What is the mechanism of action of Seroquel (quetiapine)?

Mechanism of Action of Quetiapine (Seroquel)

Quetiapine works primarily as an antagonist at both serotonin 5-HT2A and dopamine D2 receptors, with a higher affinity for serotonin receptors relative to dopamine receptors, which contributes to its atypical antipsychotic profile with minimal extrapyramidal side effects. 1, 2

Primary Mechanisms

Quetiapine's therapeutic effects are mediated through several key receptor interactions:

1. Serotonin and Dopamine Receptor Antagonism

   • Higher affinity for serotonin 5-HT2A receptors than for dopamine D2 receptors 1, 3
   • Selective effects on mesolimbic and mesocortical dopamine systems (therapeutic areas) with minimal effects on nigrostriatal dopamine system (motor control area) 3
   • This receptor binding profile explains its efficacy against both positive and negative symptoms with minimal extrapyramidal symptoms

2. Receptor Occupancy Dynamics

   • PET studies show 44% dopamine D2 receptor occupancy at 2 hours after dosing 4
   • More prolonged blockade of serotonin 5-HT2 receptors (72% at 2 hours, declining to 50% after 26 hours) 4
   • The D2/5-HT2 receptor occupancy ratio is similar to clozapine, contributing to its atypical profile

3. Metabolite Activity

   • Norquetiapine (active metabolite) inhibits noradrenaline reuptake transporter, which may contribute to antidepressant effects 1
   • This may explain quetiapine's efficacy in bipolar depression

Secondary Mechanisms

• Partial agonism of 5-HT1A receptors in the prefrontal cortex, which may increase extracellular dopamine release in this region 1
• Low affinity for D1 dopamine receptors both in vitro and in vivo 5
• Minimal activity on dopamine receptors in the tuberoinfundibular system, explaining low risk of hyperprolactinemia 3
• Short plasma half-life (2.5-5 hours) but longer receptor occupancy half-life (10 hours for D2, 27 hours for 5-HT2) 4

Clinical Implications of Mechanism

1. Efficacy Profile

   • Effective against both positive symptoms (hallucinations, delusions) and negative symptoms (emotional withdrawal, apathy) 2, 3
   • Benefits in improving cognitive deficits, affective symptoms, and hostility/aggression 2

2. Side Effect Profile

   • Placebo-level incidence of extrapyramidal symptoms across entire dose range 2
   • Does not elevate plasma prolactin levels compared to placebo 2
   • Common side effects include dry mouth, sedation, somnolence, dizziness, and constipation 1

3. Dosing Considerations

   • Available as immediate-release and extended-release formulations 1
   • Typically dosed at 300-600 mg/day for bipolar depression 1
   • For schizophrenia, dosing up to 750-800 mg/day has been studied 2

Important Clinical Distinctions

• Unlike some other antipsychotics (e.g., clozapine), quetiapine lacks appreciable activity at muscarinic receptors 5
• Unlike risperidone and amisulpride, quetiapine does not elevate plasma prolactin levels 2
• Quetiapine appears to have minimal short-term effects on body weight compared to some other atypical antipsychotics 2

The combination of these pharmacological properties explains quetiapine's effectiveness in treating various psychiatric conditions while maintaining a relatively favorable side effect profile, particularly regarding extrapyramidal symptoms and prolactin elevation.