Extended-release quetiapine fumarate in the treatment of patients with major depressive disorder: adjunct therapy

Abstract

Approximately half of the patients with major depressive disorder (MDD) respond insufficiently to current antidepressants, resulting in increased risk of relapse and residual symptoms. Strategies available include dose increase, combination with a second agent, switching antidepressants, adjunct treatment, psychotherapy or exercise. Efficacy and tolerability of once-daily extended-release quetiapine fumarate (quetiapine XR) adjunct to index antidepressant therapy in patients with MDD and an inadequate response to treatment were assessed in two acute studies as part of a global clinical trial program. Quetiapine XR significantly improved depressive symptoms versus placebo. Significant improvement in quality of life versus placebo was confined to elderly patients with MDD. Tolerability was consistent with the known pharmacological profile of quetiapine: the most common adverse events were dry mouth, somnolence, sedation, dizziness and fatigue. Quetiapine XR is approved in the EU, USA and several other countries worldwide as adjunctive treatment for patients with MDD and an inadequate response to previous antidepressants.

Keywords::

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

Acknowledgements

The authors thank C Datto from AstraZeneca, and M Brecher, W Earley, H Eriksson, A Lazarus, and R 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 bureau of, and/or received research support from 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 for 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. M Bauer has received grant/research support from The Stanley Medical Research Institute, NARSAD, Deutsche Forschungsgemeinschaft and the European Commission (FP7). He is a consultant for AstraZeneca, Bristol-Myers Squibb, Lilly Deutschland, Lundbeck, Otsuka, and Servier. The studies reported here from the quetiapine XR clinical development program in MDD were sponsored by AstraZeneca. The studies were registered at ClinicalTrials.gov (study identifier numbers NCT00326105 [Study 6: D1448C00006] and NCT00351910 [Study 7: D1448C00007]).

The authors would like to thank S Paterson and J 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 in the EU, the USA and several other countries worldwide as adjunctive treatment for patients with MDD and an inadequate response to previous antidepressants. In addition, quetiapine XR 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.

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

• • Two large, randomized placebo-controlled studies of quetiapine XR as acute adjunct therapy were significant in favor of quetiapine XR versus placebo on the primary efficacy outcome measure.

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