P0035 - Preclinical mechanisms for the broad spectrum of antipsychotic, antidepressant and mood stabilizing properties of Seroquel^®

Abstract

Background:

SEROQUEL^® (quetiapine) is an atypical antipsychotic in the dibenzothiazepine class. Clinical studies have demonstrated consistent efficacy in the treatment of schizophrenia, bipolar mania, and bipolar depression. Further clinical results suggest robust efficacy in the long-term treatment of bipolar disorder and major depressive disorder. This broad spectrum of clinical effect has not been fully predicted based on quetiapine's preclinical pharmacology. However, norquetiapine, a recently discovered major active human metabolite of quetiapine, has unexpected properties that may explain the observed clinical antidepressant and mood-stabilizing effects.

Methods:

Radioligand binding and functional assays using rat and human tissue were used to characterize receptor interactions. Positron emission tomography (PET) studies performed on cynomolgus monkeys and man explored the relationship between clinically relevant plasma exposures and occupancy at serotonin 5HT2A and dopamine D2 receptors and the norepinephrine transporter (NET).

Results:

Norquetiapine had high affinity for and potently inhibited the NET, a property shared by tricyclic antidepressants and SNRIs but not other atypical antipsychotics at clinically relevant doses. In addition, norquetiapine had moderate-to-high affinity for D2, 5HT1A, 5HT2A, and 5HT2C receptors and shared some commonality with SSRIs. PET studies confirmed the properties of norquetiapine including occupancy of D2 and 5HT2A receptors as well as the NET at clinically relevant plasma exposures.

Conclusions:

A unique combination of direct and indirect effects at noradrenergic, serotonergic, and dopaminergic receptors by quetiapine and norquetiapine provides a putative mechanism of action for the broad spectrum of clinical efficacy observed with SEROQUEL^® in psychiatric disorders.