What is the pathophysiology of extrapyramidal symptoms (EPS)?

Pathophysiology of Extrapyramidal Symptoms (EPS)

Extrapyramidal symptoms result from dopamine receptor blockade or depletion in the basal ganglia and nigrostriatal pathways, which disrupts the normal balance of dopaminergic and cholinergic neurotransmission required for coordinated movement control. 1, 2

Core Pathophysiological Mechanism

The fundamental mechanism underlying EPS involves dopamine D2 receptor blockade in the extrapyramidal motor system, particularly within the basal ganglia structures. 1, 2 This blockade creates an imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) activity in the motor control circuits, leading to the characteristic movement abnormalities seen in EPS. 2, 3

Anatomical Basis

• The nigrostriatal dopamine pathways are the primary site of dysfunction, where dopamine normally modulates motor control through connections between the substantia nigra and the striatum. 1
• The basal ganglia, which includes the striatum, globus pallidus, and substantia nigra, serves as the central processing center for motor coordination and is critically dependent on balanced dopamine signaling. 2, 3
• When dopamine receptors are blocked in these regions, the resulting neurochemical imbalance mimics the pathology seen in idiopathic Parkinson's disease and other naturally occurring extrapyramidal disorders. 2, 4

Medication-Induced Mechanism

High-potency antipsychotics cause the most severe EPS because they produce strong dopamine D2 receptor blockade with minimal anticholinergic activity to counterbalance the dopamine deficiency. 5, 1 The degree of receptor occupancy directly correlates with EPS severity—higher receptor blockade produces more pronounced symptoms. 4

Drug-Specific Considerations

• Typical (first-generation) antipsychotics, particularly high-potency agents like haloperidol, have the highest EPS risk due to potent D2 blockade without compensatory anticholinergic effects. 5, 1
• Atypical (second-generation) antipsychotics generally have lower EPS liability because they have more balanced receptor profiles, though risperidone still carries significant risk while clozapine and quetiapine have the lowest. 4
• Non-antipsychotic medications including antiemetics (metoclopramide, prochlorperazine), certain antidepressants, and lithium can also cause EPS through similar dopamine-blocking mechanisms. 1, 2, 3

Clinical Manifestations Based on Pathophysiology

The specific type of EPS that develops depends on the timing, degree, and location of dopamine receptor blockade:

Acute Dystonia

• Occurs within hours to days of treatment initiation due to sudden, severe dopamine blockade in motor pathways. 5, 1
• Results in spastic muscle contractions affecting neck, torso, or facial muscles due to unopposed cholinergic activity. 5, 1

Drug-Induced Parkinsonism

• Develops over days to weeks as sustained dopamine blockade produces bradykinesia, tremor, and rigidity identical to idiopathic Parkinson's disease. 5, 1
• The pathophysiology directly mirrors the dopamine depletion seen in degenerative parkinsonism. 1, 2

Akathisia

• Manifests as subjective restlessness with objective motor agitation, likely involving dopamine pathways in both motor and limbic regions. 5, 1
• The mechanism is less well understood but involves disruption of dopaminergic circuits controlling both movement and emotional regulation. 1, 6

Tardive Dyskinesia

• Represents a compensatory upregulation of dopamine receptors after chronic blockade, leading to hypersensitivity and involuntary movements. 1
• This delayed phenomenon reflects neuroplastic changes in response to prolonged dopamine antagonism. 1

Risk Factors Influencing Pathophysiology

Certain patient characteristics modify vulnerability to dopamine blockade:

• Young males have heightened risk for acute dystonia, possibly due to higher baseline dopamine tone. 5, 1
• Children and adolescents may be more susceptible to EPS than adults, though the mechanism is unclear. 5, 1
• Elderly patients have increased sensitivity due to age-related dopamine system changes. 1
• Rapid dose escalation overwhelms compensatory mechanisms, increasing EPS likelihood. 1, 4