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

Mechanism of Action of Quetiapine (Seroquel)

Quetiapine works primarily through antagonism of multiple neurotransmitter receptors, with its therapeutic effects stemming from antagonism at both serotonin 5-HT2A and dopamine D2 receptors, as well as activity at other receptors including histamine H1 and adrenergic receptors.

Primary Receptor Targets

Quetiapine has a complex pharmacological profile that contributes to its efficacy in various psychiatric conditions:

• Serotonin Receptors:

  • Strong antagonism at 5-HT2A receptors
  • Partial agonism at 5-HT1A receptors in the prefrontal cortex 1

• Dopamine Receptors:

  • Antagonism at D1 and D2 receptors 2
  • Unique transient D2 occupancy pattern (58-64% at 2-3 hours post-dose, decreasing to minimal levels of 0-27% by 12 hours) 3

• Other Receptors:

  • Histamine H1 receptor antagonism (contributing to sedative effects)
  • Adrenergic alpha1 and alpha2 receptor antagonism 2

Unique Pharmacokinetic Properties

Quetiapine's distinctive mechanism involves:

• Transient D2 receptor occupancy: Unlike other antipsychotics, quetiapine produces only brief high D2 occupancy followed by rapid dissociation 3
• Regional selectivity: Greater effects on mesolimbic and mesocortical dopamine systems (therapeutic targets) with minimal effects on nigrostriatal dopamine system (motor control) 4
• Active metabolite: Norquetiapine (N-desalkylquetiapine) inhibits norepinephrine reuptake transporter, contributing to antidepressant effects 1

Clinical Implications of Mechanism

The receptor profile explains quetiapine's clinical effects:

• Antipsychotic effects: Result from combined D2 and 5-HT2A antagonism
• Antidepressant effects: Likely related to 5-HT1A partial agonism, increased prefrontal dopamine release, and norepinephrine reuptake inhibition by norquetiapine 1
• Low EPS risk: Due to transient rather than sustained D2 occupancy and preferential action on limbic rather than striatal dopamine systems 4, 3
• Sedative effects: Primarily mediated through H1 receptor antagonism
• Minimal prolactin elevation: Due to limited effects on tuberoinfundibular dopamine system 4

Therapeutic Applications Related to MOA

Quetiapine's receptor profile makes it effective for:

• Schizophrenia (positive and negative symptoms)
• Bipolar disorder (both mania and depression phases)
• Anxiety disorders (off-label)

Important Clinical Considerations

• Dosing implications: Higher doses (≥400 mg/day) may be needed for full antipsychotic effect 5
• Side effect profile: Common side effects include dry mouth, sedation, somnolence, dizziness, constipation, and increased appetite 1
• Monitoring needs: Weight gain and metabolic parameters should be monitored, though these effects may be less pronounced than with some other atypical antipsychotics 5

Quetiapine's complex receptor profile and unique pharmacokinetics explain its broad therapeutic utility and relatively favorable side effect profile compared to conventional antipsychotics.