Haloperidol

Haloperidol has the highest EPS risk of any commonly prescribed antipsychotic. This includes acute dystonia (sudden sustained muscle contractions, typically within days of starting), akathisia (subjective restlessness with inability to sit still), drug-induced parkinsonism (tremor, rigidity, bradykinesia), and with chronic use, tardive dyskinesia (involuntary repetitive movements, often orofacial). EPS risk is dose-dependent, and haloperidol's lack of anticholinergic activity means there is no intrinsic offset. Prophylactic anticholinergics (benztropine, diphenhydramine) are often co-prescribed, particularly during initiation and with IM use.

High D2 affinity in the tuberoinfundibular pathway causes consistent, often substantial prolactin elevation. Clinical consequences include galactorrhea, amenorrhea, sexual dysfunction, gynecomastia, and with chronic elevation, reduced bone mineral density. Monitor prolactin symptoms at every visit. The pattern is similar to risperidone because both medications share high D2 binding affinity.

Haloperidol prolongs the QTc interval through cardiac ion channel effects. The risk is significantly higher with IV administration than with oral or IM routes. IV haloperidol requires continuous cardiac monitoring and is discouraged for routine use in most guidelines. Avoid in patients with known QTc prolongation, hypokalemia, hypomagnesemia, or concurrent use of other QTc-prolonging agents. Obtain baseline ECG when clinically feasible.

Rare but potentially fatal. Presents with severe rigidity, hyperthermia, altered mental status, and autonomic instability. Elevated CK from muscle breakdown is characteristic. Risk is highest during initiation, dose increases, dehydration, and concurrent lithium use. Haloperidol is the antipsychotic most classically associated with NMS, though it can occur with any dopamine-blocking agent. NMS mortality has decreased substantially with early recognition.

Chronic haloperidol use carries a higher risk of tardive dyskinesia than atypical antipsychotics. Annual incidence with FGAs is estimated at roughly 3-5% per year of exposure in adults, higher in elderly patients. TD can be irreversible even after stopping the causative agent. This cumulative risk is the primary reason guidelines favor atypicals for long-term maintenance. AIMS (Abnormal Involuntary Movement Scale) assessments should be performed at least every 6 months in patients on chronic haloperidol.

Haloperidol is less sedating than chlorpromazine, olanzapine, or quetiapine due to its minimal H1 antihistaminic activity. Some sedation still occurs, and IM administration (particularly with concurrent lorazepam) can produce significant sedation. This relatively low sedation profile is one reason haloperidol is sometimes preferred when alertness matters.

Haloperidol causes less weight gain, glucose dysregulation, and lipid changes than olanzapine, quetiapine, or clozapine. This is a genuine advantage in patients with significant metabolic risk. However, it does not eliminate the need for metabolic monitoring, and the lower metabolic burden must be weighed against the higher EPS and TD risk.