This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Letter to the Editor

Successful Treatment of Major Depressive Disorder With Add-On Buprenorphine in a Patient With Previous Nonresponse to Standard Antidepressants

Mohamed Elsayed, MD; Maximilian Gahr, MD; Bernhard J. Connemann; and Carlos Schönfeldt-Lecuona, MD

Published: September 28, 2017

Successful Treatment of Major Depressive Disorder With Add-On Buprenorphine in a Patient With Previous Nonresponse to Standard Antidepressants

To the Editor: Major depressive disorder (MDD) is a global mental health problem that affects people of all ages, negatively impacting their personal, academic, social, and family life.1 Prominent symptoms are depressed mood and loss of interest or pleasure in almost all activities most of the day (DSM-5 criteria).2 About 65% of MDD patients show inadequate response to initial treatment.3-5 Increasing evidence6-8 supports the hypothesis that mood disorders involve a dysregulation of the endogenous μ- and kappa-opioid system, and endorphin deficiency seems to play a role in suicidality.9-11 Buprenorphine is a central-acting partial μ- and kappa-opioid receptor agonist.12,13 A growing number of studies7 support using buprenorphine to treat MDD symptoms. However, use of opioid agonists for treating MDD in clinical practice is restricted because of unresolved issues of abuse and dependence.


Case report. A 40-year-old woman was admitted to our psychiatric clinic with an 11-year history of recurrent MDD. Psychopathologic symptoms at admission were depressed mood, loss of drive, nonspecific anxiety, and insomnia. Her antidepressant medication included tranylcypromine 20 mg/d and trimipramine 200 mg/d. A diagnosis of severe persistent MDD according to DSM-5 criteria was established since the MDD symptoms reemerged 2 years ago. She had a family history of MDD in her father and schizoaffective disorder in her sister.

Cranial magnetic resonance tomography and laboratory findings including cerebrospinal fluid analysis were unremarkable. There was no history of substance use. Since her first MDD episode in 2005, she had been treated 13 times in the inpatient setting. During the last few years, she had received almost all available antidepressants (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic and tetracyclic antidepressants, and monoamine oxidase inhibitors) in sufficient doses and durations combined with antipsychotics (as augmentation strategy) or lithium. Repetitive transcranial magnetic stimulation (rTMS) had no effect, and continuous vagus nerve stimulation (VNS, implanted in 2012) showed no significant mood-stabilizing function. She had received multiple sessions of electroconvulsive therapy (ECT) since 2011. We performed 7 ECT sessions with insufficient response. After receiving written informed consent from the patient, we started an off-label therapy trial with buprenorphine 0.2 mg sublingual in addition to current antidepressant treatment. Within a few days, there was a clinically significant improvement in mood, drive, and anxiety. The Beck Depression Inventory14 score improved from 47 to 18 within 1 week. We observed no side effects.


This case shows a clinically meaningful antidepressant effect of buprenorphine in a patient with therapy-resistant MDD who did not respond sufficiently to oral antidepressants, VNS, rTMS, or unilateral and bilateral ECT. Uncontrolled naturalistic clinical trials15,16 have described the efficacy of low-dose treatment with opioids, including buprenorphine, for treatment-refractory MDD. A newly published multicenter, randomized, double-blind, placebo-controlled, 2-stage sequential parallel comparison study17 was conducted in adults with MDD who responded insufficiently to 1 or 2 courses of antidepressants. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan, 8 mg/8 mg of buprenorphine/samidorphan, or placebo. Significant symptom improvement was shown in the 2/2 dosage group across the 3 depression outcome measures between onset and the end of the 4th week of treatment for response and remission.17 A 1-week pilot trial18 in patients with treatment-resistant MDD during a placebo-controlled crossover trial was performed to assess the opioid pharmacodynamics profile following escalating doses of samidorphan coadministered with buprenorphine in opioid-experienced adults. Following the 1-week trial, the ratio associated with maximum antagonism of opioid effects exhibited significant improvement in 17-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale scores.18

Buprenorphine might be a promising candidate for treatment of MDD in patients who do not respond to standard antidepressants.


1. Atencio BJ, Nucette E, Colina J, et al. Evaluation of depression and anxiety in patients with renal insufficiency undergoing chronic hemodialysis. Archivos Venezolanos de Psiquiatria y Neurologia. 2004;50(103):35-41.

2. Craske M, Rauch S, Andrews J, et al; American Psychiatric Association. Major depressive disorders. Diagnostic and Statistical Manual for Mental Disorders. Fifth Edition. Washington, DC: American Psychiatric Association; 2013:155-188.

3. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-659. PubMed doi:10.1016/S0006-3223(03)00231-2

4. Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26(3):477-486. PubMed doi:10.1017/S0033291700035558

5. Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252. PubMed doi:10.1056/NEJMoa052964

6. Berrocoso E, Sánchez-Blázquez P, Garzón J, et al. Opiates as antidepressants. Curr Pharm Des. 2009;15(14):1612-1622. PubMed doi:10.2174/138161209788168100

7. Carlezon WA Jr, Béguin C, Knoll AT, et al. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther. 2009;123(3):334-343. PubMed doi:10.1016/j.pharmthera.2009.05.008

8. Lutz PE, Kieffer BL. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195-206. PubMed doi:10.1016/j.tins.2012.11.002

9. Zalsman G, Molcho A, Huang Y, et al. Postmortem μ-opioid receptor binding in suicide victims and controls. J Neural Transm (Vienna). 2005;112(7):949-954. PubMed doi:10.1007/s00702-004-0239-3

10. Wentland MP, Lou R, Lu Q, et al. Syntheses and opioid receptor binding properties of carboxamido-substituted opioids. Bioorg Med Chem Lett. 2009;19(1):203-208. PubMed doi:10.1016/j.bmcl.2008.10.134

11. Gross-Isseroff R, Dillon KA, Israeli M, et al. Regionally selective increases in μ-opioid receptor density in the brains of suicide victims. Brain Res. 1990;530(2):312-316. PubMed doi:10.1016/0006-8993(90)91301-V

12. Gabilondo AM, Meana JJ, Garcí­a-Sevilla JA. Increased density of μ-opioid receptors in the postmortem brain of suicide victims. Brain Res. 1995;682(1-2):245-250. PubMed doi:10.1016/0006-8993(95)00333-L

13. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571. PubMed doi:10.1001/archpsyc.1961.01710120031004

14. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation; 1996.

15. Tenore PL. Psychotherapeutic benefits of opioid agonist therapy. J Addict Dis. 2008;27(3):49-65. PubMed doi:10.1080/10550880802122646

16. Karp JF, Butters MA, Begley AE, et al. Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in midlife and older adults. J Clin Psychiatry. 2014;75(8):e785-e793. PubMed doi:10.4088/JCP.13m08725

17. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173(5):499-508. PubMed doi:10.1176/appi.ajp.2015.15070921

18. Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacology. 2015;40(6):1448-1455. PubMed doi:10.1038/npp.2014.330

Mohamed Elsayed, MDa

Maximilian Gahr, MDa

Bernhard J. Connemanna

Carlos Schönfeldt-Lecuona, MDa

aDepartment of Psychiatry and Psychotherapy III, University of Ulm, Leimgrubenweg, Ulm, Germany

Potential conflicts of interest: None.

Funding/support: None.

Patient consent: Written informed consent was obtained from the patient for publication of this case report, and the information was de-identified to protect anonymity.

Published online: September 28, 2017.

Prim Care Companion CNS Disord 2017;19(5):16l02091

© Copyright 2017 Physicians Postgraduate Press, Inc.

Related Articles

Volume: 19

Quick Links:


Buy this Article as a PDF