Extra-Pyramidal Symptoms (EPS) 5/13/2021

Antipsychotic medications have a variety of indications, and at times are used off-label for treatment of a variety of behavioral problems. The primary mechanism of action of antipsychotic is antagonism (or partial agonism) of centrally located D2 receptors, though most agents have additional targets (including serotonin and histamine pathways). Adults will commonly take these medications for psychotic illness (schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, depression with psychotic features), but they are also used off-label at times in low dose ranges for sleep, anxiety and irritability presentations. In children and adolescents, these medications can be used for psychotic presentations (which are rare) but, more commonly, are used for management of aggression, particularly in the context of Autism Spectrum Disorders. If risks and benefits have been closely weighed, antipsychotics may be used off-label for aggression or mood instability with child and adolescents, again typically in lower dose ranges.

Extra-Pyramidal Symptoms (EPS) are involuntary motor movements of various types that may, not-uncommonly, be seen as side-effects from these medications.  EPS arise from D2 blockade in the mesolimbic and the mesocortical connections, as well as the basal ganglia (D’souza et al, 2020). EPS are generally less likely to occur with second generation antipsychotic (SGA) medications (risperidone, quetiapine, aripiprazole, ziprasidone, olanzapine, lurasidone, and others) compared to first generation antipsychotic medications, especially the high potency ones (haloperidol, fluphenazine etc.). It is important to monitor for EPS, given that it can cause significant impairment. EPS risk worsens with increased dose of medication and with long-term use of an antipsychotic medication. Tardive Dyskinesia, in particular, can become permanent, while most other presentations will resolve with withdrawal of the medication or use of an ‘antidote’..

The Abnormal Involuntary Movement Scale is a standardized tool for assessing for EPS side effects in patients. Here is a link with instructions on how to conduct the assessment (typically takes 10 minutes), how to score it and a pdf of the scale.


One useful way to distinguish the types of EPS is to remember them in the time frame that they usually present:

Type Description Time Treatment

Tongue stiffening, jaw locking, oculogyric crisis, difficulty breathing – EMERGENCY

Days – Weeks IM benztropine / IM diphenhydramine



Significant restlessness

Days – Months Propranolol, Benzodiazepines


Shuffling gait, cogwheeling, bradykinesia, masked facies Days – Months Amantadine, diphenhydramine

Tardive dyskinesia


Stereo-typed movements, lip smacking


Months to years




Propranolol (Inderal) is a beta-blocker that can be helpful for akathisia with a typical dose range of 10-40 mg bid-tid. It should be dosed bid or tid for best effect. Potential side-effects include hypotension, dizziness, and sedation. It can also be useful as an adjunctive medication for anxiety.

Benztropine (Cogentin) is an anti-cholinergic medication that can be helpful for neuroleptic-induced parkinsonism. It should be dosed bid because it has a short half-life. Starting dose is 0.5 mg bid and can increased as needed and tolerated to 2 mg bid. Side effects to monitor for include: confusion, sedation, constipation, dry mouth, urinary retention, and blurred vision, though these side effects are typically associated with higher dosing regimens. For this reason, benztropine should be avoided with low potency neuroleptic medications, to avoid additive anti-cholinergic side effects. Another commonly used anti-cholinergic medication is trihexyphenidyl (Artane), with a typical range of 5-15 mg dosed TID. Anticholinergic medications are not typically helpful for akathisia.

Amantadine is a dopamine agonist that can be used to treat neuroleptic-induced parkinsonism. Starting dose is 100mg bid with a max of 400mg/day. It is generally well tolerated and is associated with less memory impairment than anti-cholinergic medications. Primary side effects include: nausea, dry mouth, dizziness, and tremor.

IM diphenhydramine (Benadryl) can be used to treat acute dystonia. Oral diphenhydramine 25-100 mg can be helpful for neuroleptic-induced parkinsonism. Primary side effects include sleepiness, dry mouth and decreased motor coordination. It is available over the counter.

Tardive dyskinesia (TD) can be tricky. Initially it can improve if the dose of the antipsychotic is increased but over time it worsens with increases in dose. If the medication is discontinued, 1/3 of patients get better, 1/3 have no real change, and 1/3 get temporarily worse. The best option for individuals needing an anti-psychotic agent is to discontinue the medication and change to a lower potency, newer antipsychotic medication. Risk factors for TD include being female, older, smoking and being African American. Approximately 15% of patients taking long-term high-potency antipsychotics will develop TD.

The FDA recently approved a medication for the treatment of TD, Valbenazine (Ingrezza), a highly selective vesicular monoamine transporter 2 inhibitor. It is dosed as 80mg once per day. Side effects include sleepiness and OT prolongation. It is therefore important to monitor an EKG on patients taking valbenazine. It allows patients to potentially continue on a medication at a dose that is helpful for their psychotic symptoms without having to change medication or reduce the dose to treat their side effects.

Although most primary care providers will generally not be starting patients on antipsychotic agents, awareness of the baseline information provide herein on monitoring for, differentiating, and treating EPS side effects for medications may prove helpful in improving care for these patients when they are seen in the primary care setting.


D’Souza RS, Hooten WM. Extrapyramidal Symptoms. [Updated 2020 Nov 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534115/

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