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Cited by 162Treatment of Major DepressionOpioid Use Disorder TreatmentNeurotransmitter Receptor Influence on Behavior

The Efficacy of Buprenorphine in Major Depression, Treatment-Resistant Depression and Suicidal Behavior: A Systematic Review

Open access
Serafini, Gianluca, Adavastro, Giulia, Canepa, Giovanna, De Berardis, Domenico, Valchera, Alessandro, Pompili, Maurizio, Nasrallah, Henry, Amore, Mario·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19082410PMC PMC6121503
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Abstract

Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission. Thus, novel strategies are needed to successfully address those who did not respond, or partially respond, to available antidepressant pharmacotherapy. Research findings revealed that the opioid system is significantly involved in the regulation of mood and incentives salience and may be an appropriate target for novel therapeutic agents. The present study aimed to systematically review the current literature about the use of buprenorphine (BUP) for major depression, treatment-resistant depression (TRD), non-suicidal self-injury (NSSI) behavior, and suicidal behavior. We investigated Pubmed and Scopus databases using the following keywords: “buprenorphine AND depression”, “buprenorphine AND treatment resistant depression”, “buprenorphine AND suicid*”, “buprenorphine AND refractory depression”. Several evidence demonstrate that, at low doses, BUP is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and NSSI, even in patients with TRD. However, more studies are needed to evaluate the long-term effects, and relative efficacy of specific combinations (e.g., BUP + samidorphan (BUP/SAM), BUP + naloxone (BUP/NAL), BUP + naltrexone) over BUP monotherapy or adjunctive BUP treatment with standard antidepressants, as well as to obtain more uniform guidance about the optimal BUP dosing interval.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review of 13 studies found that low-dose buprenorphine, alone or with opioid antagonists, may reduce depressive symptoms, suicidal ideation, and non-suicidal self-injury, including in treatment-resistant depression. The evidence is limited by heterogeneous diagnoses, dosages, small samples, and mostly uncontrolled study designs.

Key findings

  • Across 13 included studies, BUP alone or co-administered with opioid antagonists such as naloxone, samidorphan, or naltrexone was reported to reduce depressive symptoms, NSSI, and suicidal ideation in TRD and opioid-dependent patients.
  • In TRD studies, depressive symptom improvement was about 50% in Emrich et al. and Fava et al., and 66.7% in Karp et al.; Bodkin et al. reported clinically striking improvement in 7 of 10 TRD subjects after four to six weeks.
  • For suicidal ideation, Yovell et al. found a significant decrease with ultra-low-dose sublingual BUP (mean final dosage 0.44 mg/day) as adjunctive treatment; case reports described complete absence of suicidal ideation after one week or after a single 8 mg dose.
  • In a six-patient NSSI case series, BUP was associated with improvement in NSSI behavior; the Results section states six patients improved, while the Discussion states five of six improved. Study quality was mostly moderate (N = 8), with one good-quality and four low-quality studies.

Methods

  • Systematic review following PRISMA guidelines; PubMed and Scopus were searched from January 1980 to June 2018 using terms including “buprenorphine AND depression,” “buprenorphine AND treatment resistant depression,” “buprenorphine AND suicid*,” and “buprenorphine AND refractory depression,” plus bibliography review.
  • Inclusion required clinical studies explicitly mentioning BUP and depression/TRD/refractory depression or suicid*; exclusions were studies before 1980, no abstract or abstract not mentioning the association, non-English studies, systematic reviews/meta-analyses, and studies of BUP as an analgesic. Three studies on depression in opiate-dependent patients were also included.
  • Thirteen studies were included: six clinical trials (three randomized, double-blind, placebo-controlled), one clinical case, three studies of depressive symptoms in opiate dependence, plus studies on suicidal ideation and NSSI. Reported samples included 216 TRD subjects treated with BUP, 248 opiate-dependent patients, 90 patients with suicidal ideation, and 6 NSSI patients; heterogeneity prevented meta-analysis.

Limitations

  • The paper states that disparate dosage regimens, questionable persistence of antidepressant effects, and mixed data-analysis methods prevented a meta-analysis; some studies were very short (one week or a few days), and most samples were modest in size.
  • The paper also states that included studies had heterogeneous clinical diagnoses, mixed substance-naïve and opioid-dependent populations, and that nine of 13 studies lacked a control group; three case reports were included and are difficult to generalize.
  • Evident from the text: most included studies were rated moderate or low quality (8 moderate, 1 good, 4 low), and the predominance of small, open-label, or case-report evidence limits causal conclusions about efficacy and long-term safety.

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

Integrity signals

Registry

Crossref · 10.3390/ijms19082410

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 99 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The systematic review included 10 studies on buprenorphine and depression that met inclusion criteria.

    “Thus, 10 studies met our inclusion criteria and were included in the present review.”
    Quote in the paperSubstantial claim
  • Findingown data

    The systematic review included four studies on buprenorphine and suicidal behavior that met inclusion criteria.

    “Thus, four studies met our inclusion criteria and were included in the present review.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Three additional studies investigating the course of depressive symptoms in opiate dependence patients treated with buprenorphine included a total of 248 patients.

    “Three additional studies investigating the course of depressive symptoms in opiate dependence patients treated with BUP were also considered in addition to the Striebel case (a total of 248 patients) [48,49,50].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Kosten, 1990, Depressive symptoms during buprenorphine treatment of opioid abusers, J. Subst. Abuse Treat. source

      Not checked in the free run.

    • cites [49] Dean, 2004, Depressive symptoms during buprenorphine vs. methadone maintenance: Findings from a randomised, controlled trial in opioid dependence, Eur. Psychiatry source

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    • cites [50] Gerra, 2006, Naltrexone and buprenorphine combination in the treatment of opioid dependence, J. Psychopharmacol. source

      Not checked in the free run.

  • Findingcitation

    Kosten et al. reported antidepressant effects during one month of treatment in opioid-dependent patients switched to buprenorphine from methadone or treated directly with buprenorphine, with a mean sublingual daily buprenorphine dose of 3.2 mg.

    “Kosten et al. reported antidepressant effects during one month of treatment in opioid dependent patients switched to BUP from methadone or treated directly with BUP (mean sublingual daily BUP dose of 3.2 mg).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Nyhuis et al. observed improvement of depressive symptoms in six nonpsychotic treatment-resistant depression patients after seven days of buprenorphine monotherapy at a medium dose of 1.2 mg/day.

    “Nyhuis and colleagues [46] observed in six nonpsychotic TRD patients an improvement of depressive symptoms after seven days of BUP treatment, as a monotherapy, at a medium dose of 1.2 mg/day.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Nyhuis, 2008, Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy, J. Clin. Psychopharmacol. source

      Not checked in the free run.

  • May combine two claims. 36
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingcitation

    Six clinical trials, one clinical case, and three additional studies investigating opiate-dependent patients were included, with 216 subjects with treatment-resistant depression treated with buprenorphine in monotherapy or with an opioid antagonist.

    “Overall, six clinical trials [41,42,43,44,45,46]—of which three were randomized, double-blind and placebo controlled studies [41,44,45]—and one clinical case [47], including a total of 216 subjects with TRD treated with BUP in mono-therapy or together with an opioid antagonist (naloxone or samidorphan) were included.”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [41] Emrich, 1982, Possible antidepressive effects of opioids: Action of buprenorphine, Ann. N. Y. Acad. Sci. source

      Not checked in the free run.

    • cites [42] Bodkin, 1995, Buprenorphine treatment of refractory depression, J. Clin. Psychopharmacol. source

      Not checked in the free run.

    • cites [43] Karp, 2014, Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults, J. Clin. Psychiatry source

      Not checked in the free run.

    • cites [44] Ehrich, 2015, Evaluation of opioid modulation in major depressive disorder, Neuropsychopharmacology source

      Not checked in the free run.

    • cites [45] Fava, 2016, Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: A randomized double-blind placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

    • cites [46] Nyhuis, 2008, Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy, J. Clin. Psychopharmacol. source

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    • cites [47] Striebel, 2014, The anti-suicidal potential of buprenorphine: A case report, Int. J. Psychiatry Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Fava et al. found the greatest depression reduction in the buprenorphine/samidorphan 2 mg/2 mg dosage group, while improvement did not achieve statistical significance in the 8 mg/8 mg group.

    “They found the greatest depression reduction in the 2/2 dosage group, while the improvement did not achieve statistical significance in the 8/8 dosage group.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Fava, 2016, Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: A randomized double-blind placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Most included studies (8) were of moderate quality, one was of good quality, and four were of low quality.

    “Overall, most of the included studies (N = 8) were of moderate quality, one was of good quality, and four of low quality.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The review's quality score system is a valid measure of study quality.

  • May combine two claims.

    Findingcitation

    For buprenorphine and suicidal ideation, the review included one randomized, double-blind, placebo-controlled trial and one case report in addition to the Striebel report, totaling 90 patients with heterogeneous diagnoses but clinically significant suicidal ideation.

    “Regarding the efficacy of BUP on suicidal ideation, in addition to the Striebel report, two other studies were added—one randomized, double-blind, and placebo-controlled clinical trial [51], and one case report [52]—for a total of 90 patients having heterogeneous diagnoses (i.e., Borderline Personality Disorder, Major Depressive Disorder, Adjustment Disorders, Eating Disorders, Post-Traumatic St”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Yovell, 2016, Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: A randomized controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

    • cites [52] Ahmadi, J., and Abtahi, S. (2017). Eight-milligram single dose of buprenorphine as an expeditious treatment for severe suicidal ideation: A case report. Iran. Red Crescent Med. J., 19. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Only one clinical case study about non-suicidal self-injury behavior was found, including 6 patients with self-injury behavior treated with buprenorphine.

    “Only one clinical case study about NSSI behavior was found [53]: it included 6 patients with self-injury behavior who were treated with BUP.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Norelli, 2013, Buprenorphine in the treatment of non-suicidal self-injury: A case series and discussion of the literature, Int. J. Adolesc. Med. Health source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Karp et al. found improvement of depressive symptoms in 15 treatment-resistant depression patients after buprenorphine treatment, with an average maximum dose of 0.7 mg/day and the most relevant decline in the first three weeks.

    “Similarly, Karp et al. [43] found an improvement of depressive symptoms in 15 TRD patients after BUP treatment (average maximum dose = 0.7 mg/day), with the most relevant decline observed in the first three weeks.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Karp, 2014, Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults, J. Clin. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Dean et al. reported improvements in depressive symptoms in all heroin-dependent patients comparing buprenorphine and methadone treatments, with no significant differences between the groups.

    “Dean and colleagues [49], comparing BUP and methadone treatments on a group of heroin-dependent patients, reported improvements in depressive symptoms in all subjects, with no significant differences between the groups.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Dean, 2004, Depressive symptoms during buprenorphine vs. methadone maintenance: Findings from a randomised, controlled trial in opioid dependence, Eur. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Kosten et al. found a good response in 47% of the sample; 75% of responders showed the largest improvement during the first week of buprenorphine treatment.

    “Kosten et al. [48] found a good response in 47% of the sample; in particular, 75% of responders showed the largest improvement during the first week of BUP treatment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Kosten, 1990, Depressive symptoms during buprenorphine treatment of opioid abusers, J. Subst. Abuse Treat. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    About 50% of treatment-resistant depression patients in Emrich et al. and Fava et al. showed improvement in depressive symptoms, and 66.7% in Karp et al.

    “Other studies including TRD patients, anyway, showed an improvement in depressive symptoms in different percentages: about 50% in Emrich et al. [41] and Fava et al. [45], and 66.7% in Karp and colleagues [43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [41] Emrich, 1982, Possible antidepressive effects of opioids: Action of buprenorphine, Ann. N. Y. Acad. Sci. source

      Not checked in the free run.

    • cites [45] Fava, 2016, Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: A randomized double-blind placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

    • cites [43] Karp, 2014, Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults, J. Clin. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Bodkin et al. treated 10 treatment-resistant depression subjects with buprenorphine up to a maximum daily dosage of 1.8 mg; after four to six weeks, seven patients showed clinically striking improvements in subjective and objective measures of depression.

    “Bodkin [42] treated 10 TRD subjects with BUP, according to tolerance and clinical benefits, with a maximum daily dosage of 1.8 mg. After four to six weeks, seven patients showed clinically striking improvements in both subjective and objective measures of depression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bodkin, 1995, Buprenorphine treatment of refractory depression, J. Clin. Psychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Norelli et al. described six psychiatric inpatients with severe, treatment-refractory non-suicidal self-injury treated with buprenorphine in combination with other therapies; overall, six patients showed an improvement in non-suicidal self-injury behavior.

    “Norelli et al. [53] described a case series including six psychiatric inpatients with severe, treatment refractory NSSI on which BUP has been administered—in different doses—in combination with other therapies (e.g., antipsychotic medications including clozapine, antidepressants, mood stabilizers including lithium, valproate, and carbamazepine, benzodiazepines, α-adrenergic and β-blockers, and the”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Norelli, 2013, Buprenorphine in the treatment of non-suicidal self-injury: A case series and discussion of the literature, Int. J. Adolesc. Med. Health source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Striebel and Kalapatapu described a 61-year-old woman with chronic opiate-dependent back pain and depression treated with buprenorphine/naloxone 16 mg/4 mg daily, which was associated with no craving, managed pain, improved mood, and arrested suicidal ideation.

    “Striebel and Kalapatapu [47] described the case of a 61-year old women affected by chronic-opiate dependent back pain and depression who was treated with 16 mg/4 mg of BUP/naloxone daily. This drug combination was associated with no craving, managed her pain, and improved her mood, arresting suicidal ideation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Striebel, 2014, The anti-suicidal potential of buprenorphine: A case report, Int. J. Psychiatry Med. source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In opioid-addicted patients on buprenorphine treatment, depressive symptoms are consistently reduced for a month, with a slight plateau in the second week.

    “In particular, Kosten et al. found that depressive symptoms, in opioid-addicted patients on BUP treatment, are consistently reduced for a month with a slight plateau in the second week.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kosten et al.

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

    Findingnone given

    Three types of buprenorphine preparations have generally been used: sublingual or intranasal BUP alone, BUP/SAM, BUP/NAL, or BUP/naltrexone.

    “Generally, three types of preparations have been used: sublingual or intranasal BUP alone, BUP/SAM, BUP/NAL, or BUP/naltrexone.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The most common side effects of opiate drugs include nausea, constipation, sedation, dizziness, fatigue, headache, dry mouth, and hyperhidrosis.

    “In line with what was expected, the most common side effects of opiate drugs include: (1) nausea; (2) constipation; (3) sedation; (4) dizziness; (5) fatigue; (6) headache; (7) dry mouth; and (8) hyperhidrosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    These side effects were of mild intensity, dose dependent, and transient, lasting only for the first few days of treatment.

    “These symptoms were of mild intensity, dose dependent, and transient (they seemed to last only for the first few days of treatment)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Participants in the study by Norelli et al. showed a complex history of severe and recurrent traumas, high rate of hospitalization, and suboptimal response to various medication combinations.

    “In addition, the participants in the study conducted by Norelli et al. [53] showed a complex history of severe and recurrent traumas, high rate of hospitalization, and a suboptimal response to various combinations of medications”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Norelli, 2013, Buprenorphine in the treatment of non-suicidal self-injury: A case series and discussion of the literature, Int. J. Adolesc. Med. Health source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    At low doses, buprenorphine is an efficacious, well-tolerated, and safe option for reducing depressive symptoms, serious suicidal ideation, and non-suicidal self-injury, including in patients with treatment-resistant depression.

    “Several evidence demonstrate that, at low doses, BUP is an efficacious, well-tolerated, and safe option in reducing depressive symptoms, serious suicidal ideation, and NSSI, even in patients with TRD.”
    • Also stated in: § 3.1. Summary of Main Findings · hedged
      “All the considered (13) studies concluded that BUP—alone or in co-administration with opiate antagonists such as naloxone and samidorphan—may significantly reduce depression symptoms, NSSI, and suicidal ideation in both TRD patients and opiate-dependent patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The heterogeneous included studies can be combined to support a single conclusion about buprenorphine efficacy across major depression, treatment-resistant depression, non-suicidal self-injury, and suicidal behavior.
    • Rests on an assumption: Findings in opioid-dependent patients are relevant to patients with major depression or treatment-resistant depression.

  • May combine two claims.

    Interpretationcitation

    Buprenorphine in co-administration with opiate antagonists such as samidorphan can significantly reduce depression symptoms, non-suicidal self-injury, and suicidal ideation.

    “According to specific studies [22,45], BUP in co-administration with opiate antagonists, such as samidorphan, are able to significantly reduce depression symptoms, NSSI, and suicidal ideation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Turncliff, 2015, Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers, Clin. Ther. source

      Not checked in the free run.

    • cites [45] Fava, 2016, Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: A randomized double-blind placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Approximately one third of patients who receive antidepressant medications do not respond adequately or achieve complete remission.

    “Although several pharmacological options to treat depression are currently available, approximately one third of patients who receive antidepressant medications do not respond adequately or achieve a complete remission.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Buprenorphine is a mu-opioid receptor partial agonist and a kappa/delta-opioid receptor antagonist; it binds with high affinity to mu and kappa receptors and with lower affinity to delta receptors.

    “Pharmacodynamic notions: BUP is a MOR partial agonist and a KOR/DOR antagonist; it binds with a high affinity to MOR and KOR, and it binds with a lower affinity to DOR [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Khroyan, 2015, BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice, Br. J. Pharmacol. source

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  • May combine two claims.

    Premisecitation

    Buprenorphine is a synthetic opiate that has shown, in both animal models and human studies, antidepressant-like effects and a reduction of self-injurious behavior and suicidal behavior.

    “BUP is a synthetic opiate that has shown, in both animal models and human studies, interesting antidepressant-like effects, and a reduction of self-injurious behavior and suicidal behavior [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Sher, 2016, Buprenorphine and the treatment of depression, anxiety, non-suicidal self-injury, and suicidality, Acta Psychiatr. Scand. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Remission rates are lower in treatment-resistant depression, which is associated with a higher risk of recurrence, substance abuse, and suicidal behavior.

    “These remission rates are lower in treatment-resistant depression (TRD) [5] which is associated with a higher risk of recurrence, substance abuse, and suicidal behavior [6,7].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5] Dunner, 2006, Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression, J. Clin. Psychiatry source

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    • cites [6] Serafini, 2018, Number of illness episodes as predictor of residual symptoms in major depressive disorder, Psychiatry Res. source

      Not checked in the free run.

    • cites [7] Serafini, 2014, The role of ketamine in treatment-resistant depression: A systematic review, Curr. Neuropharmacol. source

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  • May combine two claims.

    Premisecitation

    Post-mortem studies on depressed patients who committed suicide revealed increased mu-opioid receptor expression, which may refer to endogenous endorphin insufficiency and can explain, at least partially, the efficacy of buprenorphine on depression.

    “Furthermore, post-mortem studies (conducted on depressed patients who committed suicide) revealed an increased µ-opioid receptor expression which may refer to an endogenous endorphin insufficiency [54], and can explain, at least partially, the efficacy of BUP on depression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Gabilondo, 1995, Increased density of m-opioid receptors in the postmortem brain of suicide victims, Brain Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    The opioid system is significantly involved in the regulation of mood and incentive salience and may be an appropriate target for novel therapeutic agents.

    “Research findings revealed that the opioid system is significantly involved in the regulation of mood and incentives salience and may be an appropriate target for novel therapeutic agents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Buprenorphine blocks the action of kappa agonists, and functional kappa antagonism has been proposed from animal models to function therapeutically as an antidepressant compound in humans.

    “In addition, BUP has also been shown to block the action of k agonists [56] and a functional k antagonism has been proposed on the basis of the results derived by animal models to function therapeutically as an antidepressant compound in humans [24]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Leander, 1987, Buprenorphine has potent kappa opioid receptor antagonist activity, Neuropharmacology source

      Not checked in the free run.

    • cites [24] Knoll, 2010, Dynorphin, stress, and depression, Brain Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Buprenorphine has a rapid antidepressant and anti-suicidal action, acting in about a week after the first administration.

    “Taken together, according to the included studies, BUP has a rapid antidepressant and anti-suicidal action: in fact, this psychoactive compound seems to act in about a week after the first administration [41,42,43,44,46,47,48,52].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [41] Emrich, 1982, Possible antidepressive effects of opioids: Action of buprenorphine, Ann. N. Y. Acad. Sci. source

      Not checked in the free run.

    • cites [42] Bodkin, 1995, Buprenorphine treatment of refractory depression, J. Clin. Psychopharmacol. source

      Not checked in the free run.

    • cites [43] Karp, 2014, Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults, J. Clin. Psychiatry source

      Not checked in the free run.

    • cites [44] Ehrich, 2015, Evaluation of opioid modulation in major depressive disorder, Neuropsychopharmacology source

      Not checked in the free run.

    • cites [46] Nyhuis, 2008, Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy, J. Clin. Psychopharmacol. source

      Not checked in the free run.

    • cites [47] Striebel, 2014, The anti-suicidal potential of buprenorphine: A case report, Int. J. Psychiatry Med. source

      Not checked in the free run.

    • cites [48] Kosten, 1990, Depressive symptoms during buprenorphine treatment of opioid abusers, J. Subst. Abuse Treat. source

      Not checked in the free run.

    • cites [52] Ahmadi, J., and Abtahi, S. (2017). Eight-milligram single dose of buprenorphine as an expeditious treatment for severe suicidal ideation: A case report. Iran. Red Crescent Med. J., 19. source

      Not checked in the free run.

    • Rests on an assumption: The heterogeneous included studies can be combined to support a single conclusion about buprenorphine efficacy across major depression, treatment-resistant depression, non-suicidal self-injury, and suicidal behavior.

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

    Premisecitation

    The STAR*D study showed that about 50% of patients with major depressive disorder respond to the first treatment, but only 30% achieve complete remission, and the remaining percentage need additional treatment trials.

    “Although the burden and disability related to this condition, the STAR*D study clearly showed that about 50% of patients with major depressive disorder (MDD) will experience a response with the first treatment [3] but only 30% achieve a complete remission and the remaining percentage will need to undergo several additional treatment trials in order to improve response [4].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Fava, 1996, Definition and epidemiology of treatment-resistant depression, Psychiatr. Clin. N. Am. source

      Not checked in the free run.

    • cites [4] Valenstein, 2006, Keeping our eyes on STAR*D, Am. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The use of an opioid agonist/antagonist with opposing pharmacological action of similar magnitude, able to exert balanced agonist-antagonist opioid modulation, seems to be linked with normalization of dysregulated or impaired opioidergic tone and may yield therapeutic benefits in major depression.

    “Importantly, the use of both an opioid agonist/antagonist with opposing pharmacological action of similar magnitude, able to exert a balanced agonist–antagonist opioid modulation, seems to be linked with a normalization of the dysregulated/impaired opioidergic tone and may yield therapeutic benefits in major depression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High-dose opioids are linked to a worsening of cognitive functions, although not in non-opioid-naïve patients.

    “However, high dose opioids are linked to a worsening of cognitive functions [61], although not in non-opioid-naïve patients [62].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Chapman, 2002, Effects of intermediate- and long-term use of opioids on cognition in patients with chronic pain, Clin. J. Pain source

      Not checked in the free run.

    • cites [62] Dagtekin, 2007, Assessing cognitive and psychomotor performance under long-term treatment with transdermal buprenorphine in chronic noncancer pain patients, Anesth. Analg. source

      Not checked in the free run.

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

    Interpretationreasoning

    These side effects may be avoided with a slower titration.

    “and they may be avoided with a slower titration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Most included studies involve disparate dosage regimens, questionable persistence of antidepressant effects, and mixed methods for data analysis, which do not allow a meta-analysis on the main topic.

    “First, most of the studies involve relatively disparate dosage regimens, questionable persistence of antidepressant effects and mixed methods for the analysis of the data that do not allow us to conduct a meta-analysis upon the main topic.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Effective treatment of depression may be associated with a general improvement of cognitive symptoms (e.g., pseudo-dementia).

    “It is well known that the effective treatment of depression may be also associated with a general improvement of cognitive symptoms (e.g., pseudo-dementia) [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Raskin, 2007, Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: An 8-week, double-blind, placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The modest sample size of almost all samples (excluding some studies) does not allow good statistical significance and does not allow generalization of the main findings.

    “Another important shortcoming is represented by the modest sample size of almost all the samples (with the exclusion of some studies [45,50,51]) which does not allow to obtain a good statistical significance and, hence, does not allow the generalization of the main findings.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [45] Fava, 2016, Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: A randomized double-blind placebo-controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

    • cites [50] Gerra, 2006, Naltrexone and buprenorphine combination in the treatment of opioid dependence, J. Psychopharmacol. source

      Not checked in the free run.

    • cites [51] Yovell, 2016, Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: A randomized controlled trial, Am. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In the study by Karp et al., the lack of slowed psychomotor speed, inhibition, and memory suggests that low-dose buprenorphine does not worsen, and may potentially improve, cognitive functions.

    “In the study of Karp et al. [43], the lack of slowed (and potentially improved) psychomotor speed, inhibition, and memory suggests that low-dose BUP does not worsen, and may potentially improve, cognitive functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Karp, 2014, Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults, J. Clin. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Based on available evidence, there is no unique best formulation, dosage, or expected treatment time for buprenorphine.

    “Based on the available evidence, there is no uniqueness associated with the better formulation to be used, neither regarding the dosage nor the expected treatment time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Suicidal ideation and depression may be distinct but related phenomena; a reduction in depressive symptoms may accompany a reduction in suicidal ideation, as in ketamine infusion where improvements in suicidal ideation are related to, but not completely driven by, improvements in depression and anxiety.

    “Suicidal ideation and depression may be distinct, but related, phenomena (i.e., a reduction in depressive symptoms may accompany a reduction in suicidal ideation, as in ketamine infusion where improvements in suicidal ideation are related to, but not completely driven by, improvements in depression and anxiety [58]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Ballard, 2014, Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety, J. Psychiatr. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A balanced ratio of BUP/naltrexone (e.g., 1:1, 2:2) is associated with maximal blockade of opioid effects and can prevent the potential additive properties of BUP.

    “Additionally, this type of association—whether in a balanced ratio (i.e., 1:1, 2:2 etc.) which is associated with maximal blockade of opioid effects—can prevent the potential additive properties of BUP [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Ehrich, 2015, Evaluation of opioid modulation in major depressive disorder, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Current diagnoses were not clearly reported in the study by Norelli et al., which listed several lifetime diagnoses per patient; this group appeared extensively heterogeneous and there seems to be no unanimity in interpreting symptoms for diagnostic purposes.

    “Current diagnoses were not clearly reported within this study, which listed several lifetime diagnoses per patient starting from those given in the infancy”
    • Also stated in: § 3.2. Main Shortcomings/Limitations · hedged
      “Therefore, this group of patients appeared to be extensively heterogeneous and there seems to be no unanimity in the interpretation of the symptoms for diagnostic purposes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Articles were screened and selected in a two-step process to minimize bias.

    “Articles were screened and selected in a two-step process to minimize bias.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Discrepancies between the two reviewers, who were blind to each other, were solved by consultation with senior reviewers.

    “Any discrepancies between the two reviewers who, blind to each other, examined the studies for possible inclusion were solved by consultation with the senior reviewers (G.S., M.A., H.N.).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Two independent researchers conducted the literature search.

    “First, two independent researchers (G.A., G.C.) conducted the literature search.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The review excluded studies that explicitly investigated buprenorphine as an analgesic compound.

    “We excluded studies that explicitly investigated the use of BUP as an analgesic compound.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The review also included three studies that investigated depression in opiate-dependent patients.

    “We also included three studies that investigated depression in opiate dependent patients (secondarily exploring the efficacy of BUP on depressive symptoms).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Full-text articles meeting inclusion criteria were independently reviewed by other investigators.

    “In the second phase, full-text articles that met our inclusion criteria were retrieved and independently reviewed by other investigators (M.P., D.D.B.) who discussed the design and characteristics of the studies to test whether the considered studies could be included in the review.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The principal reviewers independently analyzed all studies, and other investigators finally reviewed the included documents.

    “The principal reviewers (G.S., M.A., H.N.) analyzed independently all the studies and the other investigators (M.P., D.D.B.) finally reviewed the included documents.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The review conducted a systematic search of PubMed and Scopus for titles and abstracts from January 1980 to June 2018.

    “We conducted a systematic search of two major electronic databases comprising medical and social science studies (PubMed and Scopus were used, while we did not search Psychinfo because the search did not produce any consistent results concerning the main topic, and Science Direct was not used in order to reduce redundancy) for titles and abstracts (January 1980–June 2018) relevant for our research”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The review adopted PRISMA guidelines for reporting.

    “In order to achieve a high standard of reporting, we adopted the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6. source

      Not checked in the free run.

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

    Study design and conductown data

    Data were independently extracted by G.A. and G.C. from the 13 included studies.

    “Overall, G.A. and G.C. independently extracted the following data elements from the 13 studies included of this review”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The review included studies that explicitly mentioned the association between buprenorphine and depression (or TRD or refractory depression) or buprenorphine and suicidality in clinical samples.

    “We included studies that explicitly mentioned the association between buprenorphine AND depression (OR TRD OR refractory depression), OR buprenorphine AND suicid* (including suicidal ideation OR suicidal thoughts OR suicide attempts), in clinical samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Due to the small number of findings on the main topic, three case reports were included, and their results are difficult to generalize.

    “Importantly, due to the small number of findings regarding the main topic in the investigated literature, we included in this systematic review even three case reports, the results of which are difficult to be generalized.”
    Quote in the paperSubstantial claim
51 of 51

  • The paper relies on this without support.

    The heterogeneous included studies can be combined to support a single conclusion about buprenorphine efficacy across major depression, treatment-resistant depression, non-suicidal self-injury, and suicidal behavior.

    “All the considered (13) studies concluded that BUP—alone or in co-administration with opiate antagonists such as naloxone and samidorphan—may significantly reduce depression symptoms, NSSI, and suicidal ideation in both TRD patients and opiate-dependent patients.”

  • The paper relies on this without support.

    The review's quality score system is a valid measure of study quality.

    “According to our quality score system, the mean score of the seven studies regarding BUP and TRD was 4.7; the mean score of the four studies on opiate-dependent patients was 3.5; the mean score of the three studies about BUP and suicide ideation was 3; the mean score of the Norelli et al. study about NSSI was 2, respectively.”

  • The paper relies on this without support.

    Findings in opioid-dependent patients are relevant to patients with major depression or treatment-resistant depression.

    “All the considered (13) studies concluded that BUP—alone or in co-administration with opiate antagonists such as naloxone and samidorphan—may significantly reduce depression symptoms, NSSI, and suicidal ideation in both TRD patients and opiate-dependent patients.”
3 of 3

Claims other papers make about this one

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.

  • Duplicate removal is reported with two different totals

    Minor

    The paper says 2478 articles remained after duplicates were removed, then says 2078 remained after the same step. The 2478 figure is also the total generated by the two database searches before duplicate removal.

  • NSSI improvement is reported for both six and five patients

    Minor

    For the six-patient Norelli case series, one section says all six improved, while another says five of six did.

  • Quality categories conflict with the claim that all controlled studies were moderate quality

    Minor

    The stated totals include one good-quality study and four low-quality studies. If all ten controlled studies were moderate quality and all three case reports were low quality, those totals cannot hold.

  • Minimum treatment duration conflicts with a single-dose case

    Minor

    The paper says treatment time starts at four days, but an included patient received a single BUP dose.

  • Karp study has conflicting numbers of treated patients

    Minor

    The review describes 15 patients treated with BUP in Karp et al., but later describes over 50 patients treated with BUP in that same study.

5 of 5

The citation lists haven’t been fetched yet

References 63 · Cited by 162

Authors
Serafini, G., Adavastro, G., Canepa, G., De Berardis, D., Valchera, A., Pompili, M., Nasrallah, H., & Amore, M.
Affiliations
  • Ospedale Policlinico San Martino (IT)
  • University of Genoa (IT)
  • Villa San Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy, Polyedra Research Group, 64100 Teramo, Italy
  • NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, Asl 4, 64100 Teramo, Italy
  • Azienda Ospedaliera Sant'Andrea (IT)
  • Saint Louis University (US)
Corresponding author
Serafini, Gianluca
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-08-15
Volume
19
Issue
8
Pages
2410
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms19082410
PMC
PMC6121503
OpenAlex
W2887490045
Semantic Scholar
3c6b44101de70db2faf6682c0685f0c6d472ae58
Cited by
162
References
63
Citations by year
2026: 10 · 2025: 16 · 2024: 17 · 2023: 52 · 2022: 23 · 2021: 20 · 2020: 16 · 2019: 8
FWCI
1.29
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
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 › Neurotransmitter Receptor Influence on Behavior
Keywords
buprenorphine, major depressive disorder, treatment-resistant depression, suicidal ideation, suicidal behavior, non-suicidal self-injury, opioid system, antidepressant non-response, samidorphan, naloxone, naltrexone, adjunctive therapy
MeSH terms
Suicide Prevention, Analgesics, Opioid, Buprenorphine, Major Depressive Disorder, Humans, Suicidal Ideation, Depressive Disorder, Treatment-Resistant

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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