Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[ 11 C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n = 5) and bipolar disorder (n = 5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.
Bibliographical noteFunding Information:
Dr. Yatham has been an advisory board member/consultant for and/or received honoraria and grant/ research support from Allergan, Alkermes, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Dainippon Sumitomo Pharma, Forest, GlaxoSmithKline, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, Sunovian, and Teva; and has received grant/research support from the Stanley Foundation, the National Alliance for Research on Schizophrenia and Depression, Canadian Institutes of Health Research, and the Canadian Psychiatric Foundation. Dr. Lam has received speaking honoraria or is a member of advisory boards for Treatments, Eli Lilly, Litebook Company Ltd (unpaid), Lundbeck, Lundbeck Institute, Mochida, Pfizer, Servier, and Takeda. He has received research funds through UBC from Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Psychiatric Association Foundation, Litebook Company, Lundbeck, Merk, Pfizer, St Jude Medical, and UBC Institute of Mental Health/Coast Capital Savings. He also receives book royalties from Cambridge University Press and Oxford University Press and holds a copyright on the Lam Employment Absence and Productivity Scale. Dr. Bond has received speaking fees or sat on advisory boards for the Canadian Network for Mood and Anxiety Treatments, the Canadian Psychiatric Association, Pfizer, Sunovion, BMS, Otsuka, Astra-Zeneca, Janssen-Ortho, and Myriad; and has received research support from the Canadian Institutes of Health Research (CIHR), the UBC Institute of Mental Health/Coast Capital Depression Research Fund, and Pfizer. Drs. Sossi, Ding, Puyat, and Sundar and Ms. Vafai and Ms. Dhanoa have no conflicts.
- Bipolar disorder
- Major depressive disorder
- Norepinephrine transporter
- Positron emission tomography