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Cited by 191Treatment of Major DepressionOpioid Use Disorder TreatmentNeuropeptides and Animal Physiology

Safety, Tolerability, and Clinical Effect of Low-Dose Buprenorphine for Treatment-Resistant Depression in Midlife and Older Adults

Open access
Karp, Jordan F., Butters, Meryl A., Begley, Amy E., Miller, Mark D., Lenze, Eric J., Blumberger, Daniel M., Mulsant, Benoit H., Reynolds, Charles F.·2014·The Journal of Clinical Psychiatry
DOI 10.4088/jcp.13m08725PMC PMC4157317
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Abstract

OBJECTIVE: To describe the clinical effect and safety of low-dose buprenorphine, a κ-opioid receptor antagonist, for treatment-resistant depression (TRD) in midlife and older adults. METHOD: In an 8-week open-label study, buprenorphine was prescribed for 15 adults aged 50 years or older with TRD, diagnosed with the Structured Clinical Interview for DSM-IV, between June 2010 and June 2011. The titrated dose of buprenorphine ranged from 0.2-1.6 mg/d. We assessed clinical change in depression, anxiety, sleep, positive and negative affect, and quality of life. The Montgomery-Asberg Depression Rating scale (MADRS) served as the main outcome measure. Tolerability was assessed by documenting side effects and change in vital signs, weight, and cognitive function. Clinical response durability was assessed 8 weeks after discontinuation of buprenorphine. RESULTS: The mean dose of buprenorphine was 0.4 mg/d (mean maximum dose = 0.7 mg/d). The mean depression score (MADRS) at baseline was 27.0 (SD = 7.3) and at week 8 was 9.5 (SD = 9.5). A sharp decline in depression severity occurred during the first 3 weeks of exposure (mean change = -15.0 [SD = 7.9]). Depression-specific items measuring pessimism and sadness indicated improvement during exposure, supporting a true antidepressant effect. Treatment-emergent side effects (in particular, nausea and constipation) were not sustained, vital signs and weight remained stable, and executive function and learning improved from pretreatment to posttreatment. CONCLUSION: Low-dose buprenorphine may be a novel-mechanism medication that provides a rapid and sustained improvement for older adults with TRD. Placebo-controlled trials of longer duration are required to assess efficacy, safety, and physiologic and psychological effects of extended exposure to this medication. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01071538.

AI snapshot

Written from the paper’s full text.

TL;DR

In an open-label pilot of 15 adults age 50 and older with treatment-resistant depression, low-dose buprenorphine (average 0.4 mg/day) was associated with a rapid drop in MADRS from 27.0 at baseline to 9.5 at week 8. Benefits appeared to wane after discontinuation (week 16 MADRS 17.8), and the authors call for placebo-controlled trials.

Key findings

  • Depression severity fell from baseline MADRS 27.0 (SD = 7.3) to 9.5 (SD = 9.5) at week 8; the first three weeks showed a sharp decline (mean delta = −15.0, SD = 7.9). Response (MADRS ≤ 10) occurred in 10/15 participants (66.7%, 95% CI = 38.7%–87.0%) at any week and in 8/13 (61.54%, 95% CI = 32.3%–84.9%) at week 8.
  • The average daily buprenorphine dose was 0.40 mg/day (SD = 0.21, range = 0.12–0.83), with an average maximum daily dose of 0.69 mg/day (SD = 0.37, range = 0.20–1.40).
  • Tolerability was generally favorable: nausea ≥ 2-point increase occurred in 5/15 and constipation in 8/15, but these were not sustained (mean weeks = 1.6 and 1.29, respectively); vital signs and weight remained stable, and no clinically significant withdrawal was observed (COWS average = 1.9, SD = 1.3). Cognitive measures did not worsen, with HVLT-R improvements and a trend for improved inhibition (p = 0.10).
  • At week 16, after discontinuation, average MADRS was 17.8 (SD = 12.9, n = 10, excluding 3 participants who continued low-dose buprenorphine), suggesting antidepressant benefits may require continued dosing.

Methods

  • Open-label 8-week pilot of 15 adults age ≥ 50 with treatment-resistant depression diagnosed by SCID for DSM-IV; 5 were venlafaxine nonresponders from an ongoing study, and 10 had not responded to at least two antidepressants at FDA-approved therapeutic doses for at least 6 weeks. Recruitment occurred June 2010–June 2011.
  • Buprenorphine was given as 0.2 mg sublingual tablets, titrated weekly based on MADRS and FIBSER scores, then tapered after 8 weeks; assessments were weekly through week 8, with follow-up at week 16.
  • The main outcome was MADRS; additional measures included anxiety, affect, suicidality, quality of life, sleep, side effects, vital signs, weight, cognitive tasks, HVLT-R, and COWS. Analyses summarized continuous and categorical variables and used Wilcoxon signed rank exact tests for pre- to post-treatment cognitive change.

Limitations

  • Stated by the authors: the open-label design, lack of ethnic diversity, absence of psychiatrically normal or opioid-naïve control participants for repeated cognitive testing, and the need for placebo-controlled trials of longer duration.
  • Evident from the text: the sample was very small (15 entered, 13 completed 8 weeks), there was no placebo or randomization, and the week 16 durability estimate excluded 3 participants who continued low-dose buprenorphine, so it is not a clean off-drug follow-up.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.4088/jcp.13m08725

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 19 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    At week 16, excluding participants who continued buprenorphine, average MADRS was 17.8 (SD 12.9, median 14, range 2-39, n=10).

    “The average MADRS (excluding those who continued to take buprenorphine) at week 16 was 17.8 (SD=12.9, median=14, range=2–39, n=10).”
    Quote in the paperSubstantial claim
  • Findingown data

    Response, defined as MADRS ≤10 at any week, was observed in 10 of 15 participants (66.7%, 95% CI 38.7% to 87.0%).

    “Response, defined as MADRS ≤ 10 at any week, was observed for 10/15 participants (66.7%, 95 CI = 38.7% to 87.0%).”
    Quote in the paperSubstantial claim
  • Findingown data

    The study did not observe weight gain.

    “In this study, we did not observe weight gain.”
    Quote in the paperSubstantial claim
  • Findingown data

    Depression severity fell sharply during the first three weeks of buprenorphine exposure (mean delta −15.0, SD 7.9, median −15.5, range −25.0 to 2, n=14).

    “There was a sharp decline in depression severity during the first three weeks of exposure (mean delta=-15.0 (SD=7.9, median=-15.5, range=-25.0 to 2, n=14).”
    • Also stated in: § Results · plain
      “There was a sharp decline in depression severity during the first three weeks of exposure (mean delta=−15.0 (SD=7.9)).”
    Quote in the paperSubstantial claim
  • Findingown data

    Response at the end of 8 weeks was observed in 8 of 13 participants (61.54%, 95% CI 32.3 to 84.9).

    “Response at the end of 8 weeks was observed for 8/13 participants (61.54%, 95% CI = 32.3 to 84.9).”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingown data

    On the incongruous/congruous reaction time ratio, there was a trend toward improvement from baseline to week 8 (baseline 1.38, SD 0.23, median 1.36; week 8 1.15, SD 0.23, median 1.25; Wilcoxon p=0.10), suggesting improved inhibition.

    “The ratio of Incongruous / Congruous Choice Reaction Time revealed a trend for improvement across the two time-points [Baseline=1.38 (std=0.23, median=1.36) vs. Week 8=1.15 (std=0.23, median=1.25); Wilcoxon signed rank exact p=0.10], suggesting improvement in the ability to inhibit automatic responses in favor of more effortful responses (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Depression improved without an increase in weight.

    “we observed improvement in depression without increase in weight.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The average daily buprenorphine dose in the trial was 0.40 mg/day (SD 0.21, median 0.40, range 0.12-0.83), and the average maximum daily dose was 0.69 mg/day (SD 0.37, median 0.60, range 0.20-1.40).

    “The average daily dose was 0.40 mg/day (std=0.21, median=0.40, range=0.12-0.83) with maximum average daily dose of 0.69 (std=0.37, median=0.60, range=0.20-1.40”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MADRS items for pessimistic thoughts and reported sadness followed the same trajectory as the total MADRS score, indicating depression-specific clinical improvement.

    “The trajectories for these two items match the trajectory for the total MADRS score (Figure 1) and represent depression-specific clinical improvements.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Baseline MADRS averaged 27.0 (SD 7.3, median 25, range 18-42, n=15), and week 8 MADRS averaged 9.5 (SD 9.5, median 7, range 0-33, n=13).

    “The average depression score (MADRS) at baseline was 27.0 (SD=7.3, median=25, range =18–42, n=15); and at week 8, 9.5 (SD=9.5, median=7, range=0–33, n=13).”
    • Also stated in: § Results · plain
      “The average depression score (MADRS) at baseline was 27.0 (SD=7.3); and at week 8, 9.5 (SD=9.5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No participants had clinically significant withdrawal symptoms during buprenorphine discontinuation; average COWS score was 1.9 (SD 1.3, median 1.6, range 0.3-4.3, n=12).

    “None of the subjects experienced clinically significant withdrawal symptoms. The average score on the COWS during discontinuation was 1.9 (SD=1.3, median=1.6, range=0.3–4.3, n=12)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Vital signs and weight remained stable during the 8-week treatment.

    “vital signs and weight remained stable”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study sample was not ethnically diverse.

    “The lack of ethnic diversity also needs to be remedied in future studies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In this sample of mid-life and older adults, low-dose buprenorphine did not worsen cognitive function and may potentially improve it.

    “suggest that low-dose buprenorphine in this sample of mid-life and older adults does not worsen, and may potentially improve, cognitive function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Low-dose buprenorphine could be a medication with a new mechanism that yields quick and lasting benefit in older adults whose depression is treatment-resistant.

    “Low-dose buprenorphine may be a novel-mechanism medication that provides a rapid and sustained improvement for older adults with TRD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Buprenorphine has mixed opioid receptor actions: it partly activates μ receptors, blocks κ receptors, and binds δ receptors.

  • May combine two claims.

    Interpretationown data

    Buprenorphine was well-tolerated with relatively minimal gastrointestinal side effects.

    “Buprenorphine was well-tolerated, with relatively minimal effects on these gastrointestinal symptoms.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Buprenorphine is thought to be relatively safe, with little risk of respiratory depression, and its pharmacokinetics do not change with older age or poor renal function.

  • May combine two claims.

    Interpretationown data

    In mid-life and older adults with treatment-resistant depression, low-dose buprenorphine might be safe and tolerated well.

    “The results from this pilot project also suggest that low-dose buprenorphine may be safe and well-tolerated in mid-life and older adults with TRD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Buprenorphine is thought to be relatively safe, with little risk of respiratory depression, and its pharmacokinetics do not change with older age or poor renal function.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Every participant gave written informed consent.

    “All participants provided written informed consent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The Scale for Suicide Ideation has moderately high internal consistency (Cronbach's alphas 0.84-0.89) and good agreement between raters.

    “has moderately high internal consistency with Cronbach’s alphas ranging from 0.84 to 0.89 and good inter-rater reliability (27, 29).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] Beck AT Kovacs M Weissman A Assessment of suicidal intention: the Scale for Suicide Ideation Journal of Consulting & Clinical Psychology 1979 47 2 343 352 469082

      Not checked in the free run.

    • cites [29] Beck AT Brown GK Steer RA Psychometric characteristics of the Scale for Suicide Ideation with psychiatric outpatients Behaviour Research & Therapy 1997 35 11 1039 1046 9431735

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    In older people with major depressive disorder, the BSI-anxiety scale shows good internal consistency (Cronbach's alpha 0.84).

    “We have reported that the BSI-anxiety scale has good internal consistency in older subjects with MDD (Cronbach's alpha = 0.84) (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Andreescu C Lenze E Dew M Begley A Mulsant B Dombrovski A Effect of comorbid anxiety on treatment response and relapse risk in late-life depression: controlled study British Journal of Psychiatry 2007 190 4 344 349 17401042

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The MADRS was given using a published structured interview, and agreement among 12 raters was high (intra-class correlation 0.99).

    “We administered the MADRS using a published structured interview (23) and maintained Intra-class Correlation [ICC] of 0.99 among 12 raters with backgrounds ranging from Bachelor’s degree to geriatric psychiatrist.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Williams J Kobak K Improving Inter-Rater Reliability in Clinical Trials: Development and Validation of a Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA) 2007 International Society for CNS Clinical Trials and Methodology 3rd Annual Scientific Congress Washington, DC

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Buprenorphine might affect serotonergic systems and the hypothalamic-pituitary-adrenal axis.

    “Buprenorphine may also interact with serotonergic systems and the hypothalamic-pituitary-adrenal axis (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Sbrenna S Marti M Morari M Calo G Guerrini R Beani L Modulation of 5-hydroxytryptamine efflux from rat cortical synaptosomes by opioids and nociceptin British Journal of Pharmacology 2000 130 2 425 433 10807682 PMC1572081

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Projections from the amygdala, frontal cortex, and locus coeruleus reach the periaqueductal grey matter, which suggests that opiate and monoaminergic systems modulate each other reciprocally.

    “Indeed, the periaqueductal grey matter, an area rich in opiate receptors, receives projections from the amygdala, frontal cortex, and locus coeruleus, suggesting reciprocal modulation of the opiate and monoaminergic systems (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hache G Coudore F Gardier A Guiard B Monoaminergic Antidepressants in the Relief of Pain: Potential Therapeutic Utility of Triple Reuptake Inhibitors (TRIs) Pharmaceuticals 2011 4 285 342

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    At the center's most recent reliability check, the UKU Side Effects Rating Scale had an intra-class correlation of 0.91.

    “At our last reliability testing, the ICC was 0.91.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mood improved quickly in younger patients with treatment-resistant depression who did not abuse opioids, and in opioid-dependent patients given buprenorphine.

    “Rapid improvement in mood has been observed in both younger non-opioid abusing patients with TRD (12) and opioid-dependent patients treated with buprenorphine (13).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Bodkin JA Zornberg GL Lukas SE Cole JO Buprenorphine treatment of refractory depression Journal of Clinical Psychopharmacology 1995 2 15 1 49 57 PubMed PMID: 7714228. 7714228

      Not checked in the free run.

    • cites [13] Kosten TR Morgan C Kosten TA Depressive symptoms during buprenorphine treatment of opioid abusers Journal of Substance Abuse Treatment 1990 7 1 51 54 2313769

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The University of Pittsburgh IRB and the FDA monitored and approved the project (IND 107,835).

    “This project was approved and monitored by both the University of Pittsburgh IRB and the FDA (IND 107,835).”
    Quote in the paperNot a substantial claim
21 of 21

  • The paper relies on this without support.

    Buprenorphine has mixed opioid receptor actions: it partly activates μ receptors, blocks κ receptors, and binds δ receptors.

    “Buprenorphine is a partial agonist at μ-receptors, an antagonist of kappa (κ) receptors, and also displays affinity for delta (δ) opiate receptors.”

  • The paper relies on this without support.

    Buprenorphine is thought to be relatively safe, with little risk of respiratory depression, and its pharmacokinetics do not change with older age or poor renal function.

    “Buprenorphine has a favorable safety profile with low risk of respiratory depression, and the pharmacokinetics are not affected by advanced age or renal dysfunction, supporting its use in both mid-life and older adults with TRD.”
2 of 2

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discontinuation monitoring is described as both two and four weeks

    Minor

    The follow-up methods specify two weeks of withdrawal monitoring, while the results say the COWS was used during four weeks of discontinuation.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. [3]Thase M Rush A Bloom F Kupfer D Treatment Resistant Depression Psychopharmacology - 4th Generation of Progress. 4 1995 New York Lippincott, Williams, and Wilkins
  2. [18]First M Spitzer R Gibbon M Williams J Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) 1997 Washington, D.C. American Psychiatric Press
  3. [36]Ware J Gandek B the IQOLA project group The SF-36 health survey: Development and use in mental health research and IQOLA project International Journal of Mental Health 1994 23 2 49 73

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Related

Authors
Karp, J. F., Butters, M. A., Begley, A. E., Miller, M. D., Lenze, E. J., Blumberger, D. M., Mulsant, B. H., & Reynolds, C. F.
ORCID
Venue
The Journal of Clinical Psychiatry
Publisher
Physicians Postgraduate Press, Inc
Published
2014-08-26
Volume
75
Issue
08
Pages
e785-e793
ISSN
0160-6689 (ISSN-L)
DOI
10.4088/jcp.13m08725
PMC
PMC4157317
OpenAlex
W2086769768
Semantic Scholar
48d8abb4a8374908d0e1a1f5c9f2504753811004
Cited by
191
References
40
Citations by year
2026: 3 · 2025: 9 · 2024: 11 · 2023: 10 · 2022: 16 · 2021: 20 · 2020: 23 · 2019: 18 · 2018: 25 · 2017: 21 · 2016: 18 · 2015: 14 · 2014: 3
FWCI
13.61
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000005, KL2TR000146)
  • National Institute on Aging (R01AG033575, AG033575, P30AG024827)
  • National Institute of Mental Health (R01MH072947, P30MH090333, P30 MH090330, MH 072947, MH083660, R01MH083660)
  • National Center for Research Resources (UL1RR024153, KL2RR024154)
  • National Center for Advancing Translational Sciences
  • National Institute on Minority Health and Health Disparities (P60MD000207)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
treatment-resistant depression, middle-aged and older adults, kappa opioid receptor antagonists, antidepressant efficacy, tolerability, adverse effects, cognitive function, executive function, quality of life, anxiety, sleep
MeSH terms
Aged, Buprenorphine, Cognition, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Narcotic Antagonists, Quality of Life, Sleep, Treatment Outcome, Age of Onset, Depressive Disorder, Treatment-Resistant

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