Advertisement

Potential Novel Treatments in Bipolar Depression

  • Rodrigo Machado-VieiraEmail author
  • Ioline D. Henter
  • Husseini K. Manji
  • Carlos A. ZarateJr.
Chapter
Part of the Milestones in Drug Therapy book series (MDT)

Abstract

Currently available therapeutics for bipolar disorder (BD)—and bipolar depression in particular—are scarce and often ineffective. This is particularly troubling because the long-term course of bipolar depression comprises recurrent depressive episodes and persistent residual symptoms. Glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders, as well as in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the glutamatergic modulator ketamine were first observed, similar agents have been studied in both major depressive disorder (MDD) and BD. This chapter reviews the clinical and preclinical evidence supporting the use of novel glutamate receptor modulators for the treatment of bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics. The chapter discusses several specific agents, including N-acetyl cysteine (NAC), scopolamine, biperiden, agomelatine, riluzole, ketamine, memantine, creatine, metyrapone, ketoconazole, mifepristone, and celecoxib. Non-pharmacological somatic treatments are not reviewed.

Keywords

Antidepressant Bipolar disorder Cholinergic Depression Dopamine Glutamate Melatonin Oxidative stress Treatment 

Notes

Acknowledgments

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health and National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927). A patent for the use of ketamine in depression has been awarded that lists Drs. Zarate and Manji among the inventors. Dr. Zarate has assigned his rights on the patent to the US government, but will share a percentage of any royalties that may be received by the government. Dr. Manji has also assigned his rights on the patent to the US government, and has waived his personal rights to this patent and will not receive any direct financial benefit therefrom. Dr. Manji is a full-time employee of Janssen Research & Development, LLC. The remaining authors have no conflicts of interest to disclose, financial or otherwise.

References

  1. aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ (2010) Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67(2):139–145PubMedCrossRefGoogle Scholar
  2. Aguado L, San Antonio A, Perez L, del Valle R, Gomez J (1994) Effects of the NMDA receptor antagonist ketamine on flavor memory: conditioned aversion, latent inhibition, and habituation of neophobia. Behav Neural Biol 61(3):271–281PubMedCrossRefGoogle Scholar
  3. Ahn YM, Chang J, Joo YH, Kim SC, Lee KY (2008) Chronotype distribution in bipolar I disorder and schizophrenia in a Korean sample. Bipolar Disord 10:271–275PubMedCrossRefGoogle Scholar
  4. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, Mohebbi-Rasa S, Raznahan M, Kamalipour A (2009) Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 26:607–611PubMedCrossRefGoogle Scholar
  5. Alaerts M, Venken T, Lenaerts AS, De Zutter S, Norrback KF, Adolfsson R, Del-Favero J (2006) Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population. Psychiatr Genet 16(6):235–236PubMedCrossRefGoogle Scholar
  6. Amital D, Vishne T, Rubinow A, Levine J (2006) Observed effects of creatine monohydrate in a patient with depression and fibromyalgia. Am J Psychiatry 163:1840–1841PubMedCrossRefGoogle Scholar
  7. Anand A, Gunn AD, Barkay G, Karne HS, Nurnberger JI, Mathew SJ, Ghosh S (2012) Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord 14(1):64–70PubMedCrossRefGoogle Scholar
  8. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, Cunha AB, Cereser KM, Santin A, Gottfried C, Salvador M, Kapczinski F, Goncalves CA (2007) Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 41(6):523–529PubMedCrossRefGoogle Scholar
  9. Assis LC, Rezin GT, Comim CM, Valvassori SS, Jeremias IC, Zugno AI, Quevedo J, Streck EL (2009) Effect of acute administration of ketamine and imipramine on creatine kinase activity in the brain of rats. Rev Bras Psiquiatr 31:247–252PubMedCrossRefGoogle Scholar
  10. Ballard ED, Ionescu DF, Vande Voort JL, Niciu MJ, Richards EM, Luckenbaugh DA, Brutsche NE, Ameli R, Furey ML, Zarate CA Jr (2014) Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res 58:161–166PubMedCrossRefGoogle Scholar
  11. Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL, Sanacora G (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15:501–511PubMedCrossRefGoogle Scholar
  12. Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, Schatzberg AF (2002) An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 52(5):386–392PubMedCrossRefGoogle Scholar
  13. Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI (2008) N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry 64(6):468–475PubMedCrossRefGoogle Scholar
  14. Berk M, Dean O, Cotton SM, Gama CS, Kapczinski F, Fernandes BS, Kohlmann K, Jeavons S, Hewitt K, Allwang C, Cobb H, Bush AI, Schapkaitz I, Dodd S, Malhi GS (2011) The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: An open label trial. J Affect Disord 135(1–3):389–394PubMedCrossRefGoogle Scholar
  15. Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kohlmann K, Hewitt K (2014) The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 75:628–636PubMedCrossRefGoogle Scholar
  16. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354PubMedCrossRefGoogle Scholar
  17. Bersani G, Garavani A (2000) Melatonin add-on in manic patients with treatment resistant insomnia. Biol Psychiatry 24:185–191Google Scholar
  18. Bertaina-Anglade V, la Rochelle CD, Boyer PA, Mocaer E (2006) Antidepressant-like effects of agomelatine (S 20098) in the learned helplessness model. Behav Pharmacol 17(8):703–713PubMedCrossRefGoogle Scholar
  19. Betin C, DeFeudis FV, Blavet N, Clostre F (1982) Further characterization of the behavioral despair test in mice: positive effects of convulsants. Physiol Behav 28:307–311PubMedCrossRefGoogle Scholar
  20. Bleakman D, Alt A, Witkin JM (2007) AMPA receptors in the therapeutic management of depression. CNS Neurol Disord Drug Targets 6:117–126PubMedCrossRefGoogle Scholar
  21. Blier P, Zigman D, Blier J (2012) On the safety and benefits of repeated intravenous injections of ketamine for depression. Biol Psychiatry 72(4):e11–e12PubMedCrossRefGoogle Scholar
  22. Bourin M, Prica C (2009) Melatonin receptor agonist agomelatine: a new drug for treating unipolar depression. Curr Pharm Des 15:1675–1682PubMedCrossRefGoogle Scholar
  23. Brown ES, Bobadilla L, Rush AJ (2001) Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review. Bipolar Disord 3:23–29PubMedCrossRefGoogle Scholar
  24. Brown ES, Park J, Marx CE, Hynan LS, Gardner C, Davila D, Nakamura A, Sunderajan P, Lo A, Holmes T (2014) A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology 39:2867–2873PubMedPubMedCentralCrossRefGoogle Scholar
  25. Calabrese JR, Guelfi JD, Perdrizet-Chevalier C (2007) Agomelatine adjunctive therapy for acute bipolar depression: preliminary open data. Bipolar Disord 9:628–635PubMedCrossRefGoogle Scholar
  26. Cannon DM, Carson RE, Nugent AC, Eckelman WC, Kiesewetter DO, Williams J, Rollis D, Drevets M, Gandhi S, Solorio G, Drevets WC (2006) Reduced muscarinic type 2 receptor binding in subjects with bipolar disorder. Arch Gen Psychiatry 63:741–747PubMedCrossRefGoogle Scholar
  27. Cardinali DP, Cano P, Jimenez-Ortega V, Esquifino AI (2011) Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology 93:133–142PubMedCrossRefGoogle Scholar
  28. Carroll BJ, Rubin RT (2008) Mifepristone in psychotic depression? Biol Psychiatry 63(1):e1; author reply e3Google Scholar
  29. Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, Pilc A (2013) mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 66:40–52PubMedCrossRefGoogle Scholar
  30. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237PubMedCrossRefGoogle Scholar
  31. Cryan JF, Kelly PH, Neijt HC, Sansig G, Flor PJ, van Der Putten H (2003) Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. Eur J Neurosci 17(11):2409–2417PubMedCrossRefGoogle Scholar
  32. Dale E, Bang-Andersen B, Sanchez C (2015) Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol 95:81–97PubMedCrossRefGoogle Scholar
  33. DeBattista C, Belanoff J, Glass S, Khan A, Horne RL, Blasey C, Carpenter LL, Alva G (2006) Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Biol Psychiatry 60(12):1343–1349PubMedCrossRefGoogle Scholar
  34. Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR, McShane R (2014) Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic. J Psychopharmacol 28(6):536–544PubMedCrossRefGoogle Scholar
  35. Diazgranados N, Ibrahim L, Brutsche N, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA (2010a) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67:793–802PubMedPubMedCentralCrossRefGoogle Scholar
  36. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr (2010b) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71(12):1605–1611PubMedPubMedCentralCrossRefGoogle Scholar
  37. Dilsaver SC (1986) Pathophysiology of “cholinoceptor supersensitivity” in affective disorders. Biol Psychiatry 21:813–829PubMedCrossRefGoogle Scholar
  38. Drevets WC, Zarate CAJ, Furey ML (2013) Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry 73:1156–1163PubMedCrossRefGoogle Scholar
  39. Du J, Suzuki K, Wei Y, Wang Y, Blumenthal R, Chen Z, Falke C, Zarate CA Jr, Manji HK (2007) The anticonvulsants lamotrigine, riluzole, and valproate differentially regulate AMPA receptor membrane localization: relationship to clinical effects in mood disorders. Neuropsychopharmacology 32:793–802PubMedCrossRefGoogle Scholar
  40. Dwyer JM, Lepack AE, Duman RS (2012) mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol 15:429–434PubMedCrossRefGoogle Scholar
  41. Eden Evins A, Demopulos C, Nierenberg A, Culhane MA, Eisner L, Sachs GS (2006) A double-blind, placebo-controlled trial of adjunctive donepezil in treatment-resistant mania. Bipolar Disord 8:75–80PubMedCrossRefGoogle Scholar
  42. Etain B, Dumaine A, Bellivier F, Pagan C, Francelle L, Goubran-Botros H, Moreno S, Deshommes J, Moustafa K, Le Dudal K, Mathieu F, Henry C, Kahn JP, Launay JM, Muhleisen TW, Cichon S, Bougeron T, Leboyer M, Jamain S (2012) Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Hum Mol Genet 21:4030–4037PubMedCrossRefGoogle Scholar
  43. Frizzo ME, Dall’Onder LP, Dalcin KB, Souza DO (2004) Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol 24(1):123–128PubMedCrossRefGoogle Scholar
  44. Furey ML, Drevets WC (2006) Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry 63:1121–1129PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P (2008) Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev Jan 23(1):CD005168Google Scholar
  46. Gao ZG, Jacobson KA (2013) Allosteric modulation and functional selectivity of G protein-coupled receptors. Drug Discov Today Technol 10:e237–e243PubMedCrossRefGoogle Scholar
  47. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 32(1):140–144PubMedCrossRefGoogle Scholar
  48. Geoffrey PA, Etain B, Franchi JA, Bellivier F, Ritter P (2015) Melatonin and melatonin agonists as adjunctive treatments in bipolar disorders. Curr Pharm Des 21:3352–3358CrossRefGoogle Scholar
  49. Gibbons AS, Scarr E, McLean C, Sundram S, Dean B (2009) Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects. J Affect Disord 116:184–191PubMedCrossRefGoogle Scholar
  50. Goodwin GM, Emsley R, Rembry S, Rouillon F, Agomelatine Study Group (2009) Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 70:1128–1137PubMedCrossRefGoogle Scholar
  51. Grunberg SM, Weiss MH, Russell CA, Spitz IM, Ahmadi J, Sadun A, Sitruk-Ware R (2006) Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 24(8):727–733PubMedCrossRefGoogle Scholar
  52. Hallam KT, Olver JS, Horgan JE, McGrath C, Norman TR (2005a) Low doses of lithium carbonate reduce melatonin light sensitivity in healthy volunteers. Int J Neuropsychopharmacol 8:255–259PubMedCrossRefGoogle Scholar
  53. Hallam KT, Olver JS, Norman TR (2005b) Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers. Neuropsychopharmacology 30:1400–1404PubMedGoogle Scholar
  54. Hallam KT, Olver JS, Norman TR (2005c) Melatonin sensitivity to light in monozygotic twins discordant for bipolar I disorder. Aust N Z J Psychiatry 39(10):947PubMedGoogle Scholar
  55. Hallam KT, Olver JS, Chambers V, Begg DP, McGrath C, Norman TR (2006) The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins. Psychoneuroendocrinology 31:867–875PubMedCrossRefGoogle Scholar
  56. Hannestad JO, Cosgrove KP, Dellagioia NF, Perkins E, Bois F, Bhagwagar Z, Seibyl JP, McClure-Begley TD, Picciotto MR, Esterlis I (2013) Changes in the cholinergic system between bipolar depression and euthymia as measured with [I]5IA single photon emission computed tomography. Biol Psychiatry 74:768–776PubMedPubMedCentralCrossRefGoogle Scholar
  57. Harvey AG (2008) Sleep and circadian rhythms in bipolar disorder: seeking synchrony, harmony, and regulation. Am J Psychiatry 165(7):820–829PubMedCrossRefGoogle Scholar
  58. Hasselmann H (2014) Scopolamine and depression: a role for muscarinic antagonism. CNS Neurol Disord Drug Targets 13:673–683PubMedCrossRefGoogle Scholar
  59. Iadarola ND, Niciu MJ, Richards EM, Vande Voort JL, Ballard ED, Lundin NB, Nugent AC, Machado-Vieira R, Zarate CAJ (2015) Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 6:97–114PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, Moaddel R, Wainer I, Luckenbaugh DA, Manji HK, Zarate CA (2012) Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 37:1526–1533PubMedPubMedCentralCrossRefGoogle Scholar
  61. Jaffe RJ, Novakovic V, Peselow ED (2013) Scopolamine as an antidepressant: a systematic review. Clin Neuropharmacol 36:24–26PubMedCrossRefGoogle Scholar
  62. Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K (2004) Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61(12):1235–1244PubMedCrossRefGoogle Scholar
  63. Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ (1972) A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2:632–635PubMedCrossRefGoogle Scholar
  64. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB (2002) The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 59:530–537PubMedCrossRefGoogle Scholar
  65. Karasawa J, Shimazaki T, Kawashima N, Chaki S (2005) AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 1042:92–98PubMedCrossRefGoogle Scholar
  66. Kasper S, Moises HW, Beckmann H (1981) The anticholinergic biperiden in depressive disorders. Pharmacopsychiatria 14:195–198PubMedCrossRefGoogle Scholar
  67. Kelly TF, Lieberman DZ (2014) The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. J Affect Disord 167:333–335PubMedCrossRefGoogle Scholar
  68. Kennedy SH, Emsley R (2006) Placebo-controlled trial of agomelatine in the treatment of major depressive disorder. Eur Neuropsychopharmacol 16(2):93–100PubMedCrossRefGoogle Scholar
  69. Khajavi D, Farokhnia M, Modabbernia A, Ashrafi M, Abbasi SH, Tabrizi M, Akhondzadeh S (2012) Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 73:1428–1433PubMedCrossRefGoogle Scholar
  70. Khouzam HR, Kissmeyer PM (1996) Physostigmine temporarily and dramatically reversing acute mania. Gen Hosp Psychiatry 18:203–204PubMedCrossRefGoogle Scholar
  71. Kim CH, Lee J, Lee JY, Roche KW (2008) Metabotropic glutamate receptors: phosphorylation and receptor signaling. J Neurosci Res 86(1):1–10PubMedCrossRefGoogle Scholar
  72. Knapp RJ, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, Crites G, Malatynska E (2002) Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol 440(1):27–35PubMedCrossRefGoogle Scholar
  73. Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224:107–111PubMedCrossRefGoogle Scholar
  74. Kollmar R, Markovic K, Thurauf N, Schmitt H, Kornhuber J (2008) Ketamine followed by memantine for the treatment of major depression. Aust N Z J Psychiatry 42(2):170PubMedCrossRefGoogle Scholar
  75. Kuloglu M, Ustundag B, Atmaca M, Canatan H, Tezcan AE, Cinkilinc N (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct 20(2):171–175PubMedCrossRefGoogle Scholar
  76. Larkin GL, Beautrais AL (2011) A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. Int J Neuropsychopharmacol 14:1–5Google Scholar
  77. Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY, Tzeng NS, Wang CL, Lee IH, Yeh TL, Yang YK, Lu RB (2012) The DRD2/ANKK1 gene is associated with response to add-on dextromethorphan treatment in bipolar disorder. J Affect Disord 138:295–300PubMedCrossRefGoogle Scholar
  78. Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE (1997) Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. J Clin Psychiatry 58:383–388PubMedCrossRefGoogle Scholar
  79. Liu HF, Zhou WH, Xie XH, Cao JL, Gu J, Yang GD (2004) Muscarinic receptors modulate the mRNA expression of NMDA receptors in brainstem and the release of glutamate in periaqueductal grey during morphine withdrawal in rats. Sheng Li Xue Bao 56:95–100PubMedGoogle Scholar
  80. Loo H, Hale A, D’Haenen H (2002) Determination of the dose of agomelatine, a melatoninergic agonist and selective 5-HT(2C) antagonist, in the treatment of major depressive disorder: a placebo-controlled dose range study. Int Clin Psychopharmacol 17(5):239–247PubMedCrossRefGoogle Scholar
  81. Lourenco Da Silva A, Hoffmann A, Dietrich MO, Dall'Igna OP, Souza DO, Lara DR (2003) Effect of riluzole on MK-801 and amphetamine-induced hyperlocomotion. Neuropsychobiology 48(1):27–30PubMedCrossRefGoogle Scholar
  82. MacDonald ML, Naydenov A, Chu M, Matzilevich D, Konradi C (2006) Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar Disord 8(3):255–264PubMedPubMedCentralCrossRefGoogle Scholar
  83. Machado-Vieira R, Manji HK, Zarate CA (2009a) The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 15(5):525–539PubMedPubMedCentralCrossRefGoogle Scholar
  84. Machado-Vieira R, Salvadore G, Ibrahim LA, Diaz-Granados N, Zarate CA Jr (2009b) Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders. Curr Pharm Des 15(14):1595–1611PubMedPubMedCentralCrossRefGoogle Scholar
  85. Machado-Vieira R, Ibrahim L, Henter ID, Zarate CA Jr (2012) Novel glutamatergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav 100(4):678–687PubMedCrossRefGoogle Scholar
  86. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63(4):349–352PubMedCrossRefGoogle Scholar
  87. Magalhaes PV, Dean OM, Bush AI, Copolov DL, Malhi GS, Kohlmann K, Jeavons S, Schapkaitz I, Anderson-Hung M, Berk M (2011) N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord 129:317–320PubMedCrossRefGoogle Scholar
  88. Majd M, Hashemian F, Hosseini SM, Vahdat Shariatpanahi M, Sharifi A (2015) A randomized double-blind, placebo-controlled trial of celecoxib augmentation of sertraline in treatment of drug-naive depressed women: a pilot study. Iran J Pharm Res 14:891–899PubMedPubMedCentralGoogle Scholar
  89. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS (2010) Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropsychopharmacol 13(1):71–82PubMedCrossRefGoogle Scholar
  90. Messias E, Everett B (2012) Dextromethorphan and quinidine combination in emotional lability associated with depression: a case report. Prim Care Companion CNS Disord 14:PCC.12I01400Google Scholar
  91. Mickley GA, Schaldach MA, Snyder KJ, Balogh SA, Len T, Neimanis K, Goulis P, Hug J, Sauchak K, Remmers-Roeber DR, Walker C, Yamamoto BK (1998) Ketamine blocks a conditioned taste aversion (CTA) in neonatal rats. Physiol Behav 64(3):381–390PubMedCrossRefGoogle Scholar
  92. Millan MJ, Brocco M, Gobert A, Dekeyne A (2005) Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade. Psychopharmacology (Berl) 177(4):448–458CrossRefGoogle Scholar
  93. Millar A, Espie CA, Scott J (2004) The sleep of remitted bipolar outpatients: a controlled naturalistic study using actigraphy. J Affect Disord 80:145–153PubMedCrossRefGoogle Scholar
  94. Mizuta I, Ohta M, Ohta K, Nishimura M, Mizuta E, Kuno S (2001) Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes. Neurosci Lett 310(2–3):117–120PubMedCrossRefGoogle Scholar
  95. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927PubMedGoogle Scholar
  96. Montgomery SA, Kasper S (2007) Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. Int Clin Psychopharmacol 22(5):283–291PubMedCrossRefGoogle Scholar
  97. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11(7):680–684PubMedCrossRefGoogle Scholar
  98. Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ (2013a) Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 170(10):1134–1142PubMedPubMedCentralCrossRefGoogle Scholar
  99. Murrough JW, Perez AM, Pillemer S, Stern J, Parides MK, aan het Rot M, Collins KA, Mathew SJ, Charney DS, Iosifescu DV (2013b) Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry 74(4):250–256PubMedCrossRefGoogle Scholar
  100. Musazzi L, Treccani G, Mallei A, Popoli M (2013) The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry 73:1180–1188PubMedCrossRefGoogle Scholar
  101. Nathan PJ, Burrows GD, Norman TR (1999) Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology 21:408–413PubMedCrossRefGoogle Scholar
  102. Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23(2):87–94PubMedCrossRefGoogle Scholar
  103. Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB, APA Council of Research Task Force on Novel Biomarkers and Treatments (2015) Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry 172:950–966PubMedCrossRefGoogle Scholar
  104. Nguyen L, Matsumoto RR (2015) Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice. Behav Brain Res 295:26–34PubMedCrossRefGoogle Scholar
  105. Niciu MJ, Luckenbaugh D, Ionescu DF, Mathews D, Richards EM, Zarate CA (2013) Subanesthetic dose ketamine does not induce an affective switch in three independent samples of treatment-resistant major depression. Biol Psychiatry 74:e23–e24PubMedPubMedCentralCrossRefGoogle Scholar
  106. Norris ER, Burke K, Correll JR, Zemanek KJ, Lerman J, Primelo RA, Kaufmann MW (2013) A double-blind, randomized, placebo-controlled trial of adjunctive ramelteon for the treatment of insomnia and mood stability in patients with euthymic bipolar disorder. J Affect Disord 144:141–147PubMedCrossRefGoogle Scholar
  107. Nurnberger JI Jr, Adkins S, Lahiri DK, Mayeda A, Hu K, Lewy A, Miller A, Bowman ES, Miller MJ, Rau L, Smiley C, Davis-Singh D (2000) Melatonin suppression by light in euthymic bipolar and unipolar patients. Arch Gen Psychiatry 57(6):572–579PubMedCrossRefGoogle Scholar
  108. O'Neill MJ, Witkin JM (2007) AMPA receptor potentiators: application for depression and Parkinson’s disease. Curr Drug Targets 8:603–620PubMedCrossRefGoogle Scholar
  109. Overstreet DH (1993) The Flinders sensitive line rats: a genetic animal model of depression. Neurosci Biobehav Rev 17:51–68PubMedCrossRefGoogle Scholar
  110. Pacchierotti C, Iapichino S, Bossini L, Pieraccini F, Castrogiovanni P (2001) Melatonin in psychiatric disorders: a review on the melatonin involvement in psychiatry. Front Neuroendocrinol 22:18–32PubMedCrossRefGoogle Scholar
  111. Palucha A, Pilc A (2007) Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther 115:116–147PubMedCrossRefGoogle Scholar
  112. Papp M, Gruca P, Boyer PA, Mocaer E (2003) Effect of agomelatine in the chronic mild stress model of depression in the rat. Neuropsychopharmacology 28(4):694–703PubMedCrossRefGoogle Scholar
  113. Permoda-Osip A, Kisielewski J, Bartkowska-Sniatkowska A, Rybakowski JK (2014) Single ketamine infusion and neurocognitive performance in bipolar depression. Pharmacopsychiatry 48(2):78–79PubMedCrossRefGoogle Scholar
  114. Pilc A, Wieronska JM, Skolnick P (2013) Glutamate-based antidepressants: preclinical psychopharmacology. Biol Psychiatry 73:1125–1132PubMedCrossRefGoogle Scholar
  115. Pitkanen A, Mathiesen C, Ronn LC, Moller A, Nissinen J (2007) Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat. Epilepsy Res 74(1):45–54PubMedCrossRefGoogle Scholar
  116. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, Soleimani L, Charney DS, Foulkes AL, Mathew SJ (2014) Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety 31(4):335–343PubMedPubMedCentralCrossRefGoogle Scholar
  117. Quiroz JA, Singh J, Gould TD, Denicoff KD, Zarate CA Jr, Manji HK (2004) Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology. Mol Psychiatry 9:756–776PubMedCrossRefGoogle Scholar
  118. Quiroz J, Tamburri P, Deptula D, Banken L, Beyer U, Fontoura P, Santarelli L (2014) The efficacy and safety of basimglurant as adjunctive therapy in major depression: a randomized, double-blind, placebo controlled study. Neuropsychopharmacology 39:S376–S377Google Scholar
  119. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70(1):31–41PubMedPubMedCentralCrossRefGoogle Scholar
  120. Rapoport SI, Basselin M, Kim HW, Rao JS (2009) Bipolar disorder and mechanisms of action of mood stabilizers. Brain Res Rev 61:185–209PubMedPubMedCentralCrossRefGoogle Scholar
  121. Rasmussen KG, Lineberry TW, Galardy CW, Kung S, Lapid MI, Palmer BA, Ritter MJ, Schak KM, Sola CL, Hanson AJ, Frye MA (2013) Serial infusions of low-dose ketamine for major depression. J Psychopharmacol 27(5):444–450PubMedCrossRefGoogle Scholar
  122. Rogawski MA (2006) Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 69(3):273–294PubMedPubMedCentralCrossRefGoogle Scholar
  123. Rogoz Z, Skuza G, Maj J, Danysz W (2002) Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42:1024–1030PubMedCrossRefGoogle Scholar
  124. Roitman S, Green T, Osher Y, Karni N, Levine J (2007) Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord 9(7):754–758PubMedCrossRefGoogle Scholar
  125. Romo-Nava F, Alvarez-Icaza Gonzalez D, Fresan-Orellana A, Saracco Alvarez R, Becerra-Palars C, Moreno J, Ontiveros Uribe MP, Berlanga C, Heinze G, Buijs RM (2014) Melatonin attenuates antipsychotic metabolic effects: an eight-week randomized, double-blind, parallel-group, placebo-controlled clinical trial. Bipolar Disord 16:410–421PubMedCrossRefGoogle Scholar
  126. Rothschild AJ (2003) Challenges in the treatment of depression with psychotic features. Biol Psychiatry 53(8):680–690PubMedCrossRefGoogle Scholar
  127. Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D (2007) Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356:1711–1722PubMedCrossRefGoogle Scholar
  128. Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, Krystal JH (2007) Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 61(6):822–825PubMedCrossRefGoogle Scholar
  129. Sanacora G, Zarate CA Jr, Krystal JH, Manji HK (2008) Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov 7:426–437PubMedPubMedCentralCrossRefGoogle Scholar
  130. Sauter A, Rudin M (1993) Determination of creatine kinase kinetic parameters in rat brain by NMR magnetization transfer. Correlation with brain function. J Biol Chem 268:13166–13171PubMedGoogle Scholar
  131. Schmidt PJ, Daly RC, Bloch M, Smith MJ, Danaceau MA, St. Clair LS, Murphy JH, Haq N, Rubinow DR (2005) Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry 62:154–162PubMedCrossRefGoogle Scholar
  132. Segal M, Avital A, Drobot M, Lukanin A, Derevenski A, Sandbank S, Weizman A (2007) CK levels in unmedicated bipolar patients. Eur Neuropsychopharmacol 17(12):763–767PubMedCrossRefGoogle Scholar
  133. Serra G, Koukopoulos A, De Chiara L, Koukopoulos AE, Tondo L, Girardi P, Baldessarini RJ, Serra G (2015) Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder. J Clin Psychiatry 76:e91–e97PubMedCrossRefGoogle Scholar
  134. Shaltiel G, Maeng S, Malkesman O, Pearson B, Schloesser RJ, Tragon T, Rogawski M, Gasior M, Luckenbaugh D, Chen G, Manji HK (2008) Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Mol Psychiatry 13(9):858–872PubMedPubMedCentralCrossRefGoogle Scholar
  135. Shi J, Hattori E, Zou H, Badner JA, Christian SL, Gershon ES, Liu C (2007) No evidence for association between 19 cholinergic genes and bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 144:715–723CrossRefGoogle Scholar
  136. Silvestre JS, Nadal R, Pallares M, Ferre N (1997) Acute effects of ketamine in the holeboard, the elevated-plus maze, and the social interaction test in Wistar rats. Depress Anxiety 5(1):29–33PubMedCrossRefGoogle Scholar
  137. Singh J, Fedgchin M, Daly E, De Boer P, Cooper K, Lim P, Pinter C, Murrough J, Sanacora G, Shelton R, Kurian B, Winokur A, Fava M, Manji HK, Drevets W, van Nueten L (2014) A double-blind, randomized, placebo-controlled, parallel group, dose frequency study of intravenous ketamine in patients with treatment-resistant depression. In: Poster Session 1, Janssen Research and Development, LLC, June 17 2014Google Scholar
  138. Skolnick P (1999) Antidepressants for the new millennium. Eur J Pharmacol 375(1–3):31–40PubMedCrossRefGoogle Scholar
  139. Skolnick P (2002) Modulation of glutamate receptors: strategies for the development of novel antidepressants. Amino Acids 23(1–3):153–159PubMedCrossRefGoogle Scholar
  140. Smith EG, Deligiannidis KM, Ulbricht CM, Landolin CS, Patel JK, Rothschild AJ (2013) Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 74:966–973PubMedPubMedCentralCrossRefGoogle Scholar
  141. Sokolski KN, DeMet EM (2000) Cholinergic sensitivity predicts severity of mania. Psychiatry Res 95:195–200PubMedCrossRefGoogle Scholar
  142. Streck EL, Amboni G, Scaini G, Di-Pietro PB, Rezin GT, Valvassori SS, Luz G, Kapczinski F, Quevedo J (2008) Brain creatine kinase activity in an animal model of mania. Life Sci 82(7–8):424–429PubMedCrossRefGoogle Scholar
  143. Taylor D, Sparshatt A, Varma S, Olofinjana O (2014) Antidepressant efficacy of agomelatine: meta-analysis of published and unpublished studies. BMJ 348:g1888PubMedPubMedCentralCrossRefGoogle Scholar
  144. Teng CT, Demetrio FN (2006) Memantine may acutely improve cognition and have a mood stabilizing effect in treatment-resistant bipolar disorder. Rev Bras Psiquiatr 28:252–254PubMedCrossRefGoogle Scholar
  145. Thomson PA, Wray NR, Thomson AM, Dunbar DR, Grassie MA, Condie A, Walker MT, Smith DJ, Pulford DJ, Muir W, Blackwood DH, Porteous DJ (2005) Sex-specific association between bipolar affective disorder in women and GPR50, an X-linked orphan G protein-coupled receptor. Mol Psychiatry 10(5):470–478PubMedCrossRefGoogle Scholar
  146. Valentine GW, Mason GF, Gomez R, Fasula M, Watzl J, Pittman B, Krystal JH, Sanacora G (2011) The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [(1)H]-MRS. Psychiatry Res 191(2):122–127PubMedPubMedCentralCrossRefGoogle Scholar
  147. van Enkhuizen J, Janowsky DS, Olivier B, Minassian A, Perry W, Young JW, Geyer MA (2015) The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited. Eur J Pharmacol 753:114–126PubMedCrossRefGoogle Scholar
  148. Velentgas P, West W, Cannuscio CC, Watson DJ, Walker AM (2006) Cardiovascular risk of selective cyclooxygenase-2 inhibitors and other non-aspirin non-steroidal anti-inflammatory medications. Pharmacoepidemiol Drug Saf 15(9):641–652PubMedCrossRefGoogle Scholar
  149. Voleti B, Navarria A, Liu RJ, Banasr M, Li N, Terwilliger R, Sanacora G, Eid T, Aghajanian G, Duman RS (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742–749PubMedCrossRefGoogle Scholar
  150. Watson S, Gallagher P, Porter RJ, Smith MS, Herron LJ, Bulmer S, North-East Mood Disorders Clinical Research Group, Young AH, Ferrier IN (2012) A randomized trial to examine the effect of mifepristone on neuropsychological performance and mood in patients with bipolar depression. Biol Psychiatry 72:943–949Google Scholar
  151. Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J (1999a) Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 45:1070–1074PubMedCrossRefGoogle Scholar
  152. Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E (1999b) Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 156:646–649PubMedGoogle Scholar
  153. Yoon SJ, Lyoo IK, Haws C, Kim TS, Cohen BM, Renshaw PF (2009) Decreased glutamate/glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: a longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology 34(7):1810–1818PubMedCrossRefGoogle Scholar
  154. Young AH, Gallagher P, Watson S, Del-Estal D, Owen BM, Ferrier IN (2004) Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 29:1538–1545PubMedCrossRefGoogle Scholar
  155. Zarate CA, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK (2004) An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161(1):171–174PubMedCrossRefGoogle Scholar
  156. Zarate CA, Quiroz JA, Singh JB, Denicoff KD, De Jesus G, Luckenbaugh DA, Charney DS, Manji HK (2005) An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 57(4):430–432PubMedCrossRefGoogle Scholar
  157. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864PubMedCrossRefGoogle Scholar
  158. Zarate CA, Brutsche N, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchick A, Selter J, Marquardt C, Liberty V, Luckenbaugh DA (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 71:939–946PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland (outside the USA)  2016

Authors and Affiliations

  • Rodrigo Machado-Vieira
    • 1
    Email author
  • Ioline D. Henter
    • 1
  • Husseini K. Manji
    • 2
  • Carlos A. ZarateJr.
    • 3
  1. 1.Experimental Therapeutics and Pathophysiology BranchBethesdaUSA
  2. 2.Janssen Pharmaceuticals of Johnson and Johnson, Janssen Research and DevelopmentTitusvilleUSA
  3. 3.Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of HealthBethesdaUSA

Personalised recommendations