, a related life-threatening condition requiring immediate medical attention, is beyond the scope of this column.Dystonia Dystonic reactions are involuntary muscle spasms that can be extremely painful and frightening to the patient. Dystonia is typically an acute EPS reaction, occurring within minutes to hours after receiving an antipsychotic. Patients may complain of a “heavy tongue” or “stiff jaw,” or have trouble speaking or swallowing. Other commonly affected areas include the extremities, head and neck, and eyes.4 Specifically, patients may experience their eyes involuntarily rolling upwards (i.e., an oculogyric crisis). Young males are especially at risk of this reaction.4 Management typically involves the use of anticholinergic medications (e.g., benztropine 1–2 mg) acutely, while longer-term recommendations may include a reduction in antipsychotic dose, or a switch to an alternate agent with less EPS risk.4Akathisia refers to a subjective or “inner” restlessness, with an accompanying compulsion to move or pace to relieve these symptoms. It is also typically an acute reaction, occurring within hours to days of receiving an antipsychotic.4 First-generation antipsychotics and aripiprazole are most commonly implicated. Symptoms can be assessed and monitored with an objective rating scale called the Barnes Akathisia Rating Scale.4 A variety of treatments are available, with propranolol (starting doses of 10 mg bid) and benzodiazepines (e.g., low-dose clonazepam) being most commonly used.4 As always, caution should be exercised with long-term use of benzodiazepines. Mirtazapine is also used occasionally, and may be beneficial in patients who experience concurrent mood or sleep disorders.7 Newer treatment modalities such as vitamin B6 have shown promise, but require further clinical experience.8 As with dystonic reactions, long-term management includes a reduction in antipsychotic dose, or a switch to an alternate agent.4Parkinsonism Also known as pseudoparkinsonism, symptoms resemble those seen in Parkinson’s disease. They include tremors, rigidity, bradykinesia (including shuffling gait) and salivation. Parkinsonism typically occurs later in treatment, from days to weeks after antipsychotics are introduced, with elderly females being most at risk.4 The Simpson-Angus Scale can be used to assess and monitor symptoms.4 Similar to management of symptoms in early Parkinson’s disease, anticholinergics such as benztropine (1–2 mg) are helpful.4 However, chronic use of anticholinergic medications is generally not recommended (use should be reviewed every 3 months), and extra caution should be exercised in elderly patients due to anticholinergic burden. As is the case with other forms of EPS, long-term management requires a reassessment of dose and choice of agent.4Tardive dyskinesia (TD) As suggested by the term “tardive,” TD involves the late or delayed development of involuntary movements, including lip smacking or chewing, tongue protrusions, choreiform hand movements and pelvic thrusting, months to years after starting chronic treatment with antipsychotics.4 Unfortunately, TD is irreversible in a large percentage of cases. Assessment and monitoring of symptoms can be done with the Abnormal Involuntary Movement Scale.4 Pharmacologic management includes the use of monoamine depleting agents, with tetrabenazine (starting doses of 50 mg/day divided bid-tid) being the only approved medication currently available in Canada. Clozapine has also shown some promise as the alternate antipsychotic most likely to be associated with resolution of symptoms, and may be the treatment of choice for those requiring ongoing antipsychotic treatment.4Clinical pearlsThough commonly seen, anticholinergic medications such as benztropine have no role in the treatment of akathisia or TD, and should be reassessed for potential discontinuation.Antipsychotic agents carry varying risks of EPS. Pay special attention to agents that may have differing risks of various extrapyramidal symptoms (e.g., aripiprazole carries an increased risk of akathisia, but lower risk of other EPS). Pharmacists should familiarize themselves with the EPS risk profile of the various antipsychotic agents to help inform management recommendations. For example, see the comparative table in the Clinical Handbook of Psychotropic Drugs (available for purchase).Rule out alternate causes of symptoms that may resemble EPS. For example, anxiety, ADHD and restless legs syndrome can mimic symptoms of akathisia, while osteoarthritis, other chronic pains, and even serotonin syndrome can resemble dystonic reactions.Rating scales are objective measures that are quick and easy to administer, and can be used by pharmacists to help actively monitor for EPS.Emergence of EPS is not limited to the initiation of treatment, and can occur after dose increases.Akathisia and other involuntary movement symptoms can occasionally occur as part of an antipsychotic withdrawal syndrome.9SummaryEPS are most often associated with antipsychotic agents, with differing risk profiles depending on the agent. Pharmacists play a key role in actively screening and monitoring patients for EPS, and advising on appropriate management strategies.Sunny Wang is a clinical pharmacist at the Centre for Addiction and Mental Health (CAMH) in Toronto, Ont. He is also a clinical instructor at the Leslie Dan Faculty of Pharmacy and serves as an expert hub member for the Addiction Medicine and Psychosocial Interventions Program with Project ECHO.References:D'Souza RS, Hooten WM. Extrapyramidal symptoms. Updated July 31, 2023. (accessed October 24, 2024).Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-23. doi: 10.1056/NEJMoa051688. Erratum in: N Engl J Med 2010;363(11):1092-3.Janno S, Holi M, Tuisku K, et al. Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry 2004;161(1):160-3. doi: 10.1176/appi.ajp.161.1.160.Taylor D, Barnes TRE, Young AH. The Maudsley prescribing guidelines in psychiatry, 13th ed. Hoboken, NJ: Wiley Blackwell; 2018.Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013;382:951-62. doi: 10.1016/S0140-6736(13)60733-3. Erratum in: Lancet 2013;382:940.Weng J, Zhang Y, Li H, et al. Study on risk factors of extrapyramidal symptoms induced by antipsychotics and its correlation with symptoms of schizophrenia. Gen Psychiatr 2019;32(1):e100026. doi: 10.1136/gpsych-2018-100026.Praharaj SK, Kongasseri S, Behere RV, et al. Mirtazapine for antipsychotic-induced acute akathisia: a systematic review and meta-analysis of randomized placebo-controlled trials. Ther Adv Psychopharmacol 2015;5(5):307-13. doi: 10.1177/2045125315601343.Shams-Alizadeh N, Bakhshayesh H, Rezaei F, et al. Effect of vitamin B6 versus propranolol on antipsychotic-induced akathisia: a pilot comparative double-blind study. Iran J Pharm Res 2018;17(Suppl):130-5.Sansone RA, Sawyer RJ. Aripiprazole withdrawal: a case report. Innov Clin Neurosci 2013;10(5-6):10-2.

Managing antipsychotic-induced extrapyramidal symptoms

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