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Molecular mechanisms underlying synergistic effects of SSRI–antipsychotic augmentation in treatment of negative symptoms in schizophrenia

  • Basic Neurosciences, Genetics and Immunology - Review Article
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Abstract

Negative symptoms in schizophrenia respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRIs). The molecular mechanisms underlying the augmentation are unclear. Nevertheless, significant progress has been made, pointing to some candidate systems which may be involved in SSRI–antipsychotic synergism. Thus, the enhanced dopamine release by SSRI–antipsychotic treatment is modulated by specific serotonergic receptors and by tyrosine hydroxylase. There are modifications in gamma-aminobutyric acid system via glutamate decarboxylase 67, protein kinase C beta and the receptor for activated C-kinase 1 (Rack1). Some studies indicate the input of transcription and neurotrophic factors as phospho-cyclic adenosine monophosphate response element-binding protein, Fos and fibroblast growth factor-2. Alterations in calcium signaling (neurogranin, regulator of G-protein signaling and Rack1) and in cytokine receptors for interleukin-8 and chemokine have also been reported. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI–antipsychotic synergistic actions.

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References

  • Adson DE, Kushner MG, Eiben KM, Schulz SC (2004) Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake inhibitors. Depress Anxiety 19:121–126

    Article  PubMed  CAS  Google Scholar 

  • Advokat C (2005) Differential effects of clozapine versus other antipsychotics on clinical outcome and dopamine release in the brain. Essent Psychopharmacol 6:73–90

    PubMed  Google Scholar 

  • Ago Y, Nakamura S, Baba A, Matsuda T (2005) Sulpiride in combination with fluvoxamine increases in vivo dopamine release selectively in rat prefrontal cortex. Neuropsychopharmacology 30:43–51

    Article  PubMed  CAS  Google Scholar 

  • Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113:296–320

    Article  PubMed  CAS  Google Scholar 

  • Amsterdam JD, Shults J (2005) Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression—lack of manic induction. J Affect Disord 87:121–130

    Article  PubMed  CAS  Google Scholar 

  • Andreasen NC, Nopoulos P, Schultz S, Miller D, Gupta S, Swayze V, Flaum M (1994) Positive and negative symptoms of schizophrenia: past, present, and future. Acta Psychiatr Scand Suppl 384:51–59

    Article  PubMed  CAS  Google Scholar 

  • Avenoso A, Spina E, Campo G, Facciola G, Ferlito M, Zuccaro P, Perucca E, Caputi AP (1997) Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications. Pharmacol Res 35:335–339

    PubMed  CAS  Google Scholar 

  • Baldessarini RJ, Cohen BM, Teicher MH (1988) Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 45:79–91

    PubMed  CAS  Google Scholar 

  • Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I (2008) Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 1211:37–43

    Article  PubMed  CAS  Google Scholar 

  • Barbee JG, Conrad EJ, Jamhour NJ (2004) The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry 65:975–981

    PubMed  CAS  Google Scholar 

  • Benes FM, Vincent SL, Marie A, Khan Y (1996) Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75:1021–1031

    Article  PubMed  CAS  Google Scholar 

  • Bergemann N, Frick A, Parzer P, Kopitz J (2004) Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients. Pharmacopsychiatry 37:63–68

    Article  PubMed  CAS  Google Scholar 

  • Berman RM, Narasimhan M, Charney DS (1997) Treatment-refractory depression: definitions and characteristics. Depress Anxiety 5:154–164

    Article  PubMed  CAS  Google Scholar 

  • Bloch MH, Landeros-Weisenberger A, Kelmendi B, Coric V, Bracken MB, Leckman JF (2006) A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry 11:622–632

    Article  PubMed  CAS  Google Scholar 

  • Blum BP, Mann JJ (2002) The GABAergic system in schizophrenia. Int J Neuropsychopharmacol 5:159–179

    Article  PubMed  CAS  Google Scholar 

  • Bodkin JA, Siris SG, Bermanzohn PC, Hennen J, Cole JO (2005) Double-blind, placebo-controlled, multicenter trial of selegiline augmentation of antipsychotic medication to treat negative symptoms in outpatients with schizophrenia. Am J Psychiatry 162:388–390

    Article  PubMed  Google Scholar 

  • Bogan AM, Koran LM, Chuong HW, Vapnik T, Bystritsky A (2005) Quetiapine augmentation in obsessive-compulsive disorder resistant to serotonin reuptake inhibitors: an open-label study. J Clin Psychiatry 66:73–79

    PubMed  CAS  Google Scholar 

  • Bonaccorso S, Meltzer HY, Li Z, Dai J, Alboszta AR, Ichikawa J (2002) SR46349-B, a 5-HT(2A/2C) receptor antagonist, potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Neuropsychopharmacology 27:430–441

    Article  PubMed  CAS  Google Scholar 

  • Broadbelt K, Jones LB (2008) Evidence of altered calmodulin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. J Psychiatr Res 42:612–621

    Article  PubMed  Google Scholar 

  • Brosen K (1998) Differences in interactions of SSRIs. Int Clin Psychopharmacol 13(Suppl 5):S45–S47

    PubMed  Google Scholar 

  • Brown EB, McElroy SL, Keck PE Jr, Deldar A, Adams DH, Tohen M, Williamson DJ (2006) A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 67:1025–1033

    PubMed  CAS  Google Scholar 

  • Buckley PF, Mahadik S, Pillai A, Terry A Jr (2007) Neurotrophins and schizophrenia. Schizophr Res 94:1–11

    Article  PubMed  Google Scholar 

  • Burton S (2006) Symptom domains of schizophrenia: the role of atypical antipsychotic agents. J Psychopharmacol 20:6–19

    Article  PubMed  Google Scholar 

  • Bystritsky A, Ackerman DL, Rosen RM, Vapnik T, Gorbis E, Maidment KM, Saxena S (2004) Augmentation of serotonin reuptake inhibitors in refractory obsessive-compulsive disorder using adjunctive olanzapine: a placebo-controlled trial. J Clin Psychiatry 65:565–568

    PubMed  CAS  Google Scholar 

  • Campbell DB, Lange LA, Skelly T, Lieberman J, Levitt P, Sullivan PF (2008) Association of RGS2 and RGS5 variants with schizophrenia symptom severity. Schizophr Res 101:67–75

    Article  PubMed  Google Scholar 

  • Carey PD, Vythilingum B, Seedat S, Muller JE, van Ameringen M, Stein DJ (2005) Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. BMC Psychiatry 5:5

    Article  PubMed  CAS  Google Scholar 

  • Chaichan W (2004) Olanzapine plus fluvoxamine and olanzapine alone for the treatment of an acute exacerbation of schizophrenia. Psychiatry Clin Neurosci 58:364–368

    Article  PubMed  CAS  Google Scholar 

  • Chakravarthy B, Morley P, Whitfield J (1999) Ca2+–calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. Trends Neurosci 22:12–16

    Article  PubMed  CAS  Google Scholar 

  • Chertkow Y, Weinreb O, Youdim MB, Silver H (2006) The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex. Int J Neuropsychopharmacol 9:287–296

    Article  PubMed  CAS  Google Scholar 

  • Chertkow Y, Weinreb O, Youdim MB, Silver H (2007a) Dopamine and serotonin metabolism in response to chronic administration of fluvoxamine and haloperidol combined treatment. J Neural Transm 114(11):1443–1454

    Article  PubMed  CAS  Google Scholar 

  • Chertkow Y, Weinreb O, Youdim MB, Silver H (2007b) Gene expression changes in peripheral mononuclear cells from schizophrenic patients treated with a combination of antipsychotic with fluvoxamine. Prog Neuropsychopharmacol Biol Psychiatry 31:1356–1362

    Article  PubMed  CAS  Google Scholar 

  • Chiu CC, Lane HY, Huang MC, Liu HC, Jann MW, Hon YY, Chang WH, Lu ML (2004) Dose-dependent alternations in the pharmacokinetics of olanzapine during coadministration of fluvoxamine in patients with schizophrenia. J Clin Pharmacol 44:1385–1390

    Article  PubMed  CAS  Google Scholar 

  • Chlan-Fourney J, Ashe P, Nylen K, Juorio AV, Li XM (2002) Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 954:11–20

    Article  PubMed  CAS  Google Scholar 

  • Citrome L, Jaffe A, Levine J, Lindenmayer JP (2005) Dosing of quetiapine in schizophrenia: how clinical practice differs from registration studies. J Clin Psychiatry 66:1512–1516

    PubMed  Google Scholar 

  • Cochran SM, McKerchar CE, Morris BJ, Pratt JA (2002) Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol. Neuropharmacology 43:394–407

    Article  PubMed  CAS  Google Scholar 

  • Cohen BM, Wan W (1996) The thalamus as a site of action of antipsychotic drugs. Am J Psychiatry 153:104–106

    PubMed  CAS  Google Scholar 

  • Colombo PJ (2004) Learning-induced activation of transcription factors among multiple memory systems. Neurobiol Learn Mem 82:268–277

    Article  PubMed  CAS  Google Scholar 

  • Corey-Lisle PK, Birnbaum H, Greenberg P, Marynchenko M, Dube S (2003) Economic impact of olanzapine plus fluoxetine combination therapy among patients treated for depression: a pilot study. Psychopharmacol Bull 37:90–98

    PubMed  Google Scholar 

  • Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G (2006) A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety 23:364–372

    Article  PubMed  CAS  Google Scholar 

  • Cremers TI, Rea K, Bosker FJ, Wikstrom HV, Hogg S, Mork A, Westerink BH (2007) Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32:1550–1557

    Article  PubMed  CAS  Google Scholar 

  • D’Amico G, Cedro C, Muscatello MR, Pandolfo G, Di Rosa AE, Zoccali R, La Torre D, D’Arrigo C, Spina E (2003) Olanzapine augmentation of paroxetine-refractory obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 27:619–623

    Article  PubMed  CAS  Google Scholar 

  • de Oliveira IR, Dardennes RM, Amorim ES, Diquet B, de Sena EP, Moreira EC, de Castro-e-Silva EJ, Payan C, Fermanian J, Marcilio C et al (1995) Is there a relationship between antipsychotic blood levels and their clinical efficacy? An analysis of studies design and methodology. Fundam Clin Pharmacol 9:488–502

    Article  PubMed  Google Scholar 

  • Dell’Osso B, Altamura AC, Mundo E, Marazziti D, Hollander E (2007) Diagnosis and treatment of obsessive-compulsive disorder and related disorders. Int J Clin Pract 61:98–104

    Article  PubMed  CAS  Google Scholar 

  • Deng C, Huang XF (2006) Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia. Exp Brain Res 168:587–590

    Article  PubMed  CAS  Google Scholar 

  • Denys D, de Geus F, van Megen HJ, Westenberg HG (2004a) A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 65:1040–1048

    Article  PubMed  CAS  Google Scholar 

  • Denys D, Klompmakers AA, Westenberg HG (2004b) Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine. Psychopharmacology (Berl) 176:195–203

    Article  CAS  Google Scholar 

  • Deutch AY, Duman RS (1996) The effects of antipsychotic drugs on Fos protein expression in the prefrontal cortex: cellular localization and pharmacological characterization. Neuroscience 70:377–389

    Article  PubMed  CAS  Google Scholar 

  • Devoto P, Flore G, Vacca G, Pira L, Arca A, Casu MA, Pani L, Gessa GL (2003) Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic. Psychopharmacology (Berl) 167:79–84

    CAS  Google Scholar 

  • Dono R (2003) Fibroblast growth factors as regulators of central nervous system development and function. Am J Physiol Regul Integr Comp Physiol 284:R867–R881

    PubMed  CAS  Google Scholar 

  • Doree JP, Des Rosiers J, Lew V, Gendron A, Elie R, Stip E, Tourjman SV (2007) Quetiapine augmentation of treatment-resistant depression: a comparison with lithium. Curr Med Res Opin 23:333–341

    Article  PubMed  CAS  Google Scholar 

  • Dremencov E, El Mansari M, Blier P (2007) Noradrenergic augmentation of escitalopram response by risperidone: electrophysiologic studies in the rat brain. Biol Psychiatry 61:671–678

    Article  PubMed  CAS  Google Scholar 

  • Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS (2006) Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 20:532–545

    Article  PubMed  CAS  Google Scholar 

  • Dube S, Tollefson GD, Thase ME, Briggs SD, Van Campen LE, Case M, Tohen M (2007) Onset of antidepressant effect of olanzapine and olanzapine/fluoxetine combination in bipolar depression. Bipolar Disord 9:618–627

    Article  PubMed  CAS  Google Scholar 

  • Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M (2001) Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm 10:109–115

    Article  PubMed  CAS  Google Scholar 

  • Erdely HA, Tamminga CA, Roberts RC, Vogel MW (2006) Regional alterations in RGS4 protein in schizophrenia. Synapse 59:472–479

    Article  PubMed  CAS  Google Scholar 

  • Erzegovesi S, Guglielmo E, Siliprandi F, Bellodi L (2005) Low-dose risperidone augmentation of fluvoxamine treatment in obsessive-compulsive disorder: a double-blind, placebo-controlled study. Eur Neuropsychopharmacol 15:69–74

    Article  PubMed  CAS  Google Scholar 

  • Evins AE, Amico ET, Shih V, Goff DC (1997) Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics. J Neural Transm 104(6–7):761–766

    Article  Google Scholar 

  • Fatemi SH, Reutiman TJ, Folsom TD, Bell C, Nos L, Fried P, Pearce DA, Singh S, Siderovski DP, Willard FS, Fukuda M (2006) Chronic olanzapine treatment causes differential expression of genes in frontal cortex of rats as revealed by DNA microarray technique. Neuropsychopharmacology 31:1888–1899

    Article  PubMed  CAS  Google Scholar 

  • Fava M (2001) Augmentation and combination strategies in treatment-resistant depression. J Clin Psychiatry 62(Suppl 18):4–11

    PubMed  CAS  Google Scholar 

  • Feng J, Cai X, Zhao J, Yan Z (2001) Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci 21:6502–6511

    PubMed  CAS  Google Scholar 

  • Francobandiera G (2001) Olanzapine augmentation of serotonin uptake inhibitors in obsessive-compulsive disorder: an open study. Can J Psychiatry 46:356–358

    PubMed  CAS  Google Scholar 

  • Fumagalli F, Molteni R, Bedogni F, Gennarelli M, Perez J, Racagni G, Riva MA (2004) Quetiapine regulates FGF-2 and BDNF expression in the hippocampus of animals treated with MK-801. Neuroreport 15:2109–2112

    Article  PubMed  CAS  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 

  • Gobert A, Rivet JM, Cistarelli JM, Millan MJ (1997) Buspirone enhances duloxetine- and fluoxetine-induced increases in dialysate levels of dopamine and noradrenaline, but not serotonin, in the frontal cortex of freely moving rats. J Neurochem 68:1326–1329

    Article  PubMed  CAS  Google Scholar 

  • Goff DC, Freudenreich O, Evins AE (2001) Augmentation strategies in the treatment of schizophrenia. CNS Spectr 6:904, 907–911

    PubMed  CAS  Google Scholar 

  • Goforth HW, Carroll BT (2007) Aripiprazole augmentation of tranylcypromine in treatment-resistant major depression. J Clin Psychopharmacol 27:216–217

    Article  PubMed  Google Scholar 

  • Gu Z, Jiang Q, Yan Z (2007) RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia. Mol Pharmacol 71:1030–1039

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA (2008) Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 165:479–489

    Article  PubMed  Google Scholar 

  • Heinz A, Knable MB, Coppola R, Gorey JG, Jones DW, Lee KS, Weinberger DR (1998) Psychomotor slowing, negative symptoms and dopamine receptor availability—an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients. Schizophr Res 31:19–26

    Article  PubMed  CAS  Google Scholar 

  • Hellerstein DJ (2004) Aripiprazole as an adjunctive treatment for refractory major depression. Prog Neuropsychopharmacol Biol Psychiatry 28:1347–1348

    Article  PubMed  CAS  Google Scholar 

  • Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 56:29–36

    Article  PubMed  CAS  Google Scholar 

  • Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Hartter S, Modai I, Ritsner M, Silver H (2002) Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. J Clin Psychopharmacol 22:502–506

    Article  PubMed  CAS  Google Scholar 

  • Hirose S, Ashby CR Jr (2002) An open pilot study combining risperidone and a selective serotonin reuptake inhibitor as initial antidepressant therapy. J Clin Psychiatry 63:733–736

    PubMed  CAS  Google Scholar 

  • Hishimoto A, Shirakawa O, Nishiguchi N, Aoyama S, Ono H, Hashimoto T, Maeda K (2004) Novel missense polymorphism in the regulator of G-protein signaling 10 gene: analysis of association with schizophrenia. Psychiatry Clin Neurosci 58:579–581

    Article  PubMed  CAS  Google Scholar 

  • Hollander E, Baldini Rossi N, Sood E, Pallanti S (2003) Risperidone augmentation in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol 6:397–401

    Article  PubMed  CAS  Google Scholar 

  • Horowitz JM, Goyal A, Ramdeen N, Hallas BH, Horowitz AT, Torres G (2003) Characterization of fluoxetine plus olanzapine treatment in rats: a behavior, endocrine, and immediate-early gene expression analysis. Synapse 50:353–364

    Article  PubMed  CAS  Google Scholar 

  • Huang TL, Lee CT (2006) Associations between serum brain-derived neurotrophic factor levels and clinical phenotypes in schizophrenia patients. J Psychiatr Res 40:664–668

    Article  PubMed  Google Scholar 

  • Huang KP, Huang FL, Jager T, Li J, Reymann KG, Balschun D (2004) Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci 24:10660–10669

    Article  PubMed  CAS  Google Scholar 

  • Huang M, Ichiwaka J, Li Z, Dai J, Meltzer HY (2006a) Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex. Psychopharmacology (Berl) 185:274–281

    Article  CAS  Google Scholar 

  • Huang XF, Han M, Huang X, Zavitsanou K, Deng C (2006b) Olanzapine differentially affects 5-HT2A and 2C receptor mRNA expression in the rat brain. Behav Brain Res 171:355–362

    Article  PubMed  CAS  Google Scholar 

  • Ichikawa J, Li Z, Dai J, Meltzer HY (2002) Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res 956:349–357

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC (2006) Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 19:151–157

    Article  PubMed  Google Scholar 

  • Kalkman HO, Loetscher E (2003) GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. J Neural Transm 110:803–812

    PubMed  CAS  Google Scholar 

  • Kane JM, Khanna S, Rajadhyaksha S, Giller E (2006) Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 21:21–28

    Article  PubMed  Google Scholar 

  • Keck PE Jr, Corya SA, Altshuler LL, Ketter TA, McElroy SL, Case M, Briggs SD, Tohen M (2005) Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in the treatment of bipolar depression. J Clin Psychiatry 66:611–616

    PubMed  CAS  Google Scholar 

  • Kemp DE, Dago PL, Straus JL, Fleck J, Karaffa M, Gilmer WS (2007) Aripiprazole augmentation for treatment-resistant bipolar depression: sustained remission after 36 months. J Clin Psychopharmacol 27:304–305

    Article  PubMed  Google Scholar 

  • Ketter TA, Wang PW, Chandler RA, Culver JL, Alarcon AM (2006) Adjunctive aripiprazole in treatment-resistant bipolar depression. Ann Clin Psychiatry 18:169–172

    Article  PubMed  Google Scholar 

  • Koch S, Perry KW, Bymaster FP (2004) Brain region and dose effects of an olanzapine/fluoxetine combination on extracellular monoamine concentrations in the rat. Neuropharmacology 46:232–242

    Article  PubMed  CAS  Google Scholar 

  • Konradi C, Heckers S (2003) Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 97(2):153–179

    Article  PubMed  CAS  Google Scholar 

  • Kontkanen O, Lakso M, Wong G, Castren E (2002) Chronic antipsychotic drug treatment induces long-lasting expression of fos and jun family genes and activator protein 1 complex in the rat prefrontal cortex. Neuropsychopharmacology 27:152–162

    Article  PubMed  CAS  Google Scholar 

  • Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157:683–694

    Article  PubMed  CAS  Google Scholar 

  • Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781

    PubMed  CAS  Google Scholar 

  • Kyosseva SV (2004) Differential expression of mitogen-activated protein kinases and immediate early genes fos and jun in thalamus in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28:997–1006

    Article  PubMed  CAS  Google Scholar 

  • Kyosseva SV, Elbein AD, Hutton TL, Griffin ST, Mrak RE, Sturner WQ, Karson CN (2000) Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. Arch Gen Psychiatry 57:685–691

    Article  PubMed  CAS  Google Scholar 

  • Lammers CH, Deuschle M, Weigmann H, Hartter S, Hiemke C, Heese C, Heuser I (1999) Coadministration of clozapine and fluvoxamine in psychotic patients—clinical experience. Pharmacopsychiatry 32:76–77

    Article  PubMed  CAS  Google Scholar 

  • Landen M, Thase ME (2006) A model to explain the therapeutic effects of serotonin reuptake inhibitors: the role of 5-HT2 receptors. Psychopharmacol Bull 39:147–166

    PubMed  Google Scholar 

  • Lane HY, Huang CL, Wu PL, Liu YC, Chang YC, Lin PY, Chen PW, Tsai G (2006) Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry 60:645–649

    Article  PubMed  CAS  Google Scholar 

  • Li XM, Perry KW, Wong DT, Bymaster FP (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology (Berl) 136:153–161

    Article  CAS  Google Scholar 

  • Lidow MS (2003) Calcium signaling dysfunction in schizophrenia: a unifying approach. Brain Res Brain Res Rev 43:70–84

    Article  PubMed  CAS  Google Scholar 

  • Liegeois JF, Ichikawa J, Meltzer HY (2002) 5-HT(2A) receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner. Brain Res 947:157–165

    Article  PubMed  CAS  Google Scholar 

  • Linnarsson S, Willson CA, Ernfors P (2000) Cell death in regenerating populations of neurons in BDNF mutant mice. Brain Res Mol Brain Res 75:61–69

    Article  PubMed  CAS  Google Scholar 

  • Liu W, Yuen EY, Allen PB, Feng J, Greengard P, Yan Z (2006) Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc Natl Acad Sci USA 103:18338–18343

    Article  PubMed  CAS  Google Scholar 

  • Lu B, Martinowich K (2008) Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp 289:119–129, discussion 129–135, 193–195

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, Kenis G, Bosmans E, de Jongh R, Altamura CA (2002) Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 54:281–291

    Article  PubMed  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 

  • Marazziti D, Pfanner C, Dell’Osso B, Ciapparelli A, Presta S, Corretti G, Di Nasso E, Mungai F, Dell’Osso L (2005) Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study. J Psychopharmacol 19:392–394

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205–2215

    Article  PubMed  CAS  Google Scholar 

  • McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH (2000) A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57:794–801

    Article  PubMed  CAS  Google Scholar 

  • McElroy SL, Suppes T, Frye MA, Altshuler LL, Stanford K, Martens B, Leverich GS, Post RM, Keck PE Jr (2007) Open-label aripiprazole in the treatment of acute bipolar depression: a prospective pilot trial. J Affect Disord 101:275–281

    Article  PubMed  CAS  Google Scholar 

  • Melia KR, Rasmussen K, Terwilliger RZ, Haycock JW, Nestler EJ, Duman RS (1992) Coordinate regulation of the cyclic AMP system with firing rate and expression of tyrosine hydroxylase in the rat locus coeruleus: effects of chronic stress and drug treatments. J Neurochem 58:494–502

    Article  PubMed  CAS  Google Scholar 

  • Mereu G, Casu M, Gessa GL (1983) (−)-Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats. Brain Res 264:105–110

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Lejeune F, Gobert A (2000) Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol 14:114–138

    Article  PubMed  CAS  Google Scholar 

  • Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry 6:293–301

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Bunney BS (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755–1760

    Article  PubMed  CAS  Google Scholar 

  • Morishita S, Arita S (2003) Suitable dose and duration of fluvoxamine administration to treat depression. Psychiatry Clin Neurosci 57:177–181

    Article  PubMed  CAS  Google Scholar 

  • Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B, Agid Y, Hirsch E, Raisman-Vozari R (1999) An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease. Neuroscience 88:1015–1032

    Article  PubMed  CAS  Google Scholar 

  • Nemeroff CB (1997) Dosing the antipsychotic medication olanzapine. J Clin Psychiatry 58(Suppl 10):45–49

    PubMed  CAS  Google Scholar 

  • Nierenberg AA (2007) Combined olanzapine plus fluoxetine modestly improves symptoms of acute bipolar I depression compared to lamotrigine. Evid Based Ment Health 10:12

    Article  PubMed  Google Scholar 

  • Nikitin VP (2007) A new mechanism of synapse-specific neuronal plasticity. Neurosci Behav Physiol 37:559–570

    Article  PubMed  CAS  Google Scholar 

  • Nomikos GG, Iurlo M, Andersson JL, Kimura K, Svensson TH (1994) Systemic administration of amperozide, a new atypical antipsychotic drug, preferentially increases dopamine release in the rat medial prefrontal cortex. Psychopharmacology (Berl) 115:147–156

    Article  CAS  Google Scholar 

  • Novak G, Seeman P, Tallerico T (2006) Increased expression of calcium/calmodulin-dependent protein kinase IIbeta in frontal cortex in schizophrenia and depression. Synapse 59:61–68

    Article  PubMed  CAS  Google Scholar 

  • O’Connor M, Silver H (1998) Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression. J Clin Psychopharmacol 18:89–91

    Article  PubMed  Google Scholar 

  • Ordway GA, Szebeni K (2004) Effect of repeated treatment with olanzapine or olanzapine plus fluoxetine on tyrosine hydroxylase in the rat locus coeruleus. Int J Neuropsychopharmacol 7:321–327

    Article  PubMed  CAS  Google Scholar 

  • Ostroff RB, Nelson JC (1999) Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60:256–259

    PubMed  CAS  Google Scholar 

  • Otto D, Unsicker K (1990) Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J Neurosci 10:1912–1921

    PubMed  CAS  Google Scholar 

  • Owen RT (2006) Olanzapine/fluoxetine combination for bipolar depression and other mood disorders: a review. Drugs Today (Barc) 42:185–192

    Article  CAS  Google Scholar 

  • Pak JH, Huang FL, Li J, Balschun D, Reymann KG, Chiang C, Westphal H, Huang KP (2000) Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: a study with knockout mice. Proc Natl Acad Sci USA 97:11232–11237

    Article  PubMed  CAS  Google Scholar 

  • Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE, Fava M, Nierenberg AA (2005) Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder. J Clin Psychiatry 66:1326–1330

    Article  PubMed  CAS  Google Scholar 

  • Parikh V, Khan MM, Mahadik SP (2004) Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol. Neurosci Lett 356:135–139

    Article  PubMed  CAS  Google Scholar 

  • Patkar AA, Peindl K, Mago R, Mannelli P, Masand PS (2006) An open-label, rater-blinded, augmentation study of aripiprazole in treatment-resistant depression. Prim Care Companion J Clin Psychiatry 8:82–87

    Article  PubMed  Google Scholar 

  • Patterson RL, van Rossum DB, Barrow RK, Snyder SH (2004) RACK1 binds to inositol 1,4,5-triphosphate receptors and mediates Ca2+ release. Proc Natl Acad Sci USA 101:2328–2332

    Article  PubMed  CAS  Google Scholar 

  • Pehek EA, Nocjar C, Roth BL, Byrd TA, Mabrouk OS (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265–277

    Article  PubMed  CAS  Google Scholar 

  • Pezet S, Cunningham J, Patel J, Grist J, Gavazzi I, Lever IJ, Malcangio M (2002) BDNF modulates sensory neuron synaptic activity by a facilitation of GABA transmission in the dorsal horn. Mol Cell Neurosci 21:51–62

    Article  PubMed  CAS  Google Scholar 

  • Pillai A (2008) Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia. Neurosignals 16:183–193

    Article  PubMed  CAS  Google Scholar 

  • Pillai A, Terry AV Jr, Mahadik SP (2006) Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res 82:95–106

    Article  PubMed  Google Scholar 

  • Pinna G, Costa E, Guidotti A (2006) Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology (Berl) 186:362–372

    Article  CAS  Google Scholar 

  • Pollmacher T, Hinze-Selch D, Mullington J (1996) Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 16:403–409

    Article  PubMed  CAS  Google Scholar 

  • Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63:801–808

    Article  PubMed  CAS  Google Scholar 

  • Poyurovsky M, Kurs R, Weizman A (2003) Olanzapine–sertraline combination in schizophrenia with obsessive-compulsive disorder. J Clin Psychiatry 64:611

    Article  PubMed  Google Scholar 

  • Pozzi L, Hakansson K, Usiello A, Borgkvist A, Lindskog M, Greengard P, Fisone G (2003) Opposite regulation by typical and atypical anti-psychotics of ERK1/2, CREB and Elk-1 phosphorylation in mouse dorsal striatum. J Neurochem 86:451–459

    Article  PubMed  CAS  Google Scholar 

  • Rapaport MH, Gharabawi GM, Canuso CM, Mahmoud RA, Keller MB, Bossie CA, Turkoz I, Lasser RA, Loescher A, Bouhours P, Dunbar F, Nemeroff CB (2006) Effects of risperidone augmentation in patients with treatment-resistant depression: results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology 31:2505–2513

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen K (2006) Creating more effective antidepressants: clues from the clinic. Drug Discov Today 11:623–631

    Article  PubMed  CAS  Google Scholar 

  • Reynolds GP, Zhang ZJ, Beasley CL (2001) Neurochemical correlates of cortical GABAergic deficits in schizophrenia: selective losses of calcium binding protein immunoreactivity. Brain Res Bull 55:579–584

    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 

  • Roberts DS, Hu Y, Lund IV, Brooks-Kayal AR, Russek SJ (2006) Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor alpha 4 subunits in hippocampal neurons. J Biol Chem 281:29431–29435

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Sanchez P, Tejero-Diez P, Diez-Guerra FJ (1997) Glutamate stimulates neurogranin phosphorylation in cultured rat hippocampal neurons. Neurosci Lett 221:137–140

    Article  PubMed  CAS  Google Scholar 

  • Rollema H, Lu Y, Schmidt AW, Sprouse JS, Zorn SH (2000) 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry 48:229–237

    Article  PubMed  CAS  Google Scholar 

  • Ruano D, Aulchenko YS, Macedo A, Soares MJ, Valente J, Azevedo MH, Hutz MH, Gama CS, Lobato MI, Belmonte-de-Abreu P, Goodman AB, Pato C, Heutink P, Palha JA (2008) Association of the gene encoding neurogranin with schizophrenia in males. J Psychiatr Res 42:125–133

    Article  PubMed  Google Scholar 

  • Rummel C, Kissling W, Leucht S (2006) Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev 3:CD005581

    PubMed  CAS  Google Scholar 

  • Rutherford B, Sneed J, Miyazaki M, Eisenstadt R, Devanand D, Sackeim H, Roose S (2007) An open trial of aripiprazole augmentation for SSRI non-remitters with late-life depression. Int J Geriatr Psychiatry 22(10):986–991

    Article  PubMed  Google Scholar 

  • Schmitt A, May B, Muller B, Jatzko A, Petroianu G, Braus DF, Henn FA (2003) Effects of chronic haloperidol and clozapine treatment on AMPA and kainate receptor binding in rat brain. Pharmacopsychiatry 36:292–296

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M, Silver H (2000) Lymphocytes, autoantibodies and psychosis—coincidence versus etiological factor: an update. Isr J Psychiatry Relat Sci 37:32–36

    PubMed  CAS  Google Scholar 

  • Seager MA, Huff KD, Barth VN, Phebus LA, Rasmussen K (2004) Fluoxetine administration potentiates the effect of olanzapine on locus coeruleus neuronal activity. Biol Psychiatry 55:1103–1109

    Article  PubMed  CAS  Google Scholar 

  • Seager MA, Barth VN, Phebus LA, Rasmussen K (2005) Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder. Psychopharmacology (Berl) 181:126–133

    Article  CAS  Google Scholar 

  • Seeman P, Ko F, Jack E, Greenstein R, Dean B (2007) Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Synapse 61:303–309

    Article  PubMed  CAS  Google Scholar 

  • Semba J, Sakai MW, Suhara T, Akanuma N (1999) Differential effects of acute and chronic treatment with typical and atypical neuroleptics on c-fos mRNA expression in rat forebrain regions using non-radioactive in situ hybridization. Neurochem Int 34:269–277

    Article  PubMed  CAS  Google Scholar 

  • Sevincok L, Topuz A (2003) Lack of efficacy of low doses of quetiapine addition in refractory obsessive-compulsive disorder. J Clin Psychopharmacol 23:448–450

    PubMed  CAS  Google Scholar 

  • Shapira NA, Ward HE, Mandoki M, Murphy TK, Yang MC, Blier P, Goodman WK (2004) A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry 55:553–555

    Article  PubMed  CAS  Google Scholar 

  • Shelton RC (2003) The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother 4:1175–1183

    Article  PubMed  CAS  Google Scholar 

  • Shelton RC (2006) Olanzapine/fluoxetine combination for bipolar depression. Expert Rev Neurother 6:33–39

    Article  PubMed  CAS  Google Scholar 

  • Shelton RC, Williamson DJ, Corya SA, Sanger TM, Van Campen LE, Case M, Briggs SD, Tollefson GD (2005) Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry 66:1289–1297

    PubMed  CAS  Google Scholar 

  • Shi L, Namjoshi MA, Swindle R, Yu X, Risser R, Baker RW, Tohen M (2004) Effects of olanzapine alone and olanzapine/fluoxetine combination on health-related quality of life in patients with bipolar depression: secondary analyses of a double-blind, placebo-controlled, randomized clinical trial. Clin Ther 26:125–134

    Article  PubMed  CAS  Google Scholar 

  • Shim SS, Hammonds MD, Kee BS (2008) Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. Eur Arch Psychiatry Clin Neurosci 258:16–27

    Article  PubMed  Google Scholar 

  • Silver H (2001) Fluvoxamine as an adjunctive agent in schizophrenia. CNS Drug Rev 7:283–304

    PubMed  CAS  Google Scholar 

  • Silver H, Nassar A (1992) Fluvoxamine improves negative symptoms in treated chronic schizophrenia: an add-on double-blind, placebo-controlled study. Biol Psychiatry 31:698–704

    Article  PubMed  CAS  Google Scholar 

  • Silver H, Shmugliakov N (1998) Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin Psychopharmacol 18:208–211

    Article  PubMed  CAS  Google Scholar 

  • Silver H, Kaplan A, Jahjah N (1995) Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry 152:1098

    PubMed  CAS  Google Scholar 

  • Silver H, Kushnir M, Kaplan A (1996) Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. Biol Psychiatry 40:671–674

    Article  PubMed  CAS  Google Scholar 

  • Silver H, Barash I, Aharon N, Kaplan A, Poyurovsky M (2000) Fluvoxamine augmentation of antipsychotics improves negative symptoms in psychotic chronic schizophrenic patients: a placebo-controlled study. Int Clin Psychopharmacol 15:257–261

    Article  PubMed  CAS  Google Scholar 

  • Silver H, Knoll G, Isakov V, Goodman C, Finkelstein Y (2005) Blood DHEAS concentrations correlate with cognitive function in chronic schizophrenia patients: a pilot study. J Psychiatr Res 39:569–575

    Article  PubMed  Google Scholar 

  • Simon JS, Nemeroff CB (2005) Aripiprazole augmentation of antidepressants for the treatment of partially responding and nonresponding patients with major depressive disorder. J Clin Psychiatry 66:1216–1220

    PubMed  CAS  Google Scholar 

  • Simpson GM, Glick ID, Weiden PJ, Romano SJ, Siu CO (2004) Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry 161:1837–1847

    Article  PubMed  Google Scholar 

  • Siris SG (1993) Adjunctive medication in the maintenance treatment of schizophrenia and its conceptual implications. Br J Psychiatry 22(Suppl):66–78

    Google Scholar 

  • Sokolski KN (2007) Adjunctive aripiprazole in bipolar I depression. Ann Pharmacother 41:35–40

    PubMed  CAS  Google Scholar 

  • Sokolski KN, Denson TF (2003) Adjunctive quetiapine in bipolar patients partially responsive to lithium or valproate. Prog Neuropsychopharmacol Biol Psychiatry 27:863–866

    Article  PubMed  CAS  Google Scholar 

  • Spedding M, Gressens P (2008) Neurotrophins and cytokines in neuronal plasticity. Novartis Found Symp 289:222–233, discussion 233–240

    Article  PubMed  CAS  Google Scholar 

  • Spina E, de Leon J (2007) Metabolic drug interactions with newer antipsychotics: a comparative review. Basic Clin Pharmacol Toxicol 100:4–22

    Article  PubMed  CAS  Google Scholar 

  • Sproule BA, Otton SV, Cheung SW, Zhong XH, Romach MK, Sellers EM (1997) CYP2D6 inhibition in patients treated with sertraline. J Clin Psychopharmacol 17:102–106

    Article  PubMed  CAS  Google Scholar 

  • Spurney CF, Baca SM, Murray AM, Jaskiw GE, Kleinman JE, Hyde TM (1999) Differential effects of haloperidol and clozapine on ionotropic glutamate receptors in rats. Synapse 34(4):266–276

    Article  PubMed  CAS  Google Scholar 

  • Stoll AL, Haura G (2000) Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol 20:495–496

    Article  PubMed  CAS  Google Scholar 

  • Strous RD (2005) Dehydroepiandrosterone (DHEA) augmentation in the management of schizophrenia symptomatology. Essent Psychopharmacol 6:141–147

    PubMed  Google Scholar 

  • Szabo ST, Blier P (2002) Effects of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition plus 5-HT(2A) receptor antagonism on the firing activity of norepinephrine neurons. J Pharmacol Exp Ther 302:983–991

    Article  PubMed  CAS  Google Scholar 

  • Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, Hartter S, Hiemke C, Wetzel H (1999) Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial. Pharmacopsychiatry 32:148–153

    Article  PubMed  CAS  Google Scholar 

  • Tan YL, Zhou DF, Cao LY, Zou YZ, Zhang XY (2005) Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics. Neurosci Lett 382:27–32

    Article  PubMed  CAS  Google Scholar 

  • Tani K, Takei N, Kawai M, Suzuki K, Sekine Y, Toyoda T, Minabe Y, Mori N (2004) Augmentation of milnacipran by risperidone in treatment for major depression. Int J Neuropsychopharmacol 7:55–58

    Article  PubMed  CAS  Google Scholar 

  • Tarazi FI, Baldessarini RJ, Kula NS, Zhang K (2003) Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther 306:1145–1151

    Article  PubMed  CAS  Google Scholar 

  • Tischmeyer W, Grimm R (1999) Activation of immediate early genes and memory formation. Cell Mol Life Sci 55:564–574

    Article  PubMed  CAS  Google Scholar 

  • Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A (2003) Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088

    Article  PubMed  CAS  Google Scholar 

  • Tsai G, Coyle JT (2002) Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165–179

    Article  PubMed  CAS  Google Scholar 

  • Tsai GE, Yang P, Chang YC, Chong MY (2006) d-Alanine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 59:230–234

    Article  PubMed  CAS  Google Scholar 

  • Verma V, Lim EP, Han SP, Nagarajah R, Dawe GS (2007) Chronic high-dose haloperidol has qualitatively similar effects to risperidone and clozapine on immediate-early gene and tyrosine hydroxylase expression in the rat locus coeruleus but not medial prefrontal cortex. Neurosci Res 57:17–28

    Article  PubMed  CAS  Google Scholar 

  • Volavka J, Cooper TB, Czobor P, Lindenmayer JP, Citrome LL, Mohr P, Bark N (2000) High-dose treatment with haloperidol: the effect of dose reduction. J Clin Psychopharmacol 20:252–256

    Article  PubMed  CAS  Google Scholar 

  • Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA (2000) Decreased glutamic acid decarboxylase 67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. Arch Gen Psychiatry 57:237–245

    Article  PubMed  CAS  Google Scholar 

  • Wan W, Ennulat DJ, Cohen BM (1995) Acute administration of typical and atypical antipsychotic drugs induces distinctive patterns of Fos expression in the rat forebrain. Brain Res 688:95–104

    Article  PubMed  CAS  Google Scholar 

  • Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C (2001) Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 23:410–413

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DR, Berman KF (1996) Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 351:1495–1503

    Article  PubMed  CAS  Google Scholar 

  • Weiss EL, Potenza MN, McDougle CJ, Epperson CN (1999) Olanzapine addition in obsessive-compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series. J Clin Psychiatry 60:524–527

    PubMed  CAS  Google Scholar 

  • Werme M, Ringholm A, Olson L, Brene S (2000) Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine. Brain Res 863:112–119

    Article  PubMed  CAS  Google Scholar 

  • Westerink BH, Kawahara Y, De Boer P, Geels C, De Vries JB, Wikstrom HV, Van Kalkeren A, Van Vliet B, Kruse CG, Long SK (2001) Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum. Eur J Pharmacol 412:127–138

    Article  PubMed  CAS  Google Scholar 

  • Wetmore C, Ernfors P, Persson H, Olson L (1990) Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization. Exp Neurol 109:141–152

    Article  PubMed  CAS  Google Scholar 

  • Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S, Hiemke C (1998) Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol 18:2–9

    Article  PubMed  CAS  Google Scholar 

  • Williams R (2001) Optimal dosing with risperidone: updated recommendations. J Clin Psychiatry 62:282–289

    PubMed  CAS  Google Scholar 

  • Worthington JJ 3rd, Kinrys G, Wygant LE, Pollack MH (2005) Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients. Int Clin Psychopharmacol 20:9–11

    Article  PubMed  Google Scholar 

  • Xu H, Chen Z, He J, Haimanot S, Li X, Dyck L, Li XM (2006) Synergetic effects of quetiapine and venlafaxine in preventing the chronic restraint stress-induced decrease in cell proliferation and BDNF expression in rat hippocampus. Hippocampus 16:551–559

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto BK, Cooperman MA (1994) Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159–4166

    PubMed  CAS  Google Scholar 

  • Yasui-Furukori N, Kondo T, Mihara K, Inoue Y, Kaneko S (2004) Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia. Psychopharmacology (Berl) 171:223–227

    Article  CAS  Google Scholar 

  • Yoshimura R, Kaneko S, Shinkai K, Nakamura J (2006) Successful treatment for obsessive-compulsive disorder with addition of low-dose risperidone to fluvoxamine: implications for plasma levels of catecholamine metabolites and serum brain-derived neurotrophic factor levels. Psychiatry Clin Neurosci 60:389–393

    Article  PubMed  CAS  Google Scholar 

  • Yoshino T, Nisijima K, Shioda K, Yui K, Katoh S (2004) Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medial prefrontal cortex. Neurosci Lett 364:16–21

    Article  PubMed  CAS  Google Scholar 

  • Youngren KD, Inglis FM, Pivirotto PJ, Jedema HP, Bradberry CW, Goldman-Rakic PS, Roth RH, Moghaddam B (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20:403–412

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP (2000) Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23:250–262

    Article  PubMed  CAS  Google Scholar 

  • Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC (2002) Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res 57:247–258

    Article  PubMed  Google Scholar 

  • Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC (2005) Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 30:1532–1538

    Article  PubMed  CAS  Google Scholar 

  • Zhang HX, Zhao JP, Lv LX, Li WQ, Xu L, Ouyang X, Yuan ZQ, Huang JS (2007) Explorative study on the expression of neuregulin-1 gene in peripheral blood of schizophrenia. Neurosci Lett 438(1):1–5

    Article  PubMed  CAS  Google Scholar 

  • Zink M (2005) Augmentation of olanzapine in treatment-resistant schizophrenia. J Psychiatry Neurosci 30:409–415

    PubMed  Google Scholar 

  • Zink M, Schmitt A, May B, Muller B, Braus DF, Henn FA (2004a) Differential effects of long-term treatment with clozapine or haloperidol on GABA transporter expression. Pharmacopsychiatry 37:171–174

    Article  PubMed  CAS  Google Scholar 

  • Zink M, Schmitt A, May B, Muller B, Demirakca T, Braus DF, Henn FA (2004b) Differential effects of long-term treatment with clozapine or haloperidol on GABAA receptor binding and GAD67 expression. Schizophr Res 66:151–157

    Article  PubMed  Google Scholar 

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Acknowledgment

The authors gratefully acknowledge the generous assistance of Prof. Hiemke and co-workers at Mainz, Germany.

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  1. Eve Topf Center of Excellence for Neurodegenerative Diseases Research, Department of Pharmacology, Technion-Faculty of Medicine, Haifa, Israel

    Yael Chertkow, Orly Weinreb & Moussa B. H. Youdim

  2. Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC, Mobile Post, 38814, Hefer, Israel

    Henry Silver

  3. Molecular Neuropsychiatry Unit, Shaar Menashe Brain Behavior Laboratory, Technion-Faculty of Medicine, Shaar Menashe MHC, Haifa, Israel

    Henry Silver

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  1. Yael Chertkow
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Correspondence to Henry Silver.

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Chertkow, Y., Weinreb, O., Youdim, M.B.H. et al. Molecular mechanisms underlying synergistic effects of SSRI–antipsychotic augmentation in treatment of negative symptoms in schizophrenia. J Neural Transm 116, 1529–1541 (2009). https://doi.org/10.1007/s00702-009-0255-4

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