What receptor pathway's antagonism is primarily causing a 25-year-old male with schizophrenia's shuffling gait, mask-like facial expression, and resting tremor while being treated with a first-generation (typical) antipsychotic?

Dopamine D2 Receptor Antagonism Causes Extrapyramidal Side Effects in Antipsychotic Treatment

The shuffling gait, mask-like facial expression, and resting tremor observed in this patient are primarily caused by antagonism of dopamine D2 receptors in the nigrostriatal pathway. 1

Mechanism of Action of First-Generation Antipsychotics

First-generation (typical) antipsychotics work primarily through:

• Dopamine D2 receptor antagonism: This is the principal mechanism causing both therapeutic effects and extrapyramidal side effects 2
• Secondary receptor antagonism: These medications also have varying affinities for serotonergic, histaminergic, and adrenergic receptors 2

The patient's symptoms represent drug-induced parkinsonism, a common extrapyramidal syndrome caused by typical antipsychotics. This occurs because:

1. Dopamine D2 receptor blockade in the nigrostriatal pathway disrupts normal motor function 1
2. The resulting dopamine deficiency in the basal ganglia mimics the pathophysiology of Parkinson's disease 1, 3

Clinical Manifestations of D2 Receptor Antagonism

The classic triad of drug-induced parkinsonism includes:

• Shuffling gait (bradykinesia)
• Mask-like facial expression (hypomimia)
• Resting tremor

These symptoms develop because typical antipsychotics have high affinity for D2 receptors and limited selectivity between the mesolimbic pathway (desired therapeutic target) and the nigrostriatal pathway (causing motor side effects) 4.

Comparison with Other Antipsychotics

Unlike first-generation agents, second-generation (atypical) antipsychotics generally have:

• Lower risk of extrapyramidal symptoms due to:
  • Lower D2 receptor affinity
  • Higher 5-HT2A receptor antagonism
  • Faster dissociation from D2 receptors 3, 5

For example, risperidone, quetiapine, and clozapine have progressively lower risks of EPS, with clozapine having the lowest risk but other significant side effects like agranulocytosis 3.

Management of Drug-Induced Parkinsonism

For this patient, management options include:

1. Dose reduction of the current antipsychotic if clinically feasible
2. Switching to an atypical antipsychotic with lower D2 receptor affinity
3. Adding an anticholinergic agent such as benztropine (1-2 mg daily) for symptomatic relief 3

Important Clinical Considerations

• Drug-induced parkinsonism is often reversible upon discontinuation or dose reduction of the offending agent
• Early recognition is important as continued exposure may lead to persistent symptoms 1
• Higher risk populations include elderly patients, males, those with previous tremors, and patients on higher antipsychotic doses 3
• Monitoring using standardized scales like the Abnormal Involuntary Movement Scale (AIMS) should be performed every 3-6 months 3

Drug-induced parkinsonism should be differentiated from other extrapyramidal syndromes caused by antipsychotics, including acute dystonia, akathisia, and tardive dyskinesia, as management approaches differ for each condition.