What is the mechanism of action of haloperidol (antipsychotic medication)?

From the Guidelines

Haloperidol works primarily by blocking dopamine D2 receptors in the brain, which is responsible for its antipsychotic effects. This mechanism of action is supported by the study published in the Journal of the American Academy of Child and Adolescent Psychiatry 1, which refers to the degree of dopamine receptor blockade as the primary mechanism of action for high-potency agents like haloperidol. The study also notes that high-potency agents tend to produce extrapyramidal symptoms, whereas low-potency agents have more anticholinergic side effects.

Key Points about Haloperidol's Mechanism of Action

• Haloperidol has a high affinity for D2 receptors and relatively low affinity for other receptors, making it a "typical" or first-generation antipsychotic
• By blocking dopamine transmission, haloperidol reduces hallucinations, delusions, and disorganized thinking in conditions like schizophrenia and acute psychosis
• The same mechanism accounts for its common side effects, including extrapyramidal symptoms like parkinsonism, akathisia, and dystonia
• Haloperidol also has some activity at alpha-1 adrenergic receptors and minimal anticholinergic effects, which contributes to its overall side effect profile

Other studies, such as the international clinical practice guidelines for early psychosis published in the British Journal of Psychiatry 1, also support the use of haloperidol as an antipsychotic medication, although they note that atypical antipsychotics may be better tolerated and have fewer extrapyramidal side effects. However, the primary mechanism of action of haloperidol remains the same, and its use should be carefully considered in the context of its potential side effects and benefits.

From the Research

Haloperidol Mechanism of Action

• Haloperidol is a typical antipsychotic medication that antagonizes dopamine D2 receptors, which are abundantly expressed in the striatum 2, 3, 4.
• The mechanism of action of haloperidol involves the blocking of D2 receptors, which leads to a decrease in the excitability of striatal medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) 2.
• Chronic treatment with haloperidol also affects D1-MSNs by increasing the ratio of inhibitory/excitatory synaptic transmission (I/E ratio) specifically onto D1-MSNs but not D2-MSNs, leading to a slow remodeling of D1-MSNs 2.
• The antipsychotic effectiveness of haloperidol is thought to be mediated by its ability to target the dopamine D2 receptor, which is the common target for antipsychotics 3, 4.
• Therapeutic doses of haloperidol occupy 60 to 80% of brain D2 receptors in patients, and the receptor has high- and low-affinity states, with the D2High state being functional for dopamine-like agonists 4.
• Haloperidol dopamine receptor occupancy and antagonism have been shown to correspond to delirium agitation scores and EPS risk, with variations in dopamine receptor occupancy correlating with changes in RASS scores in individuals with hyperactive delirium 5.
• The blocking of dopamine D2 receptors by haloperidol has also been shown to have negative consequences on cognition and mood, with deficits in sustained attention, reaction time, and speed of information processing, as well as negative impacts on measures of contentment, anger, and confusion 6.