What are the causes of extrapyramidal symptoms (EPS)?

From the Guidelines

Extrapyramidal symptoms (EPS) are primarily caused by medications that block dopamine receptors in the brain, particularly antipsychotic drugs, with first-generation antipsychotics carrying the highest risk due to their strong dopamine D2 receptor blockade. The main causes of EPS can be broken down into:

• Medications:
  • First-generation (typical) antipsychotics like haloperidol, chlorpromazine, and fluphenazine 1
  • Second-generation (atypical) antipsychotics such as risperidone, olanzapine, and quetiapine, which generally have lower EPS risk but can still cause these symptoms at higher doses 1
  • Antiemetics (metoclopramide, prochlorperazine)
  • Certain antidepressants (SSRIs like fluoxetine)
  • Some calcium channel blockers (cinnarizine, flunarizine)
• Non-medication causes:
  • Neurodegenerative disorders like Parkinson's disease, Wilson's disease, Huntington's disease
  • Structural brain lesions affecting the basal ganglia

The underlying mechanism involves disruption of the balance between dopamine and acetylcholine in the basal ganglia pathways, leading to symptoms such as tremor, rigidity, bradykinesia, akathisia, dystonia, and tardive dyskinesia 1. The risk of developing EPS increases with higher medication doses, longer treatment duration, older age, female gender, and pre-existing brain damage or substance use disorders. It is essential to carefully evaluate the potential benefits and risks of medications that can cause EPS, especially in vulnerable populations, and to monitor patients closely for the development of these symptoms.

From the FDA Drug Label

In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure

The causes of extrapyramidal symptoms (EPS) include:

• Untreated or inadequately treated medical conditions (e.g. pneumonia, systemic infection) 2
• Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex associated with the administration of antipsychotic drugs, including quetiapine and olanzapine 2 3
• Antipsychotic drug treatment, which may precipitate or exacerbate EPS 2 3

From the Research

Causes of Extra Pyramidal Symptoms

• Extrapyramidal symptoms (EPS) are unwanted symptoms commonly originating from the use of certain medications, including antipsychotics and non-antipsychotic agents such as antidepressants, lithium, and antiemetics 4, 5, 6.
• The symptoms can range from minimal discomfort to permanent involuntary muscular movements, and can include acute dyskinesias, dystonic reactions, tardive dyskinesia, Parkinsonism, akinesia, akathisia, and neuroleptic malignant syndrome 5, 6.
• Dopamine blockade or depletion in the basal ganglia is thought to produce these symptoms, which can mimic idiopathic pathologies of the extrapyramidal system and basal ganglia disease 5, 6.

Risk Factors for Extra Pyramidal Symptoms

• Age, smoking, tremor history, and history of taking antipsychotics are significantly associated with the development of drug-induced extrapyramidal symptoms (di-EPS) 4.
• Patients taking certain medications, such as paroxetine, imipramine, fluoxetine, or clomipramine, have a higher risk of developing di-EPS compared to patients taking citalopram 4.
• The use of high doses of antipsychotics, such as risperidone, may also be associated with a higher risk of EPS 7.

Medications Associated with Extra Pyramidal Symptoms

• Antipsychotic medications, including first-generation and second-generation antipsychotics, are commonly associated with EPS 5, 8, 7.
• Non-antipsychotic agents, such as certain antidepressants, lithium, antiemetics, and oral contraceptive agents, can also cause EPS 5, 6.
• The risk of EPS may vary depending on the specific medication and dose used, as well as individual patient factors such as age and medical history 4, 7.