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Keeping up with the clinical advances: depression

Published online by Cambridge University Press:  28 June 2019

Renee-Marie Ragguett ,
Jocelyn K. Tamura  and
Roger S. McIntyre Open the ORCID record for Roger S. McIntyre [Opens in a new window]
Renee-Marie Ragguett
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada
Jocelyn K. Tamura
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada
Roger S. McIntyre*
Affiliation:
Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Canada Department of Psychiatry, University of Toronto, Toronto, Canada Department of Pharmacology, University of Toronto, Toronto, Canada
*
*Address correspondence to: Roger S. McIntyre, Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada. (Email: [email protected])
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Abstract

Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.

Keywords

Major depressive disorderglutamateketamineesketaminerapastinelGABAbrexanoloneSAGE-217inflammationminocyclineopioidsbuprenorphine + samidorphan
Type
CME Review Article
Information
CNS Spectrums , Volume 24 , Issue S1: CME SUPPLEMENT , August 2019 , pp. 25 - 37
Copyright
© Cambridge University Press 2019 

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Footnotes

This activity is supported by an unrestricted educational grant from Sage Therapeutics.

An addendum has been issued for this article, please see DOI: https://doi.org/10.1017/S1092852919001433.

References

References:

World Health Organization. Depression. Published 2017. Accessed December 15, 2018.Google Scholar
Greenberg, PE, Kessler, RC, Birnbaum, HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003; 64(12): 1465–1475.10.4088/JCP.v64n1211CrossRefGoogle ScholarPubMed
Knight, MJ, Baune, BT. Cognitive dysfunction in major depressive disorder. Curr Opin Psychiatry. 2018; 31(1): 26–31.10.1097/YCO.0000000000000378CrossRefGoogle ScholarPubMed
Rush, AJ, Trivedi, MH, Wisniewski, SR, 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(11): 1905–1917.10.1176/ajp.2006.163.11.1905CrossRefGoogle ScholarPubMed
Mrazek, DA, Hornberger, JC, Altar, CA, et al. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. 2014; 65(8): 977–987.10.1176/appi.ps.201300059CrossRefGoogle ScholarPubMed
DiBernardo, A, Lin, X, Zhang, Q, et al. Humanistic outcomes in treatment resistant depression: a secondary analysis of the STAR*D study. BMC Psychiatry. 2018; 18(1): 352.CrossRefGoogle ScholarPubMed
Fostick, L, Silberman, A, Beckman, M, et al. The economic impact of depression: resistance or severity? Eur Neuropsychopharmacol. 2010; 20(10): 671–675.10.1016/j.euroneuro.2010.06.001CrossRefGoogle ScholarPubMed
Evans-Lacko, S, Knapp, M. Global patterns of workplace productivity for people with depression: absenteeism and presenteeism costs across eight diverse countries. Soc Psychiatry Psychiatr Epidemiol. 2016; 51(11): 1525–1537.10.1007/s00127-016-1278-4CrossRefGoogle ScholarPubMed
McIntyre, RS, Suppes, T, Tandon, R, et al. Florida best practice psychotherapeutic medication guidelines for adults with major depressive disorder. J Clin Psychiatry. 2017; 78(6): 703–713.10.4088/JCP.16cs10885CrossRefGoogle ScholarPubMed
Al-Harbi, KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012; 6: 369–388.CrossRefGoogle ScholarPubMed
U.S. Food and Drug Administration. Selective Serotonin Reuptake Inhibitors (SSRIs) Information. Published 2014. Accessed December 15, 2018.Google Scholar
Rosenblat, JD, McIntyre, RS, Alves, GS, et al. Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol. 2015; 13(5): 636–655.10.2174/1570159X13666150630175044CrossRefGoogle ScholarPubMed
Katz, MM, Tekell, JL, Bowden, CL, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology. 2004; 29(3): 566–579.CrossRefGoogle ScholarPubMed
Jick, H, Kaye, JA, Jick, SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004; 292(3): 338–343.CrossRefGoogle ScholarPubMed
Teicher, MH, Glod, CA, Cole, JO. Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf. 1993; 8(3): 186–212.CrossRefGoogle ScholarPubMed
Black, MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology. 2005; 179(1): 154–163.CrossRefGoogle ScholarPubMed
Moriguchi, S, Takamiya, A, Noda, Y, et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry. 2018. doi: 10.1038/s41380-018-0252-9 CrossRefGoogle Scholar
Yuksel, C, Ongur, D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry. 2010; 68(9): 785–794.CrossRefGoogle ScholarPubMed
Pfleiderer, B, Michael, N, Erfurth, A, et al. Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. Psychiatry Res. 2003; 122(3): 185–192.CrossRefGoogle ScholarPubMed
Inoshita, M, Umehara, H, Watanabe, SY, et al. Elevated peripheral blood glutamate levels in major depressive disorder. Neuropsychiatr Dis Treat. 2018; 14: 945–953.CrossRefGoogle ScholarPubMed
Kucukibrahimoglu, E, Saygin, MZ, Caliskan, M, et al. The change in plasma GABA, glutamine and glutamate levels in fluoxetine- or S-citalopram-treated female patients with major depression. Eur J Clin Pharmacol. 2009; 65(6): 571–577.CrossRefGoogle ScholarPubMed
Andreasen, JT, Gynther, M, Rygaard, A, et al. Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests. Neurosci Lett. 2013; 546: 6–10.CrossRefGoogle ScholarPubMed
Gulyaeva, NV. Interplay between brain BDNF and glutamatergic systems: a brief state of the evidence and association with the pathogenesis of depression. BiochemBiokhimiia. 2017; 82(3):301–307.Google ScholarPubMed
Brunoni, AR, Lopes, M, Fregni, F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008; 11(8): 1169–1180.CrossRefGoogle ScholarPubMed
Wilkinson, ST, Toprak, M, Turner, MS, et al. A survey of the clinical, off-label use of ketamine as a treatment for psychiatric disorders. Am J Psychiatry. 2017; 174(7): 695–696.CrossRefGoogle ScholarPubMed
Andrade, C. Ketamine for depression, 4: in what dose, at what rate, by what route, for how long, and at what frequency? J Clin Psychiatry. 2017; 78(7): e852–e857.CrossRefGoogle ScholarPubMed
Hijazi, Y, Boulieu, R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002; 30(7): 853–858.CrossRefGoogle ScholarPubMed
Han, Y, Chen, J, Zou, D, et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat. 2016; 12: 2859–2867.CrossRefGoogle ScholarPubMed
Coyle, CM, Laws, KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015; 30(3): 152–163.CrossRefGoogle ScholarPubMed
Sanacora, G, Schatzberg, AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology. 2015; 40(2): 259–267.CrossRefGoogle ScholarPubMed
Cooper, MD, Rosenblat, JD, Cha, DS, et al. Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review. World J Biol Psychiatry. 2017; 18(6): 410–423.CrossRefGoogle ScholarPubMed
Johnson and Johnson. New Phase 3data show esketamine nasal spray demonstrated rapid improvements in depressive symptoms in patients with treatment-resistant depression. https://www.jnj.com/media-center/press-releases/new-phase-3-data-show-esketamine-nasal-spray-demonstrated-rapid-improvements-in-depressive-symptoms-in-patients-with-treatment-resistant-depression?utm_source=Direct. Published 2018. Accessed December 12, 2018.Google Scholar
Preskorn, S, Macaluso, M, Mehra, DO, et al. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015; 21(2): 140–149.CrossRefGoogle ScholarPubMed
Serafini, G, Howland, RH, Rovedi, F, et al. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 2014; 12(5): 444–461.CrossRefGoogle ScholarPubMed
Williams, NR, Heifets, BD, Blasey, C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018; 175(12): 1205–1215.CrossRefGoogle ScholarPubMed
Janssen Pharmaceutical Companies. Janssen submits esketamine nasal spray new drug application to U.S. FDA fortreatment-resistant depression. https://www.janssen.com/janssen-submits-esketamine-nasal-spray-new-drug-application-us-fda-treatment-resistant-depression. Published 2018. Accessed December 15, 2018.Google Scholar
Daly, EJ, Singh, JB, Fedgchin, M, et al. Efficacy andsafety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018; 75(2): 139–148.CrossRefGoogle Scholar
Food and Drug Administration. Approved risk evaluation and mitigation strategies (REMS) - Spravato (esketamine). https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=386. Published 2019. Accessed 25 April 2019.Google Scholar
Allergan. Allergan’s rapastinel receives FDA breakthrough therapy designation for adjunctive treatment of major depressive disorder (MDD). https://www.allergan.com/news/news/thomson-reuters/allergan-s-rapastinel-receives-fda-breakthrough-th. Published 2016. Accessed December 12, 2018.Google Scholar
Ruhe, HG, Dekker, JJ, Peen, J, et al. Clinical use of the Hamilton Depression Rating Scale: is increased efficiency possible? A post hoc comparison of Hamilton Depression Rating Scale, Maier and Bech subscales, Clinical Global Impression, and Symptom Checklist-90 scores. Compr Psychiatry. 2005; 46(6): 417–427.CrossRefGoogle Scholar
Rajagopal, L, Burgdorf, JS, Moskal, JR, et al. GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav Brain Res. 2016; 299: 105–110.CrossRefGoogle ScholarPubMed
Axsome Therapeutics. Axsome therapeutics receives FDA breakthrough therapy designation for AXS-05 for the treatment of major depressive disorder. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-receives-fda-breakthrough-therapy?field_nir_news_date_value%5bmin%5d=2019. Published 2019. Accessed May 2019.Google Scholar
Nguyen, L, Thomas, KL, Lucke-Wold, BP, et al. Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther. 2016; 159: 1–22.CrossRefGoogle ScholarPubMed
Axsome Therapeutics. Axsome therapeutics announces AXS-05 achieves primary endpoint in Phase 2 trial in major depressive disorder. https://axsometherapeuticsinc.gcs-web.com/news-releases/news-release-details/axsome-therapeutics-announces-axs-05-achieves-primary-endpoint?field_nir_news_date_value[min]=2019. Published 2019. Accessed 25 April 2019.Google Scholar
VistaGen Therapeutics. VistaGen therapeutics initiates Phase 2 study of AV-101 for major depressive disorder. https://ir.vistagen.com/press-releases/detail/87/vistagen-therapeutics-initiates-phase-2-study-of-av-101-for. Published 2018. Accessed December 17, 2018.Google Scholar
Zanos, P, Piantadosi, SC, Wu, HQ, et al. The prodrug 4-Chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/GlycineB-Site inhibition. J Pharmacol Exp Ther. 2015; 355(1): 76–85.CrossRefGoogle Scholar
Allergan. Allergan receives FDA fast track designation for AGN-241751 for the treatment of major depressive disorder (MDD). https://www.allergan.com/News/News/Thomson-Reuters/Allergan-Receives-FDA-Fast-Track-Designation-for-A. Published 2018. Accessed December 10, 2018.Google Scholar
Slattery, DA, Desrayaud, S, Cryan, JF. GABAB receptor antagonist-mediated antidepressant-like behavior is serotonin-dependent. J Pharmacol Exp Ther. 2005; 312(1): 290–296.CrossRefGoogle ScholarPubMed
Suzdak, PD, Gianutsos, G. Parallel changes in the sensitivity of gamma-aminobutyric acid and noradrenergic receptors following chronic administration of antidepressant and GABAergic drugs. A possible role in affective disorders. Neuropharmacology. 1985; 24(3): 217–222.CrossRefGoogle ScholarPubMed
Verkuyl, JM, Hemby, SE, Joels, M. Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. Eur J Neurosci. 2004; 20(6): 1665–1673.CrossRefGoogle ScholarPubMed
Mombereau, C, Kaupmann, K, Gassmann, M, et al. Altered anxiety and depression-related behaviour in mice lacking GABAB(2) receptor subunits. Neuroreport. 2005; 16(3): 307–310.CrossRefGoogle ScholarPubMed
Sanacora, G, Mason, GF, Rothman, DL, et al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry. 2003; 160(3): 577–579.CrossRefGoogle ScholarPubMed
Bhagwagar, Z, Wylezinska, M, Taylor, M, et al. Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry. 2004; 161(2): 368–370.CrossRefGoogle ScholarPubMed
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder.3rd ed.. 2009. http://psychiatryonline.org/guidelinesaspx.Google Scholar
Sequeira, A, Mamdani, F, Ernst, C, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One. 2009; 4(8): e6585.CrossRefGoogle ScholarPubMed
Benasi, G, Guidi, J, Offidani, E, et al. Benzodiazepines as a monotherapy in depressive disorders: a systematic review. Psychother Psychosom. 2018; 87(2): 65–74.CrossRefGoogle ScholarPubMed
Sage Therapeutics. Sage therapeutics announces FDA acceptance of NDA filing and grant of priority review for Brexanolone IV in the treatment of postpartum depression. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-fda-acceptance-nda-filing-and-grant. Published 2018. Accessed January 5, 2019.Google Scholar
Sage Therapeutics. Sage therapeutics announces FDA advisory committee votes 17-1 in support of benefit-risk profile of ZULRESSO™ (brexanolone) injection for treatment of postpartum depression. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-fda-advisory-committee-votes-17-1. Published 2018. Accessed January 5, 2019.Google Scholar
Meltzer-Brody, S, Colquhoun, H, Riesenberg, R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet. 2018; 392(10152): 1058–1070.CrossRefGoogle ScholarPubMed
Martinez Botella, G, Salituro, FG, Harrison, BL, et al. Neuroactive steroids. 2. 3alpha-Hydroxy-3beta-methyl-21-(4-cyano-1H-pyrazol-1’-yl)-19-nor-5beta-pregnan-20-one (SAGE-217): aclinical next generation neuroactive steroid positive allosteric modulator of the (gamma-aminobutyric acid) A receptor. J Med Chem. 2017; 60(18): 7810–7819.CrossRefGoogle Scholar
Sage Therapeutics. Sage announces pivotal phase 3 trial status for SAGE-217 in major depressive disorder and postpartum depression based on FDA breakthrough therapy meeting. https://investor.sagerx.com/news-releases/news-release-details/sage-announces-pivotal-phase-3-trial-status-sage-217-major. Published 2018. Accessed December 1, 2018.Google Scholar
Gunduz-Bruce, H, Riesenberg, R, Sankoh, A, et al. SAGE-217 in subjects with major depressive disorder: efficacy and safety results from open-label Part A of a phase 2A study. Paper presented at: The Meeting of the 30th ECNP Congress; September 2-5, 2017; Paris, France.Google Scholar
Gunduz-Bruce, H, Silber, C, Rothschild, AJ, et al. SAGE-217 in major depressive disorder: a multi-center, randomized, double-blind, phase 2 placebo-controlled trial. Paper presented at: Annual Meeting of the European Congress of Neuropsychopharmacology; October 6–9, 2018; Barcelona, Spain.Google Scholar
Smith, RS. The macrophage theory of depression. Med Hypotheses. 1991;35(4):298–306.CrossRefGoogle ScholarPubMed
Dowlati, Y, Herrmann, N, Swardfager, W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010; 67(5): 446–457.CrossRefGoogle ScholarPubMed
Strawbridge, R, Hodsoll, J, Powell, TR, et al. Inflammatory profiles of severe treatment-resistant depression. J Affect Disord. 2018; 246: 42–51.CrossRefGoogle ScholarPubMed
O’Donovan, A, Rush, G, Hoatam, G, et al. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety. 2013; 30(4): 307–314.CrossRefGoogle ScholarPubMed
McAfoose, J, Baune, BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev. 2009; 33(3): 355–366.CrossRefGoogle ScholarPubMed
Pan, Z, Park, C, Brietzke, E, et al. Cognitive impairment in major depressive disorder. CNS Spectr. 2019; 24(1): 22–29.CrossRefGoogle ScholarPubMed
Felger, JC, Lotrich, FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013; 246: 199–229.CrossRefGoogle ScholarPubMed
Food and Drug Administration. Minocin minocycline for injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050444s049lbl.pdf. Accessed December 2, 2018.Google Scholar
Langevitz, P, Livneh, A, Bank, I, et al. Benefits and risks of minocycline in rheumatoid arthritis. Drug Saf. 2000; 22(5): 405–414.CrossRefGoogle ScholarPubMed
Rosenblat, JD, McIntyre, RS. Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord. 2018; 227: 219–225.CrossRefGoogle ScholarPubMed
Levkovitz, Y, Mendlovich, S, Riwkes, S, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry. 2010; 71(2): 138–149.CrossRefGoogle ScholarPubMed
Krogh, J, Benros, ME, Jorgensen, MB, et al. The association between depressive symptoms, cognitive function, and inflammation in major depression. Brain Behav Immun. 2014; 35: 70–76.CrossRefGoogle ScholarPubMed
Le Merrer, J, Becker, JA, Befort, K, et al. Reward processing by the opioid system in the brain. Physiol Rev. 2009; 89(4): 1379–1412.CrossRefGoogle Scholar
Holden, JE, Jeong, Y, Forrest, JM. The endogenous opioid system and clinical pain management. AACN Clin Issues. 2005; 16(3): 291–301.CrossRefGoogle ScholarPubMed
Kreek, MJ. Opiates, opioids and addiction. Mol Psychiatry. 1996; 1(3): 232–254.Google ScholarPubMed
Pecina, M, Karp, JF, Mathew, S, et al. Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches. Mol Psychiatry. 2018; 24(4): 576–587.CrossRefGoogle ScholarPubMed
Garfield, JBB, Cotton, SM, Allen, NB, et al. Evidence that anhedonia is a symptom of opioid dependence associated with recent use. Drug Alcohol Depend. 2017; 177: 29–38.CrossRefGoogle ScholarPubMed
Schreiber, S, Bleich, A, Pick, CG. Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects – a possible opioid involvement in severe depression? J Mol Neurosci. 2002; 18(1–2): 143–149.CrossRefGoogle ScholarPubMed
Tenore, PL. Psychotherapeutic benefits of opioid agonist therapy. J Addict Dis. 2008; 27(3): 49–65.CrossRefGoogle ScholarPubMed
Jordan, MR, Morrisonponce, D. Naloxone. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2019.Google ScholarPubMed
Turncliff, R, DiPetrillo, L, Silverman, B, et al. Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers. Clin Ther. 2015; 37(2): 338–348.CrossRefGoogle ScholarPubMed
Harrison, C. Trial watch: opioid receptor blocker shows promise in Phase II depression trial. Nat Rev Drug Discov. 2013; 12(6): 415.CrossRefGoogle ScholarPubMed
Alkermes. Alkermes reports on outcome of FDA advisory committee meeting on ALKS 5461 for the adjunctive treatment of major depressive disorder. http://phx.corporate-ir.net/phoenix.zhtml?c=92211&p=irol-corporateNewsArticle&ID=2375026. Published 2018. Accessed December 1, 2018.Google Scholar
Alkermes. Alkermes receives complete response letter from U.S. Food and Drug Administration for ALKS 5461 new drug application. http://phx.corporate-ir.net/phoenix.zhtml?c=92211&p=irol-newsArticle&ID=2385782. Published 2019. Accessed April 2019.Google Scholar
Ehrich, E, Turncliff, R, Du, Y, et al. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacology. 2015; 40(6): 1448–1455.CrossRefGoogle ScholarPubMed
Ragguett, RM, Rong, C, Rosenblat, JD, et al. Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder. Expert Opin Drug Metab Toxicol. 2018; 14(4): 475–482.CrossRefGoogle ScholarPubMed
Picard, N, Cresteil, T, Djebli, N, et al. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug MetabDispos. 2005; 33(5): 689–695.Google ScholarPubMed
Alkermes. ALKS 5461: FORWARD-3 and FORWARD-4. Paper presented at: American Society of Clinical Psychopharmacology Annual Meeting; June 1 2016.Google Scholar
Fava, M, Thase, ME, Trivedi, MH, et al. Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies. MolPsychiatry. 2018. doi: 10.1038/s41380-018-0284-1 CrossRefGoogle Scholar
Adler, DA, McLaughlin, TJ, Rogers, WH, et al. Job performance deficits due to depression. Am J Psychiatry. 2006; 163(9): 1569–1576.CrossRefGoogle ScholarPubMed