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Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid

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Abstract

Rationale

Combinatory therapy is widely used in psychiatry owing to the possibility that drugs with different mechanisms of action may synergize to improve functions deteriorated in schizophrenia, bipolar disorders, and major depression. While combinatory strategies rely on receptor and synaptic mechanisms, it should also be considered that two drugs may also “interact” on the long-term to determine more robust changes in neuronal plasticity, which represents a downstream target important for functional recovery.

Objective

The aim of the study is to investigate neuroadaptive changes set in motion by chronic concomitant administration of the novel antipsychotic lurasidone and the mood stabilizer valproate.

Methods

Animals were chronically treated with lurasidone, valproate, or the combination of the two drugs and killed 24 h after the last injection to evaluate alterations of different measures of neuronal plasticity such as the neurotrophin brain-derived neurotrophic factor (BDNF), the immediate early gene Activity-regulated cytoskeletal associated protein, and the epigenetic regulators HDAC 1, 2, and 5 in dorsal and ventral hippocampus.

Results

The results suggest that coadministration of lurasidone and valproate produces, when compared to the single drugs, a larger increase in the expression of BDNF in the ventral hippocampus, through the regulation of specific neurotrophin transcripts. We also found that the histone deacetylases were regulated by the drug combination, suggesting that some of the transcriptional changes may be sustained by epigenetic mechanisms.

Conclusions

Our results suggest that the beneficial effects associated with combinatory treatment between a second-generation antipsychotic and a mood stabilizer could result from the ability to modulate neuroplastic molecules, whose expression and function is deteriorated in different psychiatric conditions.

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References

  • Aid T, Kazantseva A, Piirsoo M, Palm K, Timmusk T (2007) Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 85:525–535

    Article  PubMed  CAS  Google Scholar 

  • An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B, Xu B (2008) Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134:175–187

    Article  PubMed  CAS  Google Scholar 

  • Baj G, Leone E, Chao MV, Tongiorgi E (2011) Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci U S A 108:16813–16818

    Article  PubMed  CAS  Google Scholar 

  • Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC, Davis JM, Rush AJ, Small JG et al (1994) Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. Jama 271:918–924

    Article  PubMed  CAS  Google Scholar 

  • Bowden CL, Myers JE, Grossman F, Xie Y (2004) Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder. J Clin Psychiatry 65:707–714

    Article  PubMed  CAS  Google Scholar 

  • Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125

    Article  PubMed  CAS  Google Scholar 

  • Bramham CR, Alme MN, Bittins M, Kuipers SD, Nair RR, Pai B, Panja D, Schubert M, Soule J, Tiron A, Wibrand K (2010) The Arc of synaptic memory. Exp Brain Res 200:125–140

    Article  PubMed  Google Scholar 

  • Calabrese F, Molteni R, Maj PF, Cattaneo A, Gennarelli M, Racagni G, Riva MA (2007) Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein. Neuropsychopharmacology 32:2351–2359

    Article  PubMed  CAS  Google Scholar 

  • Calabrese F, Molteni R, Racagni G, Riva MA (2009) Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology 34(Suppl 1):S208–S216

    Article  PubMed  CAS  Google Scholar 

  • Calabrese F, Molteni R, Cattaneo A, Macchi F, Racagni G, Gennarelli M, Ellenbroek BA, Riva MA (2010) Long-Term duloxetine treatment normalizes altered brain-derived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms. Mol Pharmacol 77:846–853

    Article  PubMed  CAS  Google Scholar 

  • Calabrese F, Molteni R, Gabriel C, Mocaer E, Racagni G, Riva MA (2011) Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine. Psychopharmacology (Berl) 215:267–275

    Article  CAS  Google Scholar 

  • Castren E, Voikar V, Rantamaki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Henter ID, Manji HK (2010) Translational research in bipolar disorder: emerging insights from genetically based models. Mol Psychiatry 15:883–895

    Article  PubMed  CAS  Google Scholar 

  • Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM (2002) A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 41:1216–1223

    Article  PubMed  Google Scholar 

  • Dynes JL, Steward O (2007) Dynamics of bidirectional transport of Arc mRNA in neuronal dendrites. J Comp Neurol 500:433–447

    Article  PubMed  CAS  Google Scholar 

  • Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 23:7311–7316

    PubMed  CAS  Google Scholar 

  • Enomoto T, Ishibashi T, Tokuda K, Ishiyama T, Toma S, Ito A (2008) Lurasidone reverses MK-801-induced impairment of learning and memory in the Morris water maze and radial-arm maze tests in rats. Behav Brain Res 186:197–207

    Article  PubMed  CAS  Google Scholar 

  • Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19

    Article  PubMed  CAS  Google Scholar 

  • Fountoulakis KN, Kasper S, Andreassen O, Blier P, Okasha A, Severus E, Versiani M, Tandon R, Moller HJ, Vieta E (2012) Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. Eur Arch Psychiatry Clin Neurosci 262(Suppl 1):1–48

    Article  PubMed  Google Scholar 

  • Fumagalli F, Frasca A, Racagni G, Riva MA (2008) Dynamic regulation of glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs. Mol Pharmacol 73:1484–1490

    Article  PubMed  CAS  Google Scholar 

  • Fumagalli F, Frasca A, Racagni G, Riva MA (2009) Cognitive effects of second-generation antipsychotics: current insights into neurochemical mechanisms. CNS Drugs 23:603–614

    Article  PubMed  CAS  Google Scholar 

  • Fumagalli F, Calabrese F, Luoni A, Bolis F, Racagni G, Riva MA (2012) Modulation of BDNF expression by repeated treatment with the novel antipsychotic lurasidone under basal condition and in response to acute stress. Int J Neuropsychopharmacol 15:235–246

    Article  PubMed  CAS  Google Scholar 

  • Grayson DR, Chen Y, Dong E, Kundakovic M, Guidotti A (2009) From trans-methylation to cytosine methylation: evolution of the methylation hypothesis of schizophrenia. Epigenetics 4:144–149

    Article  PubMed  CAS  Google Scholar 

  • Harvey PD, Ogasa M, Cucchiaro J, Loebel A, Keefe RS (2011) Performance and interview-based assessments of cognitive change in a randomized, double-blind comparison of lurasidone vs. ziprasidone. Schizophr Res 127:188–194

    Article  PubMed  Google Scholar 

  • Huang M, Horiguchi M, Felix AR, Meltzer HY (2012) 5-HT1A and 5-HT7 receptors contribute to lurasidone-induced dopamine efflux. Neuroreport 23:436–440

    PubMed  CAS  Google Scholar 

  • Ishibashi T, Horisawa T, Tokuda K, Ishiyama T, Ogasa M, Tagashira R, Matsumoto K, Nishikawa H, Ueda Y, Toma S, Oki H, Tanno N, Saji I, Ito A, Ohno Y, Nakamura M (2010) Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther 334:171–181

    Article  PubMed  CAS  Google Scholar 

  • Ishiyama T, Tokuda K, Ishibashi T, Ito A, Toma S, Ohno Y (2007) Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur J Pharmacol 572:160–170

    Article  PubMed  CAS  Google Scholar 

  • Krishnan V, Nestler EJ (2010) Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 167:1305–1320

    Article  PubMed  Google Scholar 

  • Lau AG, Irier HA, Gu J, Tian D, Ku L, Liu G, Xia M, Fritsch B, Zheng JQ, Dingledine R, Xu B, Lu B, Feng Y (2010) Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc Natl Acad Sci U S A 107:15945–15950

    Article  PubMed  CAS  Google Scholar 

  • Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG (2008) Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 60:358–403

    Article  PubMed  CAS  Google Scholar 

  • Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA, Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14:433–445

    Article  PubMed  CAS  Google Scholar 

  • Maragnoli ME, Fumagalli F, Gennarelli M, Racagni G, Riva MA (2004) Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain. Biol Psychiatry 55:1095–1102

    Article  PubMed  CAS  Google Scholar 

  • Marcus R, Khan A, Rollin L, Morris B, Timko K, Carson W, Sanchez R (2011) Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 13:133–144

    Article  PubMed  CAS  Google Scholar 

  • Meyer JM, Loebel AD, Schweizer E (2009) Lurasidone: a new drug in development for schizophrenia. Expert Opin Investig Drugs 18:1715–1726

    Article  PubMed  CAS  Google Scholar 

  • Molteni R, Calabrese F, Racagni G, Fumagalli F, Riva MA (2009) Antipsychotic drug actions on gene modulation and signaling mechanisms. Pharmacol Ther 124:74–85

    Article  PubMed  CAS  Google Scholar 

  • Molteni R, Calabrese F, Pisoni S, Gabriel C, Mocaer E, Racagni G, Riva MA (2010) Synergistic mechanisms in the modulation of the neurotrophin BDNF in the rat prefrontal cortex following acute agomelatine administration. World J Biol Psychiatry 11:148–153

    Article  PubMed  Google Scholar 

  • Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, Loebel A (2009) Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry 70:829–836

    Article  PubMed  CAS  Google Scholar 

  • Nivoli AM, Murru A, Goikolea JM, Crespo JM, Montes JM, Gonzalez-Pinto A, Garcia-Portilla P, Bobes J, Saiz-Ruiz J, Vieta E (2012) New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord 140:125–141

    Article  PubMed  Google Scholar 

  • Park SW, Phuong VT, Lee CH, Lee JG, Seo MK, Cho HY, Fang ZH, Lee BJ, Kim YH (2011) Effects of antipsychotic drugs on BDNF, GSK-3beta, and beta-catenin expression in rats subjected to immobilization stress. Neurosci Res 71:335–340

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1996) The rat brain in stereotaxis coordinates. Academic, New York

    Google Scholar 

  • Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276:36734–36741

    Article  PubMed  CAS  Google Scholar 

  • Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32

    Article  PubMed  CAS  Google Scholar 

  • Pruunsild P, Sepp M, Orav E, Koppel I, Timmusk T (2011) Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene. J Neurosci 31:3295–3308

    Article  PubMed  CAS  Google Scholar 

  • Riva MA, Molteni R, Tascedda F, Massironi A, Racagni G (1999) Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine. Neuropharmacology 38:1075–1082

    Article  PubMed  CAS  Google Scholar 

  • Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009a) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65:760–769

    Article  PubMed  CAS  Google Scholar 

  • Roth TL, Lubin FD, Sodhi M, Kleinman JE (2009b) Epigenetic mechanisms in schizophrenia. Biochim Biophys Acta 1790:869–877, Epub 2009 Jun 25

    Article  PubMed  CAS  Google Scholar 

  • Schloesser RJ, Martinowich K, Manji HK (2012) Mood-stabilizing drugs: mechanisms of action. Trends Neurosci 35:36–46

    Article  PubMed  CAS  Google Scholar 

  • Tascedda F, Blom JM, Brunello N, Zolin K, Gennarelli M, Colzi A, Bravi D, Carra S, Racagni G, Riva MA (2001) Modulation of glutamate receptors in response to the novel antipsychotic olanzapine in rats. Biol Psychiatry 50:117–122

    Article  PubMed  CAS  Google Scholar 

  • Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese JR, Bowden CL, Sachs GS, Kupfer DJ, Baker RW, Risser RC, Keeter EL, Feldman PD, Tollefson GD, Breier A (2002) Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 59:62–69

    Article  PubMed  CAS  Google Scholar 

  • Tomasetti C, Dell'Aversano C, Iasevoli F, Marmo F, de Bartolomeis A (2011) The acute and chronic effects of combined antipsychotic-mood stabilizing treatment on the expression of cortical and striatal postsynaptic density genes. Prog Neuropsychopharmacol Biol Psychiat 35:184–197

    Article  CAS  Google Scholar 

  • Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525

    Article  PubMed  CAS  Google Scholar 

  • Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367

    Article  PubMed  CAS  Google Scholar 

  • Vieta E, Gunther O, Locklear J, Ekman M, Miltenburger C, Chatterton ML, Astrom M, Paulsson B (2011) Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 14:1029–1049

    Article  PubMed  CAS  Google Scholar 

  • Wong EH, Tarazi FI, Shahid M (2010) The effectiveness of multi-target agents in schizophrenia and mood disorders: relevance of receptor signature to clinical action. Pharmacol Ther 126:173–185

    Article  PubMed  CAS  Google Scholar 

  • Xu H, Qing H, Lu W, Keegan D, Richardson JS, Chlan-Fourney J, Li XM (2002) Quetiapine attenuates the immobilization stress-induced decrease of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 321:65–68

    Article  PubMed  CAS  Google Scholar 

  • Yasuda S, Liang MH, Marinova Z, Yahyavi A, Chuang DM (2009) The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol Psychiatry 14:51–59

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dainippon Sumitono Pharma C. Ltd. for the generous gift of Lurasidone. This study was supported by a grant from Dainippon Sumitono Pharma C. Ltd/Sunovion Pharmaceuticals Inc. to M.A.R.

Conflict of interest

The authors Calabrese F, Luoni A., Guidotti G, and Fumagalli F have no financial interest or potential conflicts of interest. Racagni G has received compensation as speaker/consultant for Eli Lilly and Servier. Riva MA has received compensation as speaker/consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Servier, Takeda.

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Authors and Affiliations

  1. Center of Neuropharmacology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy

    F. Calabrese, A. Luoni, G. Guidotti, G. Racagni, F. Fumagalli & M. A. Riva

  2. Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milan, Italy

    G. Racagni & M. A. Riva

  3. I.R.C.C.S., Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

    G. Racagni

Authors
  1. F. Calabrese
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  2. A. Luoni
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  3. G. Guidotti
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  4. G. Racagni
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  5. F. Fumagalli
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  6. M. A. Riva
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Corresponding author

Correspondence to M. A. Riva.

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Calabrese, F., Luoni, A., Guidotti, G. et al. Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. Psychopharmacology 226, 101–112 (2013). https://doi.org/10.1007/s00213-012-2900-0

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  • DOI: https://doi.org/10.1007/s00213-012-2900-0

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