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Opioidergic Agents as Antidepressants: Rationale and Promise

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Abstract

Research concerning psychiatric issues relating to opioid drugs currently focuses primarily on their role in reinforcing addictive behaviors, given the recent proliferation of lethal abuse of illicit opiates in the United States and around the world. In contrast, this article will review the mechanism of action of opioids in affective disorders and the available evidence and potential for their use, especially in the treatment of resistant major depression. Buprenorphine is the opioid derivative of special interest; we review this and other opioid derivatives, highlighting the growing role of opioids in treating depressive illnesses and other related psychopathologies.

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Notes

  1. Samidorphan combined with buprenorphine differs from naloxone combined with buprenorphine, as naloxone is not absorbed sublingually, and leaves buprenorphine’s μ-activity unaffected when administered sublingually. Naloxone is intended to prevent illicit administration of buprenorphine parenterally, as parenteral naloxone blocks μ-activity.

References

  1. Goodman and Gilman’s. The pharmacological basis of therapeutics, 13th edn. Dec 5, 2017 by Laurence Brunton and Bjorn Knollmann; 2017.

  2. Brownstein MJ. A brief history of opiates, opioid peptides and opioid receptors. Proc Natl Acad Sci USA. 1993;90:5391–3.

    Article  CAS  Google Scholar 

  3. Baraka A. Historical aspects of opium. Middle East J Anesthesiol. 2000;15:423–36.

    CAS  PubMed  Google Scholar 

  4. Weber MM, Emrich HM. Current and historical concepts of opiate treatment in psychiatric disorders. Int Clin Psychopharmacol. 1988;3(3):255–66.

    Article  CAS  Google Scholar 

  5. Kraeplin E. Manic depressive illness and paranoia. Edinburgh: Livingstone; 1921.

    Google Scholar 

  6. Mayer-Gross W, Slater E, Roth M. Clinical psychiatry. Baltimore: Williams and Wilkins; 1954.

    Google Scholar 

  7. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40.

    Article  Google Scholar 

  8. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  Google Scholar 

  9. Tenor Peter L. Psychotherapeutic benefits of opioid agonist therapy. J Addict Dis. 2008;27(3):49–65.

    Article  Google Scholar 

  10. Contet C, Kieffer BL, Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol. 2004;14(3):370–8.

    Article  CAS  Google Scholar 

  11. Lutz P, Kieffer B. Opioid receptors: distinct roles in mood disorders. Trends Neurosci. 2013;36(3):195–206.

    Article  CAS  Google Scholar 

  12. Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69(suppl E1):4–7.

    PubMed  Google Scholar 

  13. Svingos AL, Chavkin C, Colago EE, Pickel VM. Major coexpression of kappa-opioid receptors and the dopamine transporter in nucleus accumbens axonal profiles. Synapse. 2001;42(3):185–92.

    Article  CAS  Google Scholar 

  14. Carlezon W Jr, Beguin C, Knoll AT, Cohen BM. Kappa opioid ligands in the study and treatment of mood disorders. Pharmacol Ther. 2009;123:334–43.

    Article  CAS  Google Scholar 

  15. Bear DM, Kessler RM. United States Patent 8,883,831; 2014a.

  16. Bear DM, Kessler RM. US Patent Application PCT/US2014/013874. Washington, DC; 2014b.

  17. Mischoulon D, Hylek L, Yeung AS, Clain AJ, Baer L, Cusin C, Ionefscu DF, Alpert JE, Soskin DP, Fava M. Randomized, proof of concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. J Affect Disord. 2017;208:6–14.

    Article  CAS  Google Scholar 

  18. Berrocos E, Sanchez-Blazquez P, Garzón J, Mico JA. Opiates as antidepressants. Curr Pharm Design. 2009;15:1612–22.

    Article  Google Scholar 

  19. Lauterbach EC. Treatment resistant depression with loss of antidepressant response: rapid—acting antidepressant action of dextromethorphan, a possible treatment bridging molecule. Psychopharmacol Bull. 2016;46(2):53–8.

    PubMed  PubMed Central  Google Scholar 

  20. Snyder CB, Pert SH. Opiate receptor: demonstration in nervous tissue. Science. 1973;179(4077):1011–4.

    Article  Google Scholar 

  21. Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav. 2003;43(1):60–6.

    Article  CAS  Google Scholar 

  22. Vuong C, Van Uum SH, O’Dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31(1):98–132.

    Article  CAS  Google Scholar 

  23. Dickenson AH. NMDA receptor antagonists: interactions with opioids. Acta Anaesthesiol Scand. 1997;41(1 Pt 2):112–5.

    Article  CAS  Google Scholar 

  24. Schwartz-Lifshitz M, Zalsman G, Giner L, Oquendo MA. Can we really prevent suicide? Curr Psychiatry Rep. 2012;14(6):624–33.

    Article  Google Scholar 

  25. Gross-Isseroff R, Dillon KA, Israeli M, Biegon A. Regionally selective increases in mu opioid receptor density in the brains of suicide victims. Brain Res. 1990;530(2):312–6.

    Article  CAS  Google Scholar 

  26. Gabilondo AM, Meana JJ, García-Sevilla JA. Increased density of mu-opioid receptors in the postmortem brain of suicide victims. Brain Res. 1995;682(1–2):245–50.

    Article  CAS  Google Scholar 

  27. Kennedy SE, Koeppe RA, Young EA, Zubieta JK. Dysregulation of endogenous opioid emotion regulation circuitry in major depression in women. Arch Gen Psychiatry. 2006;63(11):1199–208.

    Article  CAS  Google Scholar 

  28. Scarr E, Money TT, Pavey G, Neo J, Dean B. Mu opioid receptor availability in people with psychiatric disorders who died by suicide: a case control study. BMC Psychiatry. 2012;28(12):126.

    Article  Google Scholar 

  29. Kosten T, Morgan C, Kosten TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7:51–4.

    Article  CAS  Google Scholar 

  30. Dean AJ, Bell J, Mascord DJ, Parker G, Christie MJ. A randomised, controlled trial of fluoxetine in methadone maintenance patients with depressive symptoms. J Affect Disord. 2002;72:85–90.

    Article  CAS  Google Scholar 

  31. Dean AJ, Bell J, Christie MJ, Mattick RP. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence. Eur Psychiatry. 2004;19:510–3.

    Article  Google Scholar 

  32. Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M, Du Y, Leigh-Pemberton R, DiPetrillo L, Silverman B, 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.

    Article  Google Scholar 

  33. Leander JD. Buprenorphine has potent kappa opioid receptor antagonist activity. Neuropharmacology. 1987;26(9):1445–7.

    Article  CAS  Google Scholar 

  34. Knoll AT, Carlezon WA. Dynorphin, stress, and depression. Brain Res. 2010;1314:56–73.

    Article  CAS  Google Scholar 

  35. Thase ME, Stanford AD, Memisoglu A, Martin W, Claxton A, Bodkin JA, Trivedi MH, Fava M, Pathak S. Long-term efficacy, safety and tolerability of adjunctive ALKS 5461 as adjunctive treatment in patients with major depressive disorder enrolled in an ongoing Phase 3 study: poster session presented at American Psychiatric Association annual meeting. NY: NYC; 2018.

    Google Scholar 

  36. Emrich HM, Vogt P, Herz A, Kissling W. Antidepressant effects of buprenorphine. Lancet. 1982;2(8300):709.

    Article  CAS  Google Scholar 

  37. Morgan L, Calloway E. Buprenorphine responders. Biol Psychiat. 1990;28(12):1078–80.

    Article  Google Scholar 

  38. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15(1):49–57.

    Article  CAS  Google Scholar 

  39. Nyhuis PW, Gastpar M, Scherbaum N. Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy. J Clin Psychopharmacol. 2008;28(5):593–5.

    Article  Google Scholar 

  40. Karp JF, Butters MA, Begley AE, Miller MD, Lenze EJ, Blumberger DM, Mulsant BH, Reynolds CF 3rd. Safety, tolerability, and clinical effect of low-dose buprenorphine for treatment-resistant depression in mid-life and older adults. J Clin Psychiatry. 2014;75(8):e785–93.

    Article  Google Scholar 

  41. Ehrich E, Turncliff R, Du Y, Leigh-Pemberton R, Fernandez E, Jones R, Fava M. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacology. 2015;40:1448–55.

    Article  CAS  Google Scholar 

  42. Yowell Y, Bar G, Mashiah M, Baruch Y, Briskman I, Asherov J, Lotan A, Rigbi A, Panksepp J. Ultra-low-dose buprenorphine as a time-limited treatment for severe suicidal ideation: a randomized controlled trial. Am J Psychiatry. 2016;173(5):491–8.

    Article  Google Scholar 

  43. Guerdjikova A, Walsh B, Shan K, Halseth AE, Dunayevich E, McElroy SL. Concurrent improvement in both binge eating and depressive symptoms with naltrexone/bupropion therapy in overweight or obese subjects with major depressive disorder in an open-label, uncontrolled study. Adv Ther. 2017;34(10):2307–15.

    Article  CAS  Google Scholar 

  44. Murphy B, Ravichandran C, Babb SM, Cohen BM. Naltrexone in bipolar disorder with depression: a double-blind, placebo-controlled study. Clin Psychopharmacol. 2014;34(6):749–51.

    Article  Google Scholar 

  45. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther. 1992;260(1):275–85.

    CAS  PubMed  Google Scholar 

  46. Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM. Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012;13(10):1437–49.

    Article  CAS  Google Scholar 

  47. Shapira NA, Verduin ML, DeGraw JD. Treatment of refractory major depression with tramadol monotherapy. J Clin Psychiatry. 2001;62(3):205–6.

    Article  CAS  Google Scholar 

  48. Spencer C. The efficacy of intramuscular tramadol as a rapid-onset antidepressant. Aust N Z J Psychiatry. 2000;34(6):1032–3.

    Article  CAS  Google Scholar 

  49. Rougemont-Bücking A, Gamma F, Panksepp J. Use of tramadol in psychiatric care: a comprehensive review and report of two cases. Swiss Med Wkly. 2017;147:w14428.

    PubMed  Google Scholar 

  50. Press release 14 January 2009. E-therapeutics. http://www.firstwordpharma.com/node/39762#axzz54JR5qryu.

  51. Press release 15 February 2016. E therapeutics https://www.fiercebiotech.com/biotech/e-therapeutics-reports-top-line-phase-iib-results-major-depressive-disorder.

  52. Stanley B, Siever L. The Interpersonal Dimension of borderline personality disorder: toward a neuropeptide model. Am J Psychiatry. 2010;167:24–39.

    Article  Google Scholar 

  53. Stanley B, Sher L, Wilson S, Ekman R, Huang YY, Mann JJ. Non suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters. J Affect Disord. 2010;124(1–2):134–40.

    Article  CAS  Google Scholar 

  54. Bresin K, Gordon KH. Endogenous opioids and nonsuicidal self-injury: a mechanism of affect regulation. Neurosci Biobehav Rev. 2013;37(3):374–83.

    Article  CAS  Google Scholar 

  55. Resnick R, Falk F. Buprenorphine: pilot trials in borderline patients and opiate dependence—treatment of a common disorder? Monograph. In: Harris LS, editor. Problems of drug dependence. Washington, DC: National Institute on Drug Abuse Research; 1987. p. 155–68.

    Google Scholar 

  56. Koran LM, Aboujaoude E, Bullock KD, Franz B, Gamel N, Elliott M. Double-blind treatment with oral morphine in treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2005;66(3):353–9.

    Article  CAS  Google Scholar 

  57. Shapira NA, Keck PE Jr, Goldsmith TD, et al. Open-label pilot study of tramadol hydrochloride in treatment-refractory obsessive-compulsive disorder. Depress Anxiety. 1997;6:170–3.

    Article  CAS  Google Scholar 

  58. Goldsmith TB, Shapira NA, Keck PE Jr. Rapid remission of OCD with tramadol hydrochloride. Am J Psychiatry. 1999;156:660–1.

    CAS  PubMed  Google Scholar 

  59. Liddell Malcolm B, Aziz Victor, Briggs Patrick, Kanakkehewa Nimalee, Rawi Omar. Buprenorphine augmentation in the treatment of refractory obsessive–compulsive disorder. Ther Adv Psychopharmacol. 2013;3(1):15–9.

    Article  CAS  Google Scholar 

  60. Ahmadpanah M, Reihani A, Ghaleiha A, Soltanian A, Haghighi M, Jahangard L, Sadeghi Bahmani D, Holsboer-Trachsler E, Brand S. Buprenorphine augmentation improved symptoms of OCD, compared to placebo—results from a randomized, double-blind and placebo-controlled clinical trial. J Psychiatr Res. 2017;94:23–8.

    Article  Google Scholar 

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Authors and Affiliations

  1. Brockton Neighborhood Health Center, 63 Main St, Brockton, MA, 02301, USA

    Parnika P. Saxena

  2. McLean Hospital, 115 Mill St, North Belknap, Belmont, MA, 02478, USA

    J. Alexander Bodkin

  3. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA

    J. Alexander Bodkin

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  1. Parnika P. Saxena
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Correspondence to Parnika P. Saxena.

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Conflict of Interest

Parnika Saxena has no conflicts of interest to declare. J. Alexander Bodkin has a potential conflict due to longstanding efforts to advance the development of buprenorphine as an effective treatment for resistant depressive illness. He has helped Alkermes to engage in a development program of a buprenorphine/samidorphan preparation for use as an adjunctive treatment for resistant depression. This guidance was provided gratis; however, compensation was provided for participation in annual day-long group meetings with a group of academics held by Alkermes in Boston. His lab was also provided with funding for their work on a study on the long-term safety and efficacy of Alkermes’s buprenorphine/samidorphan preparation. Dr Bodkin will not benefit financially if the Alkermes preparation is approved and marketed, nor will he be harmed financially if it is not approved. Dr Bodkin authored one of the first American studies of buprenorphine in depression in 1995 and is one of the leading experts in the US on the use of opioids in depressive illness. He has assessed legal cases over the years as an expert on behalf of psychiatrists facing regulatory or civil litigation for having used opioids in treating resistant depression.

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No sources of funding were used to assist with the preparation of this review.

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Saxena, P.P., Bodkin, J.A. Opioidergic Agents as Antidepressants: Rationale and Promise. CNS Drugs 33, 9–16 (2019). https://doi.org/10.1007/s40263-018-0584-7

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