Review 10.1517/14656566.8.9.1211 © 2007 Informa UK Ltd ISSN 1465-6566 1211 A preclinical and clinical rationale for quetiapine in mood syndromes Roger S McIntyre † , Joanna K Soczynska, Hanna O Woldeyohannes, Mohammad Alsuwaidan & Jakub Z Konarski † Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, ON, Canada The main objective of this review is to discuss results from preclinical studies that aim to elucidate the putative mechanistic basis of the antidepressant action of quetiapine. Results from pivotal, randomized clinical trials in bipolar depression are also briefly reviewed. The authors conducted a PubMed search of all English-language articles published between January 1990 and December 2006. The key search term was quetiapine paired with: serotonin, dopamine, noradrenaline, glutamate, γ-aminobutyric acid, signal transduction, neuro- genesis, oxidative stress, glucocorticoid, antidepressant, major depressive disorder, bipolar disorder and randomized controlled trial. The search was augmented with a manual review of relevant article reference lists. Articles selected for review were based on author consensus, adequacy of sample size, the use of standardized experimental procedures, validated assessment measures and overall manuscript quality. Quetiapine enhances central serotonergic neurotransmission via its high affinity for serotonergic receptors (e.g., 5-HT 2A receptor antagonism and partial agonistic activity at the 5-HT 1A receptor). Activation of the 5HT 1A receptor results in an increase in prefrontal cortex dopaminergic neurotransmission. Affinity for the α 2 -adrenoceptor mediates a relative increase in extracellular noradrenergic release in the prefrontal cortex. Emerging evidence indicates that quetiapine's principal, active, human plasma metabolite, N-desalkyl quetiapine, has high affinity for, and is a potent inhibitor of, the noradrenergic transporter. This latter finding is a point of commonality with other conventional antidepressant agents and may differentiate quetiapine from other atypical antipsychotics. Activity at other intracellular targets (e.g., signal transduction pathways and nerve growth transcription factors), neurotransmitters, inflammatory and oxidative stress networks, and endocrine systems may also mediate the antidepressant effects of quetiapine. The in vitro pharmacodynamic profile of quetiapine is predictive of antidepressant activity in mood syndromes. Available clinical evidence has established quetiapine as an effective monotherapy in bipolar depression. Keywords: antidepressant, antipsychotic, bipolar, clinical, depression, preclinical, quetiapine Expert Opin. Pharmacother. (2007) 8(9):1211-1219 1. Introduction Over the past two decades, substantial progress has been made in the pharmacologic treatment of major depressive disorder (MDD). Nevertheless, short-term efficacy studies indicate that most contemporary antidepressants fail to offer a consistently higher remission rate when compared with first-generation antidepressants (e.g., tricyclic antidepressants [TCAs]) [1]. Moreover, results from the recently completed STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial provide effectiveness evidence that naturalistically treated, depressed individuals demonstrate suboptimal remission rates [2]. With some incredulity, five decades after the psychopharmacologic revolution began, there remains a pressing need for novel 1. Introduction 2. Methods 3. Models of depression and antidepressant activity 4. Serotonin (5-hydroxytryptamine) 5. Dopamine 6. Noradrenaline 7. Glutamate 8. γ-aminobutyric acid 9. Second messenger signaling pathways 10. Inflammation and oxidative st ress 11. Hypothalamic–pituitary–adrenal axis 12. Clinical studies 13. Summary and conclusion 14. Expert opinion For reprint orders, please contact: Ben.Fisher@informa.com Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Toronto on 06/09/11 For personal use only.