Is haloperidol less likely than second-generation (SGA) antipsychotics to cause extrapyramidal (EPS) side effects?

Haloperidol and Extrapyramidal Side Effects Compared to Second-Generation Antipsychotics

Haloperidol is MORE likely than second-generation antipsychotics to cause extrapyramidal side effects (EPS). This is clearly documented in multiple guidelines and clinical studies.

Evidence for Higher EPS Risk with Haloperidol

The FDA drug label for haloperidol explicitly states that extrapyramidal symptoms occur frequently during administration, often during the first few days of treatment 1. These symptoms include:

• Parkinson-like symptoms
• Akathisia
• Dystonia (including opisthotonos and oculogyric crisis)

Multiple clinical studies confirm this increased risk:

• A systematic review of first-episode psychosis trials found that haloperidol was consistently associated with significantly higher rates/severity of parkinsonism and akathisia compared to SGAs, as well as greater use of anticholinergic medications 2
• Even low-dose haloperidol (≤4 mg) showed significantly worse EPS outcomes versus SGAs 2
• The EIRE study demonstrated that haloperidol caused EPS in 78.3% of patients, significantly higher than risperidone (55.1%), quetiapine (39.5%), and olanzapine (35.8%) 3

Differences Among Second-Generation Antipsychotics

Not all second-generation antipsychotics have equal EPS risk profiles:

• Risperidone shows higher EPS risk (55.1%) compared to olanzapine (35.8%) and quetiapine (39.5%) 3
• Akathisia specifically was more frequent with risperidone (19.7%) than olanzapine (11.4%) and quetiapine (2.6%) 3
• Clozapine has shown EPS advantages over both first-generation antipsychotics and some second-generation agents 4, 5

Risk Factors for EPS

Several factors increase the risk of developing EPS:

• Higher doses of antipsychotics 1
• Elderly and very young patients 5
• Male gender 5
• Previous history of tremors 5
• Previous use of antipsychotics 5
• Polypharmacy 5
• Substance abuse 5

Clinical Implications

When choosing between haloperidol and second-generation antipsychotics:

1. For patients with high EPS risk, second-generation antipsychotics are generally preferred

2. If haloperidol must be used, consider:

   • Using the lowest effective dose
   • Monitoring closely for EPS, especially during the first few days
   • Having anticholinergic medications (e.g., benztropine) available for rapid treatment

3. Among second-generation options:

   • Quetiapine and olanzapine appear to have the lowest EPS risk
   • Risperidone has an intermediate risk profile
   • Clozapine has the lowest EPS risk but is typically reserved for treatment-resistant cases due to other serious side effects

Management of EPS When They Occur

If EPS develop, management options include:

• Dose reduction when clinically feasible
• Addition of anticholinergic agents (benztropine 1-2 mg/day) for parkinsonism and dystonia
• Beta-blockers or benzodiazepines for akathisia
• Switching to an antipsychotic with lower EPS risk

Important Caveats

While second-generation antipsychotics generally have lower EPS risk, they may have other significant side effects:

• Weight gain (particularly olanzapine)
• Metabolic disturbances
• Sedation
• QT prolongation

The choice of antipsychotic should consider the complete side effect profile, not just EPS risk.