The role of extended-release quetiapine fumarate monotherapy in the treatment of patients with major depressive disorder

Abstract

Pharmacotherapy, psychotherapy and other nonpharmacological interventions are used in patients with major depressive disorder (MDD). However, 50% of the patients with MDD fail to achieve a response to first-line antidepressant treatment. In four of five acute monotherapy studies, once-daily extended-release quetiapine fumarate (quetiapine XR) significantly improved depressive symptoms compared with placebo in patients with MDD. One acute monotherapy study demonstrated that neither quetiapine XR nor escitalopram had a statistically significant separation from placebo on the primary endpoint. Quetiapine XR maintenance therapy also significantly reduced the risk of recurrence of a depressive event. No significant improvement in overall quality of life was observed versus placebo except in the acute elderly study. Tolerability findings were consistent with the known pharmacological profile of quetiapine; the most common adverse events were dry mouth, sedation, somnolence and dizziness. Quetiapine XR monotherapy has been approved as a treatment for MDD in a limited number of countries.

Keywords::

• atypical antipsychotic
• efficacy
• extended-release quetiapine fumarate
• major depressive disorder
• monotherapy
• norquetiapine
• tolerability

Acknowledgements

The authors thank Catherine Datto from AstraZeneca, Martin Brecher, Willie Earley, Hans Eriksson, Arthur Lazarus and Robin McCoy, formerly of AstraZeneca, and all the study investigators for their invaluable contribution to the conduct of the quetiapine XR clinical development program.

Financial & competing interests disclosure

R Weisler in his career, has been a consultant to, on the speakers' bureaux of, and/or received research support from, and/or has held or holds stock in the following: Abbott – speaker's bureau, consultant, received research support; Agency for Toxic Substances and Disease Registry – consultant; AstraZeneca – speaker's bureau, consultant, received research support, Biovail – speaker's bureau, consultant, received research support; Bristol-Myers Squibb – speaker's bureau, consultant, received research support, stockholder (has held or holds stock); Burroughs Wellcome – speaker's bureau, received research support; CeNeRx – received research support; Centers of Disease Control and Prevention – consultant; Cephalon – speaker's bureau, consultant, received research support; Ciba Geigy – speaker's bureau, received research support, CoMentis – received research support; Corcept – consultant; Cortex – stockholder (has held or holds stock); Dainippon Sumitomo Pharma America – received research support; Eisai – received research support; Elan – received research support; Eli Lilly – speaker’s bureau, consultant, received research support; Forest – speaker's bureau, consultant, received research support; GlaxoSmithKline – speaker's bureau, consultant, received research support; Janssen – speaker's bureau, received research support; Johnson & Johnson – speaker's bureau, consultant, received research support; Lundbeck – received research support; McNeil Pharmaceuticals – received research support; Medicinova – received research support; Medscape Advisory Board – consultant; Merck – received research support, speaker's bureau, stockholder (has held or holds stock); National Institute of Mental Health – consultant, received research support; Neurochem – received research support; New River Pharmaceuticals – received research support; Novartis – speaker's bureau, received research support; Organon – speaker's bureau, consultant, received research support; Otsuka America Pharma – consultant; Pfizer – speaker's bureau, consultant, received research support, stockholder (has held or holds stock); Pharmacia – consultant, received research support, Repligen – received research support; Saegis – received research support; Sandoz – received research support; Sanofi – speaker's bureau, consultant, received research support; Sanofi-Synthelabo – speaker's bureau, consultant, received research support; Schwabe/Ingenix – received research support; Sepracor – received research support; Shire – speaker's bureau, consultant, received research support; Solvay – speaker's bureau, consultant; Sunovion – speaker's bureau, consultant, received research support; Synaptic – received research support; Takeda – received research support; TAP – received research support; Theravance – received research support; Transcept Pharma – consultant, received research support; Transtech – consultant; UCB Pharma – received research support; Validus – speaker's bureau, consultant; Vela – received research support; and Wyeth – speaker's bureau, consultant, received research support. RS McIntyre has received research grants, provided speaker/advisor services to, participated in CME activities with, or received travel funding from AstraZeneca, Biovail, Bristol-Myers Squibb, CME Outfitters, Eli Lilly, France Foundation, GlaxoSmithKline, I3CME, Janssen-Ortho, Lundbeck, Optum Health, Organon, Physician’s Postgraduate Press, Pfizer, Schering-Plough, Shire, Solvay/Wyeth and Wyeth. The studies in the quetiapine XR monotherapy trial program in MDD were sponsored by AstraZeneca. The studies were registered at ClinicalTrials.gov (identifier numbers NCT00320268 [Study 1: D1448C00001], NCT00321490 [Study 2: D1448C00002], NCT00326144 [Study 3: D1448C00003], NCT00351169 [Study 4: D1448C00004], NCT00278941 [Study 5: D1448C00005], NCT00388973 [Study 14: D1448C00014]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors would like to thank Stephen Paterson and Jane Bryant from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

Key issues

• • Approximately 50% of patients with major depressive disorder (MDD) fail to respond to first-line antidepressants. There is a significant unmet need for new treatments for patients with MDD in order to improve rates of response, remission and long-term prognosis. This is particularly important due to the excess morbidity and mortality associated with MDD.

• • Extended-release quetiapine is a once-daily formulation of quetiapine that has been approved for use as a monotherapy treatment for MDD in a limited number of countries, including Canada and Australia, where treatment is targeted to patients who are intolerant of, or have had an inadequate response to, alternative antidepressant drugs. In addition, quetiapine XR has been approved in the EU, the USA and several other countries worldwide as adjunctive treatment for patients with MDD and an inadequate response to previous antidepressants.

• • Quetiapine XR is characterized by a lower maximum plasma concentration and a longer time to reach maximum plasma concentration compared with the IR formulation.

• • It is recommended that quetiapine XR is taken without food or with a light meal (~300 calories). Quetiapine XR should be administered once-daily and can be taken 1–2 h earlier in the evening compared with the suggested administration of quetiapine IR at bedtime.

• • Norquetiapine is the only active major metabolite of quetiapine and, unlike its parent compound, is an inhibitor of the NET. This property may be a mechanism that contributes to the antidepressant effects observed in quetiapine XR-treated patients with MDD.

• • Four (three studies in adult patients and one in the elderly) out of five large, randomized, placebo-controlled studies of quetiapine XR as acute monotherapy were significant in favor of quetiapine XR versus placebo on the primary efficacy outcome measure [one acute monotherapy study was a failed study where neither quetiapine XR nor the active control (escitalopram) separated from placebo]. In the five acute monotherapy studies, significant improvements in quality of life were confined to the study in elderly patients. One large, time-to-withdrawal monotherapy maintenance study was conducted and demonstrated a significant reduction in the risk of a depressed event for quetiapine XR monotherapy maintenance treatment of patients with MDD compared with placebo. Furthermore, quetiapine XR monotherapy showed significantly better long-term maintenance of patient functioning compared with placebo. Treatment effects on quality of life were not assessed in the quetiapine XR maintenance study.

• • Tolerability findings across the quetiapine XR studies in patients with MDD were consistent with the known profile of quetiapine.