Low-Dose Augmentation With Buprenorphine for Treatment-Resistant Depression: A Multisite Randomized Controlled Trial With Multimodal Assessment of Target Engagement
Bibliographic record
Abstract
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. 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. 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. Our findings suggest a lack of clinical effect of low-dose BPN augmentation and lack of target engagement with this dosage and physiological probes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".