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Buprenorphine and samidorphan.svg
Buprenorphine (top) + samidorphan (bottom)
Combination of
Buprenorphine Opioid modulator
Samidorphan Opioid antagonist
Clinical data
Routes of
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Buprenorphine/samidorphan (developmental code name ALKS-5461) is a combination drug formulation of buprenorphine and samidorphan acting as a κ-opioid receptor (KOR) antagonist which is under development by Alkermes as an adjunct to antidepressant therapy in treatment-resistant depression (TRD).[1][2] It is also under investigation by Alkermes as a treatment for cocaine dependence, which is being funded by a grant from the National Institute on Drug Abuse (NIDA).[3]

Clinical results with ALKS-5461 in Phase II have been described as "very encouraging", and researchers have stated that KOR antagonists including ALKS-5461 might work "extremely well for the treatment of major depression."[4][5] However, data from two of three core Phase III trials was recently released and revealed that ALKS-5461 was safe and well-tolerated but, disappointingly, failed to meet its primary efficacy endpoints, although some efficacy was observed.[6][7][8][9] The third and final core Phase III study is currently ongoing, with results expected sometime in 2016.

As of March 2016, results of FORWARD-5 trial are reportedly expected by Q4 2016. Also, failures of endpoint efficacy goals in FORWARD 3 & 4 Phase III clinical trials; were analyzed and found to be unreliable based on a usually strong placebo effect. In addition, near-efficacious results were received using higher dosages only, indicating that ALKS-5641 will only be effective in higher than initially expected doses. No clinically relevant side effects were reported with the higher dosage trials.[6][7][8][9]

On 20 October 2016, it was announced that ALKS-5461 met its primary endpoint on the final core phase III clinical study, FORWARD-5.[10][11]


Following very positive phase II trial results, ALKS-5461 was granted Fast Track Designation by the Food and Drug Administration (FDA) for TRD in October 2013.[12][13] During June and July 2014, three major phase III clinical trials were initiated in the United States to evaluate core efficacy for the use of ALKS-5461 as an adjunctive treatment for patients who have had an inadequate treatment response to antidepressant monotherapy with an agent such as a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).[1][2][14] Results of these trials are expected in 2016.[1][14] In addition to these trials, nine smaller supplementary studies will also be conducted, and will together conclude phase III research.[1] In January 2015, Alkermes announced positive results from FORWARD-1, the first completed phase III study.[15]

Alkermes has expressed its intent to submit a New Drug Application (NDA) to the FDA for the approval of adjunctive ALKS-5461 for the indication of TRD once phase III research has been completed.[1] Assuming positive phase III trial results and NDA acceptance, initial sales of ALKS-5461 are forecast for 2016, with $25 million in sales estimated for that year and $350 million in total sales anticipated by 2019.[16] Alkermes is looking to out-license ALKS-5461.[16]

In December 2015, Alkermes revealed that the development schedule of ALKS-5461 is still on-track and data from the first two phase III core efficacy studies was to be expected in quarter I 2016 while the data from the third and final core efficacy study is to be expected in mid-2016.[17] Negative results from the pivotal FORWARD-3 and FORWARD-4 studies were announced in late January 2016.[18] None of the dosages of ALKS-5461 (0.5 mg/day and 2 mg/day) met the FORWARD studies' primary endpoint, which was the change from baseline vs. placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS). The FORWARD-5 study remains ongoing, and Alkermes will provide an update on the timing of study completion in the first quarter of 2016.


ALKS-5461 is a (1:1 ratio) combination of: (1) buprenorphine, a weak partial agonist of the μ-opioid receptor (MOR), antagonist/very weak partial agonist of the κ-opioid receptor (KOR), and, to a lesser extent, antagonist of the δ-opioid receptor (DOR) and weak partial agonist of the nociceptin receptor (NOP);[19][20][21][22] and (2) samidorphan, a preferential antagonist of the MOR (but also, to a slightly lesser extent, weak partial agonist of the KOR and DOR).[23][24][25][26] The combination of these two drugs putatively results in what is functionally a blockade of KORs with negligible activation of MORs.[21][24]

Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins,[27] induce dysphoria and stress-like responses in both animals and humans,[28] as well as psychotomimetic effects in humans,[29][30] and are thought to be essential for the mediation of the dysphoric aspects of stress.[31] In addition, dynorphins are believed to be critically involved in producing the changes in neuroplasticity evoked by chronic stress that lead to the development of depressive and anxiety disorders, increased drug-seeking behavior, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.[27][31][32] In support of this, in knockout mice lacking the genes encoding the KOR and/or prodynorphin (the endogenous precursor of the dynorphins), many of the usual effects of exposure to chronic stress are completely absent, such as increased immobility in the forced swimming test (a widely employed assay of depressive-like behavior) and increased conditioned place preference for cocaine (a measure of the rewarding properties and addictive susceptibility to cocaine).[33] Accordingly, KOR antagonists show robust efficacy in animal models of depression, anxiety, anhedonia, drug addiction, and other stress-related behavioral and physiological abnormalities.[27][28][34][35] As such, there has been great interest in developing KOR antagonists for the treatment of these and other psychiatric conditions in humans.[27][34] Progress has been limited until recently however, due to difficulty in finding selective KOR antagonists with suitable drug profiles (e.g., good pharmacokinetic parameters, short-acting (non-"inactivating") KOR inhibition, lack of toxicity, etc.) for clinical development and use in humans.[28][34]

It has been known since the 1980s that buprenorphine binds to at high affinity and antagonizes the KOR.[36][37] In addition, there have been many reports over the years supporting the notion of the drug being effective in the management of depressive and anxious symptomatology, and two small clinical trials have shown it to produce remission even in depressive patients refractory to conventional antidepressants and electroconvulsive therapy.[27][38][39][40][41][42][43][44][45][46][47][48] However, buprenorphine has never previously been seriously pursued for mental health indications, presumably due to concerns about its liability for abuse and dependence (and the additional difficulty in gaining regulatory approval that would certainly come with that).[49] In conjunction with samidorphan, as in ALKS-5461, however, its potential for abuse and dependence has been shown to be effectively abolished.[17][50] As a result, it seems that ALKS-5461 may allow for buprenorphine to be employed safely and without restriction in the treatment of depression and other conditions that it has shown efficaciousness in but that it would otherwise very likely not be employed in.

A mouse study found that knockout of the MOR or DOR or selective pharmacological ablation of the NOP did not affect the antidepressant-like effects of buprenorphine, whereas knockout of the KOR abolished the antidepressant-like effects of the drug, supporting the notion that the antidepressant-like effects of buprenorphine are indeed mediated by modulation of the KOR by the drug (and not of the MOR, DOR, or NOP).[51]

As described above, buprenorphine is not actually a silent antagonist of the KOR but rather a weak partial agonist.[52][53] In vitro, it has shown some activation of the KOR at concentrations of ≥ 100 nM, with an Emax of 22% at 30 µM; no plateau in maximal response (EC50) was observed at concentrations up to 30 µM.[53] Samidorphan similarly shows activation of the KOR in vitro, but to an even greater extent, with an EC50 of 3.3 nM and an Emax of 36%.[25][26] According to Alkermes researchers:[52]

In addition to its effects on μ-opioid receptors, buprenorphine has also been shown in vivo to block the action of κ-opioid agonists (21) and has been characterized in vitro to be a partial κ agonist with low intrinsic activity (19). The buprenorphine/samidorphan combination results in high affinity binding with net low intrinsic activity at both μ- and κ-opioid receptors. It is hypothesized that the combination serves to decrease or dampen opioid tone in regions of excess endogenous μ- and κ-opioid ligand activity and restore opioid tone in regions where such activity is impaired.

As such, ALKS-5461 may actually possess both antagonistic and agonistic potential at the KOR.[52] However, as antagonism of the KOR seems to be responsible for the antidepressant effects of ALKS-5461, this property could in theory actually serve to limit the effectiveness of ALKS-5461 in the treatment of depression.[51][54] This might explain the finding that a lower dose of ALKS-5461 (2 mg/2 mg) was more effective in the treatment of depression than a higher dose (8 mg/8 mg) (which failed to separate from placebo) in a phase II clinical trial, for instance.[52] In light of the aforementioned, it is noteworthy that a silent antagonist of the KOR, CERC-501 (LY-2456302), which also happens to have far improved selectivity for the KOR (30-fold relative to other opioid receptors) relative to ALKS-5461, is in clinical development for the treatment of depression and cocaine dependence as well.[28][34]


In phase I and phase II trials, augmentation of an SSRI or SNRI with ALKS-5461 demonstrated a rapid onset of action and substantial effectiveness in the adjunctive treatment of TRD.[55] Therapeutic responses were observed by day seven of treatment,[55] and 35–50% of patients achieved remission by the collective phase I and II trial endpoints.[2] In addition, a relatively small set of 32 patients but nonetheless high quality (i.e., double-blind, placebo-controlled, etc.) phase I/II trial showed a remarkable 100% of patients (32/32) experiencing a significant antidepressant response.[56]

Based on the above findings, compared to most currently available antidepressant monotherapies, which generally require several weeks of treatment for a significant therapeutic response to be seen and have significantly lower comparative response and remission rates (which are approximately 50–70% and 20–50%, respectively),[57][58] adjunctive ALKS-5461 could prove to be advantageous in many regards.[50][59] In addition, vilazodone (Viibryd), a relatively new antidepressant, was recently approved by the FDA with two positive phase III trials showing Montgomery–Åsberg Depression Rating Scale (MADRS) score decreases of 3.2 and 2.5 points in depressive symptomatology as verification of its effectiveness in major depressive disorder (MDD); in comparison, treatment with ALKS-5461 as an adjunct to an SSRI or SNRI in a phase II trial for TRD demonstrated MADRS score decreases of 5.3 and 8.7 points for a low-dose (2 mg/day) and a high-dose (8 mg/day) formulation of the drug, respectively.[50] These differences are approximately two- to three-fold higher than those of vilazodone monotherapy, suggesting that adjunctive ALKS-5461 could possess substantially greater effectiveness in comparison.[50]

On 21 January 2016, data from two of three core Phase III trials was released.[6][7][8][9] The two trials, which each studied the drug at dosages including 0.5 mg/day and 2 mg/day, failed to meet their primary efficacy endpoints.[6][7][8][9] However, there was a clear trend towards efficacy for 2 mg/day (but not 0.5 mg/day) on the primary endpoint of one of the trials (FORWARD-4), as well as statistically significant efficacy on the MADRS endpoint in post hoc analyses of that trial.[6][7][8][9] In addition, the placebo response was unusually high in the other trial (FORWARD-3), potentially confounding results.[60] Moreover, Phase II studies investigated ALKS-5461 at dosages of 2 mg/day and 8 mg/day (and notably not 0.5 mg/day) and found effectiveness with both dosages but significantly greater improvement with the 8 mg/day dose (5.3- and 8.7-point MADRS score decreases for 2 mg/day and 8 mg/day, respectively), suggesting that higher dosages of ALKS-5461 might demonstrate more marked effectiveness.[50] Alkermes has expressed that it fully intends to continue development and seek FDA approval for ALKS-5461, with the third of the core Phase III studies, FORWARD-5 (which is assessing dosages of 1 mg/day and 2 mg/day), yet-to-be-completed.[61] In addition, Alkermes may decide to investigate ALKS-5461 at a higher dosage again, such as 8 mg/day, in a Phase III trial.[62]

Side effects[edit]

In the clinical trials conducted thus far, ALKS-5461 has been found to be generally well-tolerated, with the adverse effects seen including nausea, vomiting, headaches, sedation, and dizziness.[55][63] These side effects are generally transient, being experienced commonly upon initiation of treatment but lessening or disappearing with continued use.[55][63] The most common side effects observed in phase III trials thus far have been nausea, headache, dizziness, constipation, and dry mouth.[15][60]


A small clinical study found that pentazocine, a KOR agonist, was able to rapidly and substantially reduce symptoms of mania in individuals with bipolar disorder that were in the manic phase of the condition.[64] It has been postulated that the efficacy observed was due to KOR activation-mediated amelioration of hyperdopaminergia in the reward pathways.[64] As such, similarly to other antidepressants,[65] ALKS-5461 might be able to precipitate or worsen manic states in individuals with bipolar disorder or cause a switch from depressive state to manic state. Potentially in accordance, a case report of buprenorphine-induced hypomania exists.[66] Hence, caution might be warranted in the use of ALKS-5461 in people with bipolar illness.

Due to occupation and antagonism of the MOR by ALKS-5461, an anticipatable drug interaction between ALKS-5461 and opioid analgesics may exist in that the effects of the latter may be significantly reduced or possibly abolished, and hence ALKS-5461 may prove contraindicated in patients who require opioid analgesics for pain management.

Abuse potential[edit]

A phase III human abuse potential study found that all dosages of ALKS-5461 tested did not share the abuse potential of buprenorphine, and no difference in drug liking for ALKS-5461 was observed relative to placebo.[17]

See also[edit]


  1. ^ a b c d e Alkermes (2014). "Alkermes Announces Initiation of FORWARD-3 and FORWARD-4 Efficacy Studies in Pivotal Program for ALKS 5461 for Treatment of Major Depressive Disorder". 
  2. ^ a b c Alkermes (2014). "Alkermes Announces Advances With Its Late-Stage CNS Pipeline". 
  3. ^ Reuters (2012). "Alkermes Presents Positive Clinical Data of ALKS 5461 at 52nd Annual New Clinical Drug Evaluation Unit Meeting". 
  4. ^ Dale, Elena; Bang-Andersen, Benny; Sánchez, Connie (2015). "Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs". Biochemical Pharmacology. 95 (2): 81–97. doi:10.1016/j.bcp.2015.03.011. ISSN 0006-2952. PMID 25813654. 
  5. ^ Dogra, Shalini; Yadav, Prem N. (2015). "Biased agonism at kappa opioid receptors: Implication in pain and mood disorders". European Journal of Pharmacology. 763: 184–190. doi:10.1016/j.ejphar.2015.07.018. ISSN 0014-2999. 
  6. ^ a b c d e Anne Steele (21 January 2016). "Alkermes Depression Drug Disappoints in Trials". WSJ. Retrieved 21 January 2016. 
  7. ^ a b c d e Emma Court. "Alkermes shares plunge after drug misses trial goals". MarketWatch. Retrieved 21 January 2016. 
  8. ^ a b c d e Amrutha Penumudi (21 January 2016). "Alkermes depression drug fails in studies, shares plunge". Reuters. Retrieved 21 January 2016. 
  9. ^ a b c d e Rebecca Spalding (21 January 2016). "Alkermes Falls Most Since 2002 as Depression Drug Trials Fail". Bloomberg.com. Retrieved 21 January 2016. 
  10. ^ "Alkermes Announces Positive Topline Results From FORWARD-5 Pivotal Phase 3 Study of ALKS 5461 for Major Depressive Disorder". BusinessWire. 21 October 2016. Retrieved 21 October 2016. 
  11. ^ David Holley (20 October 2016). "Alkermes Eyes FDA Nod After Retooled Study Yields Desired Results". Xconomy. Retrieved 21 October 2016. 
  12. ^ PR Newswire (2014). "ALKS-5461 (Major Depressive Disorder) - Forecast and Market Analysis to 2023". 
  13. ^ Business Wire (2013). "Alkermes Receives Fast Track Designation for ALKS 5461 for Major Depressive Disorder". 
  14. ^ a b Digital Journal (2014). "Alkermes Announces Initiation of FORWARD-5 Clinical Study of ALKS 5461 For Treatment of Major Depressive Disorder". 
  15. ^ a b Alkermes (2015). "Alkermes Announces Positive Results From Study of ALKS 5461 for Treatment of Major Depressive Disorder". 
  16. ^ a b D'Souza P, Jago C (March 2014). "Spotlight on depression: a Pharma Matters report" (PDF). Drugs Today. 50 (3): 251–67. doi:10.1358/dot.2014.50.3.2134450. PMID 24696870. 
  17. ^ a b c Business Wire (2015). "Alkermes Announces Achievement of Milestones for CNS Medicines in Proprietary Product and Pipeline Portfolio". 
  18. ^ "Alkermes PLC > Investor Relations > Press Release". phx.corporate-ir.net (Press release). Retrieved 2016-01-21. 
  19. ^ Kress HG (March 2009). "Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine". Eur J Pain. 13 (3): 219–30. doi:10.1016/j.ejpain.2008.04.011. PMID 18567516. 
  20. ^ Lutfy K, Cowan A (October 2004). "Buprenorphine: a unique drug with complex pharmacology". Curr Neuropharmacol. 2 (4): 395–402. doi:10.2174/1570159043359477. PMC 2581407free to read. PMID 18997874. 
  21. ^ a b Ehrich, Elliot; Turncliff, Ryan; Du, Yangchun; Leigh-Pemberton, Richard; Fernandez, Emilio; Jones, Reese; Fava, Maurizio (2014). "Evaluation of Opioid Modulation in Major Depressive Disorder". Neuropsychopharmacology. doi:10.1038/npp.2014.330. ISSN 0893-133X. 
  22. ^ Khroyan TV, Wu J, Polgar WE, et al. (June 2014). "BU08073 a Buprenorphine Analog with Partial Agonist Activity at mu Receptors in vitro but Long-Lasting Opioid Antagonist Activity in vivo in Mice". Br. J. Pharmacol. 172 (2): 668–680. doi:10.1111/bph.12796. PMC 4292977free to read. PMID 24903063. 
  23. ^ Almarsson, O., Deaver, D., Turncliff, R., Wentland, M., & Ehrich, E. (2010). Discovery and early development of ALKS-33, an opioid modulator for treatment of reward disorders. Abstracts Of Papers Of The American Chemical Society, 240
  24. ^ a b Rorick-Kehn LM, Witkin JM, Statnick MA, et al. (February 2014). "LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders". Neuropharmacology. 77: 131–44. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566. 
  25. ^ a b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4. 
  26. ^ a b Wentland, Mark P.; Lou, Rongliang; Lu, Qun; Bu, Yigong; Denhardt, Christoph; Jin, Jin; Ganorkar, Rakesh; VanAlstine, Melissa A.; Guo, Chengyun; Cohen, Dana J.; Bidlack, Jean M. (2009). "Syntheses of novel high affinity ligands for opioid receptors". Bioorganic & Medicinal Chemistry Letters. 19 (8): 2289–2294. doi:10.1016/j.bmcl.2009.02.078. ISSN 0960-894X. 
  27. ^ a b c d e Shippenberg TS (January 2009). "The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?". Neuropsychopharmacology. 34 (1): 247. doi:10.1038/npp.2008.165. PMID 19079072. 
  28. ^ a b c d Zoran Rankovic; Richard Hargreaves; Matilda Bingham (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6. 
  29. ^ Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). "Psychotomimesis mediated by kappa opiate receptors". Science. 233 (4765): 774–6. doi:10.1126/science.3016896. PMID 3016896. 
  30. ^ Yan F, Roth BL (October 2004). "Salvinorin A: a novel and highly selective kappa-opioid receptor agonist". Life Sci. 75 (22): 2615–9. doi:10.1016/j.lfs.2004.07.008. PMID 15369697. 
  31. ^ a b Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". J. Neurosci. 28 (2): 407–14. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708free to read. PMID 18184783. 
  32. ^ Knoll AT, Carlezon WA (February 2010). "Dynorphin, stress, and depression". Brain Res. 1314: 56–73. doi:10.1016/j.brainres.2009.09.074. PMC 2819644free to read. PMID 19782055. 
  33. ^ McLaughlin JP, Marton-Popovici M, Chavkin C (July 2003). "Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses". J. Neurosci. 23 (13): 5674–83. PMC 2104777free to read. PMID 12843270. 
  34. ^ a b c d Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494. 
  35. ^ Carlezon WA, Béguin C, Knoll AT, Cohen BM (September 2009). "Kappa-opioid ligands in the study and treatment of mood disorders". Pharmacol. Ther. 123 (3): 334–43. doi:10.1016/j.pharmthera.2009.05.008. PMC 2740476free to read. PMID 19497337. 
  36. ^ Su TP (January 1985). "Further demonstration of kappa opioid binding sites in the brain: evidence for heterogeneity". J. Pharmacol. Exp. Ther. 232 (1): 144–8. PMID 2856939. 
  37. ^ Leander JD (September 1987). "Buprenorphine has potent kappa opioid receptor antagonist activity". Neuropharmacology. 26 (9): 1445–7. doi:10.1016/0028-3908(87)90112-2. PMID 2823167. 
  38. ^ Emrich HM, Vogt P, Herz A, Kissling W (September 1982). "Antidepressant effects of buprenorphine". Lancet. 2 (8300): 709. doi:10.1016/s0140-6736(82)90727-9. PMID 6126640. 
  39. ^ Emrich HM, Vogt P, Herz A (1982). "Possible antidepressive effects of opioids: action of buprenorphine". Ann. N. Y. Acad. Sci. 398: 108–12. doi:10.1111/j.1749-6632.1982.tb39483.x. PMID 6760767. 
  40. ^ Emrich HM (1984). "Endorphins in psychiatry". Psychiatr Dev. 2 (2): 97–114. PMID 6091098. 
  41. ^ Mongan L, Callaway E (December 1990). "Buprenorphine responders". Biol. Psychiatry. 28 (12): 1078–80. doi:10.1016/0006-3223(90)90619-d. PMID 2289007. 
  42. ^ Kosten TR, Morgan C, Kosten TA (1990). "Depressive symptoms during buprenorphine treatment of opioid abusers". J Subst Abuse Treat. 7 (1): 51–4. doi:10.1016/0740-5472(90)90035-o. PMID 2313769. 
  43. ^ Bodkin JA, Zornberg GL, Lukas SE, Cole JO (February 1995). "Buprenorphine treatment of refractory depression". J Clin Psychopharmacol. 15 (1): 49–57. doi:10.1097/00004714-199502000-00008. PMID 7714228. 
  44. ^ Dean AJ, Bell J, Christie MJ, Mattick RP (December 2004). "Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence". Eur. Psychiatry. 19 (8): 510–3. doi:10.1016/j.eurpsy.2004.09.002. PMID 15589713. 
  45. ^ Gerra G, Leonardi C, D'Amore A, et al. (March 2006). "Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study". Prog. Neuropsychopharmacol. Biol. Psychiatry. 30 (2): 265–72. doi:10.1016/j.pnpbp.2005.10.007. PMID 16309810. 
  46. ^ Nyhuis PW, Gastpar M (2005). "Opiate treatment in ECT-resistant depression". Pharmacopsychiatry. 38 (5). doi:10.1055/s-2005-918797. 
  47. ^ Nyhuis PW, Specka M, Gastpar M (2006). "Does the antidepressive response to opiate treatment describe a subtype of depression?". European Neuropsychopharmacology. 16 (S16): S309. doi:10.1016/S0924-977X(06)70328-5. 
  48. ^ Nyhuis PW, Gastpar M, Scherbaum N (October 2008). "Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy". J Clin Psychopharmacol. 28 (5): 593–5. doi:10.1097/JCP.0b013e31818638a4. PMID 18794671. 
  49. ^ Van’t Veer, Ashlee; Carlezon, William A. (2013). "Role of kappa-opioid receptors in stress and anxiety-related behavior". Psychopharmacology. 229 (3): 435–452. doi:10.1007/s00213-013-3195-5. ISSN 0033-3158. 
  50. ^ a b c d e Xconomy (2013). "Alkermes Unveils Full Mid-Stage Data On Depression Drug". 
  51. ^ a b Falcon, Edgardo; Browne, Caroline A; Leon, Rosa M; Fleites, Vanessa C; Sweeney, Rachel; Kirby, Lynn G; Lucki, Irwin (2016). "Antidepressant-Like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors". Neuropsychopharmacology. doi:10.1038/npp.2016.38. ISSN 0893-133X. 
  52. ^ a b c d Fava, Maurizio; Memisoglu, Asli; Thase, Michael E.; Bodkin, J. Alexander; Trivedi, Madhukar H.; de Somer, Marc; Du, Yangchun; Leigh-Pemberton, Richard; DiPetrillo, Lauren; Silverman, Bernard; Ehrich, Elliot (2016). "Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial". American Journal of Psychiatry: appi.ajp.2015.1. doi:10.1176/appi.ajp.2015.15070921. ISSN 0002-953X. 
  53. ^ a b Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY (1997). "Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands". J. Pharmacol. Exp. Ther. 282 (2): 676–84. PMID 9262330. 
  54. ^ Falcon, Edgardo; Maier, Kaitlyn; Robinson, Shivon A.; Hill-Smith, Tiffany E.; Lucki, Irwin (2014). "Effects of buprenorphine on behavioral tests for antidepressant and anxiolytic drugs in mice". Psychopharmacology. 232 (5): 907–915. doi:10.1007/s00213-014-3723-y. ISSN 0033-3158. 
  55. ^ a b c d Alkermes (2013). "Alkermes Presents Positive Results from Phase 2 Clinical Study of ALKS 5461 in Major Depressive Disorder at 53rd Annual NCDEU Meeting". 
  56. ^ Fox News (2012). "Non-addictive, 'heroin-like' medicine may soon crush major depression". 
  57. ^ Ferrier IN (1999). "Treatment of major depression: is improvement enough?". J Clin Psychiatry. 60 Suppl 6: 10–4. PMID 10235119. 
  58. ^ McIntyre RS, O'Donovan C (March 2004). "The human cost of not achieving full remission in depression". Can J Psychiatry. 49 (3 Suppl 1): 10S–16S. PMID 15147032. 
  59. ^ Xconomy (2013). "Alkermes Stock Climbs on Positive Trial for Depression Drug". 
  60. ^ a b StreetInsider (21 January 2016). "Alkermes' (ALKS) Two Phase 3 Studies of ALKS 5461 in MDD Failed to Meet Primary Efficacy Endpoint". Retrieved 30 January 2016. 
  61. ^ 24/7 Wall St. (21 January 2016). "Why Alkermes Top-Line Results Might Not Be as Bad as Once Thought". Retrieved 30 January 2016. 
  62. ^ Daniel Chancellor (22 January 2016). "Alkermes is unlikely to resuscitate ALKS 5461 and must instead redefine its strategy". Datamonitor Healthcare. Retrieved 30 January 2016. 
  63. ^ a b "Abstracts of Poster Presentations: CNS Summit 2013". 2013. 
  64. ^ a b Chartoff, Elena H.; Mavrikaki, Maria (2015). "Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction". Frontiers in Neuroscience. 9. doi:10.3389/fnins.2015.00466. ISSN 1662-453X. 
  65. ^ McInerney, Shane J.; Kennedy, Sidney H. (2014). "Review of Evidence for Use of Antidepressants in Bipolar Depression". The Primary Care Companion For CNS Disorders. doi:10.4088/PCC.14r01653. ISSN 2155-7780. 
  66. ^ "Possible manic potential of buprenorphine". Australian and New Zealand Journal of Psychiatry. 38 (7): 560–561. 2004. doi:10.1080/j.1440-1614.2004.01411.x. ISSN 0004-8674. 

Further reading[edit]

External links[edit]