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Review

Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician’s perspective

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Pages 221-228 | Received 22 Aug 2017, Accepted 12 Jan 2018, Published online: 22 Jan 2018

References

  • Yatham LN, Kennedy SH, Schaffer A, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009. Bipolar Disord. 2009;11(3):225–255.
  • McIntyre RS. Treatment-resistant mood disorders. New york, USA:Oxford Psychiatry Library; 2014.
  • Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England J Med. 2007;356(17):1711–1722.
  • Zarate CA, Quiroz JA. Combination treatment in bipolar disorder: a review of controlled trials. Bipolar Disord. 2003;5(3):217–225.
  • Sachs GS. Unmet clinical needs in bipolar disorder. J Clin Psychopharmacol. 2003;23(3):SS2-S8.
  • Fornaro M, Martino M, De Pasquale C, et al. The argument of antidepressant drugs in the treatment of bipolar depression: mixed evidence or mixed states? Expert Opin Pharmacother. 2012;13(14):2037–2051.
  • Freeman MP, Freeman SA, McElroy SL. The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues. J Affect Disord. 2002;68(1):1–23.
  • Fornaro M, Nardi AE, De Berardis D, et al. Experimental drugs for bipolar psychosis. Expert Opin Investig Drugs. 2016;25(12):1371–1375.
  • Stromgaard K, Krogsgaard-Larsen P, Madsen U. Textbook of drug design and discovery, Fifth Edition. London, UK: CRC Press; 2016.
  • Tollenaere J. The role of structure-based ligand design and molecular modelling in drug discovery. Pharm World Sci. 1996;18(2):56–62.
  • Dixon SJ, Stockwell BR. Identifying druggable disease-modifying gene products. Curr Opin Chem Biol. 2009;13(5–6):549–555.
  • Xiong C, Van Belle G, Miller JP, et al. Designing clinical trials to test disease-modifying agents: application to the treatment trials of Alzheimer’s disease. Clin Trials. 2011;8(1):15–26.
  • McGhee DJ, Ritchie CW, Zajicek JP, et al. A review of clinical trial designs used to detect a disease-modifying effect of drug therapy in Alzheimer’s disease and Parkinson’s disease. BMC Neurol. 2016;16(1):92.
  • Anderson AC. The process of structure-based drug design. Chem Biol. 2003;10(9):787–797.
  • Recanatini M, Bottegoni G, Cavalli A. In silico antitarget screening. Drug Discov Today Technol. 2004;1(3):209–215.
  • Ganellin CR, Jefferis R, Roberts SM. Introduction to biological and small molecule drug research and development: theory and case studies. Oxford, UK: Academic Press; 2013.
  • Yuan Y, Pei J, Lai L. Binding site detection and druggability prediction of protein targets for structure-based drug design. Curr Pharm Des. 2013;19(12):2326–2333.
  • Healy D. Mania: a short history of bipolar disorder. Maryland, USA:JHU Press; 2008.
  • Klein DF. The loss of serendipity in psychopharmacology. Jama. 2008;299(9):1063–1065.
  • Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci. 2007;64(16):2090–2103.
  • Rybakowski JK. Genetic influences on response to mood stabilizers in bipolar disorder. CNS Drugs. 2013;27(3):165–173.
  • Chen G, Pan B, Hawver DB, et al. Attenuation of cyclic AMP production by carbamazepine. J Neurochem. 1996;67(5):2079–2086.
  • Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry. 1999;156(5):702–709.
  • Fornaro M, De Berardis D, Perna G, et al. Lurasidone in the treatment of bipolar depression: systematic review of systematic reviews. Biomed Res Int. 2017;2017:1–17.
  • Solmi M, Murru A, Pacchiarotti I, et al. Safety, tolerability, and risks associated with first-and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–777.
  • Fornaro M, Aguglia E, Dell’Osso L, et al. Could the underestimation of bipolarity obstruct the search for novel antidepressant drugs? Expert Opin Pharmacother. 2011;12(18):2817–2831.
  • Fornaro M, Giosue P. Current nosology of treatment resistant depression: a controversy resistant to revision. Clin Pract Epidemiol Ment Health. 2010 May 4;6:20–24. DOI:10.2174/1745017901006010020
  • Undurraga J, Baldessarini RJ, Valentí M, et al. Bipolar depression: clinical correlates of receiving antidepressants. J Affect Disord. 2012;139(1):89–93.
  • Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry. 2007;64(4):442–455.
  • Malhi GS, Adams D, Berk M. Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Bipolar Disord. 2009;11(s2):55–76.
  • Fornaro M, Stubbs B, De Berardis D, et al. Does the “Silver Bullet” lose its shine over the time? Assessment of loss of lithium response in a preliminary sample of bipolar disorder outpatients. Clin Pract Epidemiol Ment Health. 2016;12:142–157.
  • Prien RF, Caffey EM, Klett CJ. Comparison of lithium carbonate and chlorpromazine in the treatment of mania: report of the Veterans Administration and National Institute of Mental Health Collaborative Study Group. Arch Gen Psychiatry. 1972;26(2):146–153.
  • Cruceanu C, Alda M, Turecki G. Lithium: a key to the genetics of bipolar disorder. Genome Med. 2009;1(8):79.
  • Singh N, Sharpley AL, Emir UE, et al. Effect of the putative lithium mimetic ebselen on brain myo-inositol, sleep and emotional processing in humans. Neuropsychopharmacology. 2016;41(7):1768–1778.
  • Freland L, Beaulieu J-M. Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front Mol Neurosci. 2012;5.
  • Gould TD, Manji HK. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology. 2005;30(7):1223–1237.
  • Patel P, Woodgett JR. Chapter eight-glycogen synthase kinase 3: a kinase for all pathways? Curr Top Dev Biol. 2017;123:277–302.
  • Jope RS. Glycogen synthase kinase-3 in the etiology and treatment of mood disorders. Front Mol Neurosci. 2011;4.
  • Yadranji Aghdam S, Barger SW. Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithium. Curr Alzheimer Res. 2007;4(1):21–31.
  • Marmol F. Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium. Prog Neuro-Psychopharmacology Biol Psychiatry. 2008;32(8):1761–1771.
  • Bowden CL, Swann AC, Calabrese JR, et al. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Psychopharmacol Bull. 1997;33(4):693.
  • Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11(5):453–473.
  • Calabrese JR, Rapport DJ, Shelton MD, et al. Evolving methodologies in bipolar disorder maintenance research. Br J Psychiatry. 2001;178(41):s157–s163.
  • Carvalho AF, Vieta E. The treatment of bipolar disorder: integrative clinical strategies and future directions. New York, USA: Oxford University Press; 2017.
  • Berk M. Neuroprogression: pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol. 2009;12(4):441–445.
  • Berk M, Conus P, Lucas N, et al. Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9(7):671–678.
  • Konstantakopoulos G. Challenges with bipolar disorder drug discovery. Oxford, UK: Taylor & Francis; 2016.
  • Fornaro M. Beyond monoamines towards the development of novel antidepressants. J Psychopathology. 2012;18:226–233.
  • Krystal JH, Sanacora G, Blumberg H, et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol Psychiatry. 2002;7(S1):SS71–S80.
  • Zarate CA, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry. 2006;59(11):1006–1020.
  • Sanacora G, Zarate CA Jr, Krystal J, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426–437.
  • Riedel G, Platt B, Micheau J. Glutamate receptor function in learning and memory. Behav Brain Res. 2003;140(1–2):1–47.
  • Partin KM. AMPA receptor potentiators: from drug design to cognitive enhancement. Curr Opin Pharmacol. 2015;20:46–53.
  • van Wissen K, Blanchard D. Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults. Issues Ment Health Nurs. 2017;38(6):526–527.
  • Veronese N, Solmi M, Luchini C, et al. Acetylcholinesterase inhibitors and memantine in bipolar disorder: a systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions. J Affect Disord. 2016;197:268–280.
  • Park LT, Lener MS, Hopkins M, et al. A double-blind, placebo-controlled, pilot study of riluzole monotherapy for acute bipolar depression. J Clin Psychopharmacol. 2017;37(3):355–358.
  • Naughton M, Clarke G, Olivia F, et al. A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action. J Affect Disord. 2014;156:24–35.
  • Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014;159:56–61.
  • Yang C, Shirayama Y, Zhang J, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5(9):e632.
  • Zarate CA, Niciu MJ. Ketamine for depression: evidence, challenges and promise. World Psychiatry. 2015;14(3):348–350.
  • Chen S-L, Lee S-Y, Chang Y-H, et al. Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder. Eur Neuropsychopharmacol. 2014;24(11):1753–1759.
  • Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct. 2012;8(1):61.
  • Zarate CA, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry. 2005;57(4):430–432.
  • Je Jeon W, Dean B, Scarr E, et al. The role of muscarinic receptors in the pathophysiology of mood disorders: a potential novel treatment? Curr Neuropharmacol. 2015;13(6):739–749.
  • Chen J, Lu Z, Zhang M, et al. A randomized, 4-week double-blind placebo control study on the efficacy of donepezil augmentation of lithium for treatment of acute mania. Neuropsychiatr Dis Treat. 2013;9:839.
  • van Enkhuizen J, Milienne-Petiot M, Geyer MA, et al. Modeling bipolar disorder in mice by increasing acetylcholine or dopamine: chronic lithium treats most, but not all features. Psychopharmacology. 2015;232(18):3455–3467.
  • Alexis Geoffroy P, Etain B, Franchi J-AM, et al. Melatonin and melatonin agonists as adjunctive treatments in bipolar disorders. Curr Pharm Des. 2015;21(23):3352–3358.
  • Mahableshwarkar AR, Calabrese JR, Macek TA, et al. Efficacy and safety of sublingual ramelteon as an adjunctive therapy in the maintenance treatment of bipolar I disorder in adults: a phase 3, randomized controlled trial. J Affect Disord. 2017;221:275–282.
  • Gallagher P, Malik N, Newham J, et al. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005168. DOI:10.1002/14651858.CD005168.pub2.
  • Howland RH. Mifepristone as a therapeutic agent in psychiatry. J Psychosoc Nurs Ment Health Serv. 2013;51(6):11–14.
  • Arabzadeh S, Ameli N, Zeinoddini A, et al. Celecoxib adjunctive therapy for acute bipolar mania: a randomized, double‐blind, placebo‐controlled trial. Bipolar Disord. 2015;17(6):606–614.
  • Baldessarini RJ. Potential novel treatments for bipolar depression: ketamine, fatty acids, anti-inflammatory agents, and probiotics. CNS Neurol Disord Drug Targets. 2017;16:211–216.
  • Olsson SK, Sellgren C, Engberg G, et al. Cerebrospinal fluid kynurenic acid is associated with manic and psychotic features in patients with bipolar I disorder. Bipolar Disord. 2012;14(7):719–726.
  • Mansour HA, Monk TH, Nimgaonkar VL. Circadian genes and bipolar disorder. Ann Med. 2005;37(3):196–205.
  • Nievergelt CM, Kripke DF, Barrett TB, et al. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B: Neuropsychiatric Genet. 2006;141(3):234–241.
  • Gao Z-G, Jacobson KA. Allosteric modulation and functional selectivity of G protein-coupled receptors. Drug Discov Today Technol. 2013;10(2):e237–e243.
  • De Berardis D, Marini S, Fornaro M, et al. The melatonergic system in mood and anxiety disorders and the role of agomelatine: implications for clinical practice. Int J Mol Sci. 2013;14(6):12458–12483.
  • Daban C, Vieta E, Mackin P, et al. Hypothalamic-pituitary-adrenal axis and bipolar disorder. Psychiatr Clin. 2005;28(2):469–480.
  • Rapoport SI, Bosetti F. Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry. 2002;59(7):592–596.
  • Rosenblat JD, Kakar R, Berk M, et al. Anti‐inflammatory agents in the treatment of bipolar depression: a systematic review and meta‐analysis. Bipolar Disord. 2016;18(2):89–101.
  • Waterdrinker A, Berk M, Venugopal K, et al. Effects of N-Acetyl cysteine on suicidal ideation in bipolar depression. J Clin Psychiatry. 2015;76(5):665.
  • Toniolo RA, Fernandes FBF, Silvia M, et al. Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: results from a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2017;224:69–75.
  • Yoon SJ, Lyoo IK, Haws C, et al. Decreased glutamate/glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: a longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology. 2009;34(7):1810–1818.
  • Ong WY, Farooqui T, Kokotos G, et al. Synthetic and natural inhibitors of phospholipases A2: their importance for understanding and treatment of neurological disorders. ACS Chem Neurosci. 2015;6(6):814–831.
  • Chowdhury MI, Hasan M, Islam MS, et al. Elevated serum MDA and depleted non-enzymatic antioxidants, macro-minerals and trace elements are associated with bipolar disorder. J Trace Elem Med Biol. 2017;39:162–168.
  • Iwahashi K, Nishizawa D, Narita S, et al. Haplotype analysis of GSK-3β gene polymorphisms in bipolar disorder lithium responders and nonresponders. Clin Neuropharmacol. 2014;37(4):108–110.
  • Vasconcelos-Moreno MP, Fries GR, Gubert C, et al. Telomere length, oxidative stress, inflammation and BDNF levels in siblings of patients with bipolar disorder: implications for accelerated cellular aging. Int J Neuropsychopharmacol. 2017;20(6):445–454.
  • Soczynska JK, Kennedy SH, Alsuwaidan M, et al. A pilot, open‐label, 8‐week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression. Bipolar Disord. 2017;19(3):198–213.
  • Dean OM, Turner A, Malhi G, et al. Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression. Rev Bras Psiquiatr. 2015;37(1):03–12.
  • Bartoli F, Crocamo C, Clerici M, et al. Allopurinol as add-on treatment for mania symptoms in bipolar disorder: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry. 2017;210(1):10–15.
  • Zarate CA, Manji HK. Putative drugs and targets for bipolar disorder. Mt Sinai J Med. 2008;75(3):226–247.
  • Amoruso A, Bardelli C, Cattaneo CI, et al. Neurokinin (NK)-1 receptor expression in monocytes from bipolar disorder patients: a pilot study. J Affect Disord. 2015;178:188–192.
  • Fries GR, Valvassori SS, Bock H, et al. Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania. J Psychiatr Res. 2015;68:329–336.
  • Berk M, Brnabic A, Dodd S, et al. Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disord. 2011;13(1):87–98.
  • Dimitrakopoulos S, Konstantakopoulos G. Pharmacological agents under research for the maintenance treatment in bipolar disorder. Psychiatriki. 2015 Jul-Sep;26(3):169–180. PubMed PMID: 26480221.
  • Peedicayil J. Epigenetic approaches for bipolar disorder drug discovery. Expert Opin Drug Discov. 2014;9(8):917–930.
  • Lavebratt C, Olsson S, Backlund L, et al. The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol Psychiatry. 2014;19(3):334–341.
  • Shioya A, Saito Y, Arima K, et al. Neurodegenerative changes in patients with clinical history of bipolar disorders. Neuropathology. 2015;35(3):245–253.
  • Sanches M, Soares JC. New drugs for bipolar disorder. Curr Psychiatry Rep. 2011 Dec;13(6):513–521. DOI:10.1007/s11920-011-0231-1. PubMed PMID: 21877160.
  • Goodwin FK, Jamison KR. Manic-depressive illness: bipolar disorders and recurrent depression. Vol. 1. Oxford, UK: Oxford University Press; 2007.
  • Fornaro M, Stubbs B, De Berardis D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci. 2016 Feb 16;17(2):241. PubMed PMID: 26891297; PubMed Central PMCID: PMCPMC4783972. DOI:10.3390/ijms17020241
  • Fernandes BS, Williams LM, Steiner J, et al. The new field of ‘precision psychiatry’. BMC Med. 2017;15(1):80.
  • Perugi G, Fornaro M. Bipolar disorder treatment guidelines and their limits in every day clinical practice. Giorn Ital Psicopatl. 2011;17(3):261–264.
  • Soares JC, Young AH. Bipolar disorders: basic mechanisms and therapeutic implications. 3rd. Oxford, UK: CRC Press; 2017.
  • Zohar J, Nutt DJ, Kupfer DJ, et al. A proposal for an updated neuropsychopharmacological nomenclature. Eur Neuropsychopharmacol. 2014 Jul;24(7):1005–1014. PubMed PMID: 24630385. DOI:10.1016/j.euroneuro.2013.08.004
  • Bowden CL. Bipolar pathophysiology and development of improved treatments. Brain Res. 2008;1235:92–97.
  • Fountoulakis KN, Vieta E, Young A, et al. The International College of Neuropsychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), part 4: unmet needs in the treatment of bipolar disorder and recommendations for future research. Int J Neuropsychopharmacol. 2017;20(2):196–205.

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