TY - JOUR
T1 - Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression
T2 - A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement
AU - Lee, Hyewon H.
AU - Blumberger, Daniel M.
AU - Lenze, Eric J.
AU - Anderson, Stewart J.
AU - Barch, Deanna M.
AU - Black, Kevin J.
AU - Cristancho, Pilar
AU - Daskalakis, Zafiris J.
AU - Eisenstein, Sarah A.
AU - Huang, Yiyun
AU - Li, Songye
AU - Lissemore, Jennifer
AU - McConathy, Jonathan
AU - Mulsant, Benoit H.
AU - Rajji, Tarek K.
AU - Reynolds, Charles F.
AU - Su, Yi
AU - Tu, Zhude
AU - Voineskos, Daphne
AU - Karp, Jordan F.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2022/4
Y1 - 2022/4
N2 - Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery–Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery–Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level–dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.
AB - Background: The experimental therapeutics approach that combines a placebo-controlled clinical trial with translational neuroscience methods can provide a better understanding of both the clinical and physiological effects of pharmacotherapy. We aimed to test the efficacy and tolerability of low-dose augmentation with buprenorphine (BPN) for treatment-resistant depression, combined with multimodal assessment of target engagement. Methods: In this multisite randomized clinical trial, 85 participants ≥50 years of age with a major depressive episode that had not responded to venlafaxine extended release were randomized to augmentation with BPN or placebo for 8 weeks. The primary outcome measure was the Montgomery–Åsberg Depression Rating Scale. In addition, three linked experiments were conducted to test target engagement: 1) functional magnetic resonance imaging using the monetary incentive delay task, 2) brain positron emission tomography of healthy participants using a novel kappa opioid receptor antagonist tracer [11C]LY2795050, and 3) transcranial magnetic stimulation measure of cortical transmission after daily BPN administration. Results: The mean ± SD dosage of BPN was 0.59 ± 0.33 mg/day. There were no significant differences between the BPN and placebo groups in Montgomery–Åsberg Depression Rating Scale changes over time or adverse effects. BPN administration had minimal effects on functional magnetic resonance imaging blood oxygen level–dependent responses in regions involved in reward anticipation and response, no significant displacement of kappa opioid receptor radioligand in positron emission tomography imaging, and no significant changes in transcranial magnetic stimulation measures of inhibitory and excitatory cortical transmission. Conclusions: Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.
KW - Antidepressants
KW - Buprenorphine
KW - Depression
KW - PET
KW - TMS
KW - fMRI
UR - http://www.scopus.com/inward/record.url?scp=85148555579&partnerID=8YFLogxK
U2 - 10.1016/j.bpsgos.2021.09.003
DO - 10.1016/j.bpsgos.2021.09.003
M3 - Article
C2 - 36325158
AN - SCOPUS:85148555579
SN - 2667-1743
VL - 2
SP - 127
EP - 135
JO - Biological Psychiatry Global Open Science
JF - Biological Psychiatry Global Open Science
IS - 2
ER -