When Clozapine Fails: Augmentation Strategies in the Management of Clozapine-Resistant Schizophrenia

  • Domenico De BerardisEmail author
  • Michele Fornaro
  • Annalisa Anastasia
  • Federica Vellante
  • Alessandro Valchera
  • Marilde Cavuto
  • Giampaolo Perna
  • Marco Di Nicola
  • Gianluca Serafini
  • Alessandro Carano
  • Maurizio Pompili
  • Laura Orsolini
  • Carmine Tomasetti
  • Gabriella Di Emidio
  • Giovanni Martinotti
  • Massimo Di Giannantonio


Schizophrenia is a chronic and debilitating illness affecting about 0.5% of the population. Antipsychotics are the mainstay of the pharmacological treatment of such burdensome condition, although documented that roughly 20% up to 60% of the patients with schizophrenia do not respond sufficiently to conventional treatments. These patients may have a good response when clozapine is introduced with a great efficacy often seen in everyday clinical practice. However, it has been estimated that around 40–70% of patients with ascertained treatment-resistant schizophrenia receiving clozapine may have an incomplete remission and are referred to as “ultra-resistant” or “refractory.” Clozapine-resistant schizophrenia represents a challenge for the clinician and a misfortune for the patients, and several strategies have been proposed to overcome this problem, yet, to date, it remains high-bar goal. The aim of this chapter was to provide an overview of the managing strategies of clozapine-resistant schizophrenia with a particular focus on augmentation strategies aimed to improve efficacy on schizophrenia symptoms.


Clozapine Refractory Ultra-resistant Augmentation Add-on Efficacy Tolerability 


  1. 1.
    Simeone JC, Ward AJ, Rotella P, Collins J, Windisch R. An evaluation of variation in published estimates of schizophrenia prevalence from 1990 horizontal line 2013: a systematic literature review. BMC Psychiatry. 2015;15:193.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Galderisi S, Rucci P, Kirkpatrick B, Mucci A, Gibertoni D, Rocca P, et al. Interplay among psychopathologic variables, personal resources, context-related factors, and real-life functioning in individuals with schizophrenia: a network analysis. JAMA Psychiat. 2018;75:396–404.CrossRefGoogle Scholar
  3. 3.
    Ebisch SJ, Mantini D, Northoff G, Salone A, De Berardis D, Ferri F, et al. Altered brain long-range functional interactions underlying the link between aberrant self-experience and self-other relationship in first-episode schizophrenia. Schizophr Bull. 2014;40(5):1072–82.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Marasco V, De Berardis D, Serroni N, Campanella D, Acciavatti T, Caltabiano M, et al. Alexithymia and suicide risk among patients with schizophrenia: preliminary findings of a cross-sectional study. Riv Psichiatr. 2011;46(1):31–7.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Ebisch SJ, Salone A, Ferri F, De Berardis D, Romani GL, Ferro FM, et al. Out of touch with reality? Social perception in first-episode schizophrenia. Soc Cogn Affect Neurosci. 2013;8(4):394–403.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Iasevoli F, Giordano S, Balletta R, Latte G, Formato MV, Prinzivalli E, et al. Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;65:34–48.CrossRefGoogle Scholar
  7. 7.
    Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216–29.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Orsolini L, Tomasetti C, Valchera A, Vecchiotti R, Matarazzo I, Vellante F, et al. An update of safety of clinically used atypical antipsychotics. Expert Opin Drug Saf. 2016;15(10):1329–47.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    De Berardis D, Marini S, Carano A, Lang AP, Cavuto M, Piersanti M, et al. Efficacy and safety of long acting injectable atypical antipsychotics: a review. Curr Clin Pharmacol. 2013;8(3):256–64.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Warnez S, Alessi-Severini S. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry. 2014;14:102.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–96.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Siskind D, McCartney L, Goldschlager R, Kisely S. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    De Berardis D, Serroni N, Campanella D, Olivieri L, Marini S, Moschetta FS, et al. Safety and efficacy of combined clozapine-azathioprine treatment in a case of resistant schizophrenia associated with Behcet’s disease: a 2-year follow-up. Gen Hosp Psychiatry. 2013;35(2):213.e9–11.CrossRefGoogle Scholar
  14. 14.
    Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;21(1):CD000059.Google Scholar
  15. 15.
    Nucifora FC Jr, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a model for antipsychotic development. Neurotherapeutics. 2017;14(3):750–61.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    De Berardis D, Serroni N, Campanella D, Olivieri L, Ferri F, Carano A, et al. Update on the adverse effects of clozapine: focus on myocarditis. Curr Drug Saf. 2012;7(1):55–62.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Williams L, Newton G, Roberts K, Finlayson S, Brabbins C. Clozapine-resistant schizophrenia: a positive approach. Br J Psychiatry. 2002;181:184–7.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Dratcu L, Grandison A, McKay G, Bamidele A, Vasudevan V. Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day. Am J Ther. 2007;14(3):314–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jain M, Karia S, De Sousa A. Clozapine-resistant schizophrenia: strategies for the busy clinician. Ind J Priv Psychiatry. 2017;11(2):17–23.Google Scholar
  20. 20.
    Li YY, Zhang YS, Wang J, Li KQ, Wang HY. Optimal treatment strategies of clozapine for refractory schizophrenia. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2016;38(6):666–78.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Mouaffak F, Tranulis C, Gourevitch R, Poirier MF, Douki S, Olie JP, et al. Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia. Clin Neuropharmacol. 2006;29(1):28–33.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Remington G, Saha A, Chong SA, Shammi C. Augmenting strategies in clozapine-resistant schizophrenia. CNS Drugs. 2006;20(2):171.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Kudva G, Gupta D. Strategies in clozapine-resistant schizophrenia: a literature review. J Ment Health Hum Behav. 2016;21(1):6–15.CrossRefGoogle Scholar
  24. 24.
    Vayisoglu S, Anil YE. Augmentation strategies in patients with schizophrenia who show partial response to clozapine treatment. Turk Psikiyatri Derg. 2014;25(3):201–11.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Silveira da Mota Neto JI, et al. Amisulpride versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;1:CD006624.Google Scholar
  26. 26.
    Tufan AE, Yalug I. Clozapine augmented with amisulpride in 3 cases of treatment-resistant early- and very early-onset schizophrenia. J Clin Psychopharmacol. 2013;33(4):572–4.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Zink M, Knopf U, Henn FA, Thome J. Combination of clozapine and amisulpride in treatment-resistant schizophrenia – case reports and review of the literature. Pharmacopsychiatry. 2004;37(1):26–31.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry. 2008;41(1):24–8.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Hotham JE, Simpson PJ, Brooman-White RS, Basu A, Ross CC, Humphreys SA, et al. Augmentation of clozapine with amisulpride: an effective therapeutic strategy for violent treatment-resistant schizophrenia patients in a UK high-security hospital. CNS Spectr. 2014;19(5):403–10.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Kreinin A, Miodownik C, Sokolik S, Shestakova D, Libov I, Bergman J, et al. Amisulpride versus moclobemide in treatment of clozapineinduced hypersalivation. World J Biol Psychiatry. 2011;12(8):620–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Kreinin A, Novitski D, Weizman A. Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol. 2006;21(2):99–103.PubMedCrossRefGoogle Scholar
  32. 32.
    Croissant B, Hermann D, Olbrich R. Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-induced hypersalivation-a case report. Pharmacopsychiatry. 2005;38(1):38–9.PubMedCrossRefGoogle Scholar
  33. 33.
    De Berardis D, Fornaro M, Serroni N, Marini S, Piersanti M, Cavuto M, et al. Treatment of antipsychotic-induced hyperprolactinemia: an update on the role of the dopaminergic receptors D2 partial agonist aripiprazole. Recent Pat Endocr Metab Immune Drug Discov. 2014;8(1):30–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Martinotti G, Orsolini L, Fornaro M, Vecchiotti R, De Berardis D, Iasevoli F, et al. Aripiprazole for relapse prevention and craving in alcohol use disorder: current evidence and future perspectives. Expert Opin Investig Drugs. 2016;25(6):719–28.PubMedCrossRefGoogle Scholar
  35. 35.
    de Bartolomeis A, Tomasetti C, Iasevoli F. Update on the mechanism of action of aripiprazole: translational insights into antipsychotic strategies beyond dopamine receptor antagonism. CNS Drugs. 2015;29(9):773–99.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Sepede G, Di Iorio G, Spano MC, Lorusso M, Sarchione F, Santacroce R, et al. A case of resistant schizophrenia successfully treated with clozapine/long-acting injectable aripiprazole combination. Clin Neuropharmacol. 2016;39(6):322–4.PubMedCrossRefGoogle Scholar
  37. 37.
    Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(5):720–31.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Fleischhacker WW, Heikkinen ME, Olie JP, Landsberg W, Dewaele P, McQuade RD, et al. Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine: a randomized, double-blind, placebo-controlled trial. Int J Neuropsychopharmacol. 2010;13(8):1115–25.PubMedCrossRefGoogle Scholar
  39. 39.
    Henderson DC, Kunkel L, Nguyen DD, Borba CP, Daley TB, Louie PM, et al. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand. 2006;113(2):142–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Cipriani A, Accordini S, Nose M, Purgato M, Girlanda F, Tansella M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial. J Clin Psychopharmacol. 2013;33(4):533–7.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Bachmann CJ, Lehr D, Theisen FM, Preiss M. Aripiprazole as an adjunct to clozapine therapy in adolescents with early-onset schizophrenia: a retrospective chart review. Pharmacopsychiatry. 2009;42(4):153–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, et al. Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: an open-label pilot study. Prog Neuro-Psychopharmacol Biol Psychiatry. 2007;31(2):373–7.CrossRefGoogle Scholar
  43. 43.
    Karunakaran K, Tungaraza TE, Harborne GC. Is clozapine-aripiprazole combination a useful regime in the management of treatmentresistant schizophrenia? J Psychopharmacol. 2007;21(4):453–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Ziegenbein M, Wittmann G, Kropp S. Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia: a clinical observation. Clin Drug Investig. 2006;26(3):117–24.PubMedCrossRefGoogle Scholar
  45. 45.
    De Risio A, Pancheri A, Simonetti G, Giannarelli D, Stefanutto L, Gentile B. Add-on of aripiprazole improves outcome in clozapine-resistant schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2011;35(4):1112–6.CrossRefGoogle Scholar
  46. 46.
    Muscatello MR, Bruno A, Pandolfo G, Mico U, Scimeca G, Di Nardo F, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res. 2011;127(1–3):93–9.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Galling B, Roldan A, Hagi K, Rietschel L, Walyzada F, Zheng W, et al. Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta-analysis and meta-regression analysis. World Psychiatry. 2017;16(1):77–89.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    McCarthy RH, Terkelsen KG. Risperidone augmentation of clozapine. Pharmacopsychiatry. 1995;28(2):61–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Raskin S, Katz G, Zislin Z, Knobler HY, Durst R. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand. 2000;101(4):334–6.PubMedGoogle Scholar
  50. 50.
    Agarwal V. Risperidone augmentation of clozapine. Indian J Psychiatry. 1999;41(1):86.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Morera AL, Barreiro P, Cano-Munoz JL. Risperidone and clozapine combination for the treatment of refractory schizophrenia. Acta Psychiatr Scand. 1999;99(4):305–6.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Paplos KG, Pappa DA, Christodoulou GN. Risperidone augmentation of clozapine: a critical review. Eur Arch Psychiatry Clin Neurosci. 2006;256(6):350–5.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Akdede BB, Anil Yagcioglu AE, Alptekin K, Turgut TI, Tumuklu M, Yazici MK, et al. A double-blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry. 2006;67(12):1912–9.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006;354(5):472–82.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Weiner E, Conley RR, Ball MP, Feldman S, Gold JM, Kelly DL, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology. 2010;35(11):2274–83.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005;66(1):63–72.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Zink M, Kuwilsky A, Krumm B, Dressing H. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Psychopharmacol. 2009;23(3):305–14.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Se Hyun K, Dong Chung J, Yong Min A, Yong SK. The combined use of risperidone long-acting injection and clozapine in patients with schizophrenia non-adherent to clozapine: a case series. J Psychopharmacol. 2010;24(7):981–6.CrossRefGoogle Scholar
  59. 59.
    Kaye NS. Ziprasidone augmentation of clozapine in 11 patients. J Clin Psychiatry. 2003;64(2):215–6.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Zink M, Mase E, Dressing H. Ziprasidone-augmentation of clozapine. Psychiatr Prax. 2004;31(5):259–61.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Kuwilsky A, Krumm B, Englisch S, Dressing H, Zink M. Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry. 2010;43(6):216–20.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Muscatello MR, Pandolfo G, Mico U, Lamberti Castronuovo E, Abenavoli E, Scimeca G, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2014;34(1):129–33.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Vieweg WV, Hasnain M. Question regarding ziprasidone and QTc interval prolongation in the ZODIAC study. Am J Psychiatry. 2011;168(6):650–1.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Gupta S, Sonnenberg SJ, Frank B. Olanzapine augmentation of clozapine. Ann Clin Psychiatry. 1998;10(3):113–5.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2010;123(2–3):225–33.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Nielsen J, Emborg C, Gydesen S, Dybbro J, Aagaard J, Haderup K, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2012;32(2):173–8.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Kalenderoglu A, Celik M. Augmentation of clozapine with Paliperidone in schizophrenia patients with partial response to treatment: a case series. Turk Psikiyatri Derg. 2016;27(1):57–62.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Hou YC. Improvement in psychotic symptoms and social functioning after augmentation of paliperidone with clozapine in a patient with schizoaffective disorder. J Neuropsychiatry Clin Neurosci. 2014;26(1):E26.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Maia-de-Oliveira JP, Nunes EA, Ushirohira JM, Machado-de-Sousa JP, Bressan RA, Hallak JE. Paliperidone palmitate for refractory and clozapine-resistant schizophrenia. J Neuropsychiatry Clin Neurosci. 2015;27(1):e14–6.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Rajarethinam R, Gilani S, Tancer M, DeQuardo J. Augmentation of clozapine partial responders with conventional antipsychotics. Schizophr Res. 2003;60(1):97–8.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Mowerman S, Siris SG. Adjunctive loxapine in a clozapine-resistant cohort of schizophrenic patients. Ann Clin Psychiatry. 1996;8(4):193–7.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Mendhekar DN, Gupta D, Lohia D, Jiloha RC. Pimozide augmentation of clozapine in hebephrenic schizophrenia: a case report. Indian J Psychiatry. 2003;45(1):55.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Friedman J, Ault K, Powchik P. Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biol Psychiatry. 1997;42(6):522–3.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Friedman JI, Lindenmayer JP, Alcantara F, Bowler S, Parak M, White L, et al. Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology. 2011;36(6):1289–95.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Gunduz-Bruce H, Oliver S, Gueorguieva R, Forselius-Bielen K, D’Souza DC, Zimolo Z, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res. 2013;143(2–3):344–7.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry. 2004;65(6):766–71.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Silver H, Kushnir M, Kaplan A. Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. PubMed PMID: 8886304.Google Scholar
  78. 78.
    Wigard ME, van Gool AR, Schulte PF. Addition of fluvoxamine to clozapine: theory and practice. Tijdschr Psychiatr. 2013;55(2):113–21.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Lu ML, Lane HY, Chen KP, Jann MW, Su MH, Chang WH. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry. 2000;61(8):594–9.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Lu ML, Chen TT, Kuo PH, Hsu CC, Chen CH. Effects of adjunctive fluvoxamine on metabolic parameters and psychopathology in clozapinetreated patients with schizophrenia: a 12-week, randomized, double-blind, placebo-controlled study. Schizophr Res. 2017;193:126–33.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Hinze-Selch D, Deuschle M, Weber B, Heuser I, Pollmacher T. Effect of coadministration of clozapine and fluvoxamine versus clozapine monotherapy on blood cell counts, plasma levels of cytokines and body weight. Psychopharmacology. 2000;149(2):163–9.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Papetti F, Morel-Pingault V, Buisse V, Maziere L, Banayan M, Thauby S, et al. Clozapine-resistant schizophrenia related to an increased metabolism and benefit of fluvoxamine: four case reports. L’Encéphale. 2007;33(5):811–8.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Polcwiartek C, Nielsen J. The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology. 2016;233(5):741–50.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Silver H, Kaplan A, Jahjah N. Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry. 1995;152(7):1098.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Spina E, Avenoso A, Salemi M, Facciola G, Scordo MG, Ancione M, et al. Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline. Pharmacopsychiatry. 2000;33(6):213–7.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Wetzel H, Anghelescu I, Szegedi A, Wiesner J, Weigmann H, Harter S, et al. Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol. 1998;18(1):2–9.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A. Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry. 1996;153(12):1625–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Rahman MS, Grace JJ, Pato MT, Priest B. Sertraline in the treatment of clozapine-induced obsessive-compulsive behavior. Am J Psychiatry. 1998;155(11):1629–30.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Allen L, Tejera C. Treatment of clozapine-induced obsessive-compulsive symptoms with sertraline. Am J Psychiatry. 1994;151(7):1096–7.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Taylor D, Ellison Z, Ementon Shaw L, Wickham H, Murray R. Co-administration of citalopram and clozapine: effect on plasma clozapine levels. Int Clin Psychopharmacol. 1998;13(1):19–21.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Cupina D, Boulton M. Secondary delusional parasitosis treated successfully with a combination of clozapine and citalopram. Psychosomatics. 2012;53(3):301–2.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Gambi F, De Berardis D, Campanella D, Carano A, Sepede G, Salini G, et al. Mirtazapine treatment of generalized anxiety disorder: a fixed dose, open label study. J Psychopharmacol. 2005;19(5):483–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Gambi F, De Berardis D, Sepede G, Campanella D, Galliani N, Carano A, et al. Effect of mirtazapine on thyroid hormones in adult patients with major depression. Int J Immunopathol Pharmacol. 2005;18(4):737–44.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Benjamin S, Doraiswamy PM. Review of the use of mirtazapine in the treatment of depression. Expert Opin Pharmacother. 2011;12(10):1623–32.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Zoccali R, Muscatello MR, Torre DL, Malara G, Canale A, Crucitti D, et al. Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia. Pharmacol Res. 2003;48(4):411–4.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Zoccali R, Muscatello MR, Cedro C, Neri P, La Torre D, Spina E, et al. The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2004;19(2):71–6.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Delle Chiaie R, Salviati M, Fiorentini S, Biondi M. Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol. 2007;15(6):563–8.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Sahli C, Bryois C. Psychotropics and weight gain. Praxis (Bern 1994). 2004;93(35):1393–401.CrossRefGoogle Scholar
  99. 99.
    Carano A, De Berardis D, Gambi F, Salerno MR, Campanella D, Castrovilli M, et al. Psychopathologic patterns in obesity. Ann Ital Chir. 2005;76(5):461–4.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Repo-Tiihonen E, Eloranta A, Hallikainen T, Tiihonen J. Effects of venlafaxine treatment on clozapine plasma levels in schizophrenic patients. Neuropsychobiology. 2005;51(4):173–6.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Mico U, Bruno A, Pandolfo G, Maria Romeo V, Mallamace D, D’Arrigo C, et al. Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2011;26(6):303–10.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Smith T, Riskin J. Effect of clozapine on plasma nortriptyline concentration. Pharmacopsychiatry. 1994;27(1):41–2.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Biondi M, Fedele L, Arcangeli T, Pancheri P. Development of obsessive-compulsive symptoms during clozapine treatment in schizophrenia and its positive response to clomipramine. Psychother Psychosom. 1999;68(2):111–2.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Sinha S, Simlai J, Praharaj SK. Very low dose amitriptyline for clozapine-associated Sialorrhea. Curr Drug Saf. 2016;11(3):262–3.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Bastiampillai T, Gupta A, Allison S, Chan SK. NICE guidance: why not clozapine for treatment-refractory bipolar disorder? Lancet Psychiatry. 2016;3(6):502–3.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Li XB, Tang YL, Wang CY, de Leon J. Clozapine for treatment-resistant bipolar disorder: a systematic review. Bipolar Disord. 2015;17(3):235–47.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y. The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry. 2006;67(3):461–7.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Bender S, Linka T, Wolstein J, Gehendges S, Paulus HJ, Schall U, et al. Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol. 2004;7(1):59–63.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Dembowski C, Rechlin T. Successful antimanic treatment and mood stabilization with lamotrigine, clozapine, and valproate in a bipolar patient after lithium-induced cerebellar deterioration. A case report. Pharmacopsychiatry. 2003;36(2):83–6.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Mattai A, Fung L, Bakalar J, Overman G, Tossell J, Miller R, et al. Adjunctive use of lithium carbonate for the management of neutropenia in clozapine-treated children. Hum Psychopharmacol. 2009;24(7):584–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Pinninti NR, Houdart MP, Strouse EM. Case report of long-term lithium for treatment and prevention of clozapine-induced neutropenia in an African American male. J Clin Psychopharmacol. 2010;30(2):219–21.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Kelly DL, Conley RR, Feldman S, Yu Y, McMahon RP, Richardson CM. Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia. Psychiatry Q. 2006;77(1):81–95.CrossRefGoogle Scholar
  113. 113.
    Small JG, Klapper MH, Malloy FW, Steadman TM. Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol. 2003;23(3):223–8.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Foster R, Olajide D. A case of clozapine-induced tonic-clonic seizures managed with valproate: implications for clinical care. J Psychopharmacol. 2005;19(1):93–6.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Balen RM, Procyshyn RM. Valproic acid for seizure prophylaxis during clozapine therapy: where’s the evidence? Int J Psychiatry Clin Pract. 1999;3(4):249–51.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Suzuki T, Uchida H, Takeuchi H, Nakajima S, Nomura K, Tanabe A, et al. Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia. Hum Psychopharmacol. 2009;24(8):628–38.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Horowitz E, Bergman LC, Ashkenazy C, Moscona-Hurvitz I, Grinvald-Fogel H, Magnezi R. Off-label use of sodium valproate for schizophrenia. PLoS One. 2014;9(3):e92573.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Citrome L, Casey DE, Daniel DG, Wozniak P, Kochan LD, Tracy KA. Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone. Psychiatr Serv. 2004;55(3):290–4.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpicelli SA, Puopolo PR, et al. Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. Am J Psychiatry. 1994;151(1):123–5.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Facciola G, Avenoso A, Scordo MG, Madia AG, Ventimiglia A, Perucca E, et al. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999;21(3):341–5.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Kando JC, Tohen M, Castillo J, Centorrino F. Concurrent use of clozapine and valproate in affective and psychotic disorders. J Clin Psychiatry. 1994;55(6):255–7.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Malik S, Lally J, Ajnakina O, Pritchard M, Krivoy A, Gaughran F, et al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res. 2018;195:267–73.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Pantelis C, Adesanya A. Increased risk of neutropaenia and agranulocytosis with sodium valproate used adjunctively with clozapine. Aust N Z J Psychiatry. 2001;35(4):544–5.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    De Berardis D, Campanella D, Serroni N, Rapini G, Olivieri L, Fornaro M, et al. Clozapine-related pericarditis during titration phase in a patient with resistant schizophrenia and concomitant valproate treatment: a case report. J Clin Psychopharmacol. 2014;34(5):649–51.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res. 2012;141(2–3):173–8.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Migliardi G, D’Arrigo C, Santoro V, Bruno A, Cortese L, Campolo D, et al. Effect of topiramate on plasma concentrations of clozapine, olanzapine, risperidone, and quetiapine in patients with psychotic disorders. Clin Neuropharmacol. 2007;30(2):107–13.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry. 2000;45(2):198.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Greg Deardorff O, Syed A, Ames CJ, Yaeger JS. Ranitidine, metformin, and topiramate: managing weight gain in a clozapine-treated patient with schizoaffective disorder. Prim Care Companion CNS Disord. 2014;16(3). PCC.13/01598.Google Scholar
  129. 129.
    Navarro V, Pons A, Romero A, Bernardo M. Topiramate for clozapine-induced seizures. Am J Psychiatry. 2001;158(6):968–9.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Hahn MK, Remington G, Bois D, Cohn T. Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects. J Clin Psychopharmacol. 2010;30(6):706–10.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Muscatello MR, Bruno A, Pandolfo G, Mico U, Bellinghieri PM, Scimeca G, et al. Topiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. J Psychopharmacol. 2011;25(5):667–74.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Goff DC. Review: lamotrigine may be an effective treatment for clozapine resistant schizophrenia. Evid Based Ment Health. 2009;12(4):111.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Kalyoncu A, Mirsal H, Pektas O, Unsalan N, Tan D, Beyazyurek M. Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect? J Psychopharmacol. 2005;19(3):301–5.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and metaanalysis. Schizophr Res. 2009;109(1–3):10–4.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Vayisoglu S, Anil Yagcioglu AE, Yagcioglu S, Karahan S, Karci O, Gurel SC, et al. Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment. Schizophr Res. 2013;143(1):207–14.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Urban AE, Wiglusz MS, Cubala WJ, Landowski J, Krysta K. Rapid-onset agranulocytosis in a patient treated with clozapine and lamotrigine. Psychiatr Danub. 2015;27(Suppl 1):S459–61.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Egger C, Muehlbacher M, Grohmann R, Stuppaeck C. Clozapine intoxication in a patient with lamotrigine-induced rash. Pharmacopsychiatry. 2010;43(1):35–6.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Tourian L, Margolese HC. Late-onset agranulocytosis in a patient treated with clozapine and lamotrigine. J Clin Psychopharmacol. 2011;31(5):665–7.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Risch SC, Horner MD, McGurk SR, Palecko S, Markowitz JS, Nahas Z, et al. Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res. 2007;93(1–3):131–5.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Stryjer R, Strous R, Bar F, Shaked G, Shiloh R, Rozencwaig S, et al. Donepezil augmentation of clozapine monotherapy in schizophrenia patients: a double blind cross-over study. Hum Psychopharmacol. 2004;19(5):343–6.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Bora E, Veznedaroglu B, Kayahan B. The effect of galantamine added to clozapine on cognition of five patients with schizophrenia. Clin Neuropharmacol. 2005;28(3):139–41.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Kishi T, Matsuda Y, Iwata N. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis. Psychopharmacology. 2017;234(14):2113–25.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Thomas C, Carroll BT, Maley RT, Jayanti K, Koduri A. Memantine and catatonic schizophrenia. Am J Psychiatry. 2005;162(3):626.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Veerman S, Schulte P, de Haan L. Memantine add-on to clozapine treatment for residual negative symptoms of schizophrenia. Psychopharmacology. 2017;234(23–24):3535–6.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    de Lucena D, Fernandes BS, Berk M, Dodd S, Medeiros DW, Pedrini M, et al. Improvement of negative and positive symptoms in treatment-refractory schizophrenia: a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine. J Clin Psychiatry. 2009;70(10):1416–23.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Veerman SR, Schulte PF, Smith JD, de Haan L. Memantine augmentation in clozapine-refractory schizophrenia: a randomized, doubleblind, placebo-controlled crossover study. Psychol Med. 2016;46(9):1909–21.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Veerman SR, Schulte PF, Deijen JB, de Haan L. Adjunctive memantine in clozapine-treated refractory schizophrenia: an open-label 1-year extension study. Psychol Med. 2017;47(2):363–75.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Seddigh R, Azarnik S, Keshavarz-Akhlaghi AA. Levothyroxine augmentation in clozapine resistant schizophrenia: a case report and review. Case Rep Psychiatry. 2015;2015:678040.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Lin CH, Lin CH, Chang YC, Huang YJ, Chen PW, Yang HT, et al. Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry. 2018;84(6):422–32.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Qurashi I, Collins JD, Chaudhry IB, Husain N. Promising use of minocycline augmentation with clozapine in treatment-resistant schizophrenia. J Psychopharmacol. 2014;28(7):707–8.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Marini S, De Berardis D, Vellante F, Santacroce R, Orsolini L, Valchera A, et al. Celecoxib adjunctive treatment to antipsychotics in schizophrenia: a review of randomized clinical add-on trials. Mediat Inflamm. 2016;2016:3476240.CrossRefGoogle Scholar
  152. 152.
    Muscatello MR, Bruno A, De Fazio P, Segura-Garcia C, Pandolfo G, Zoccali R. Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine. Expert Opin Pharmacother. 2014;15(16):2329–45.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Behdani F, Roudbaraki SN, Saberi-Karimian M, Tayefi M, Hebrani P, Akhavanrezayat A, et al. Assessment of the efficacy of omega-3 fatty acids on metabolic and inflammatory parameters in patients with schizophrenia taking clozapine and sodium valproate. Psychiatry Res. 2018;261:243–7.PubMedCrossRefGoogle Scholar
  154. 154.
    Peet M, Horrobin DF. Group EEMS. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res. 2002;36(1):7–18.PubMedCrossRefGoogle Scholar
  155. 155.
    Caniato RN, Alvarenga ME, Garcia-Alcaraz MA. Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine. Aust N Z J Psychiatry. 2006;40(8):691–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ. Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry. 2002;159(9):1596–8.PubMedCrossRefGoogle Scholar
  157. 157.
    Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry. 2001;158(12):2071–4.PubMedCrossRefGoogle Scholar
  158. 158.
    Zhang L, Zhao J. Profile of minocycline and its potential in the treatment of schizophrenia. Neuropsychiatr Dis Treat. 2014;10:1103–11.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Orsolini L, Sarchione F, Vellante F, Fornaro M, Matarazzo I, Martinotti G, et al. Protein-C reactive as biomarker predictor of schizophrenia phases of illness? A systematic review. Curr Neuropharmacol. 2018;16:583–606.PubMedCrossRefGoogle Scholar
  160. 160.
    Martinotti G, Di Iorio G, Marini S, Ricci V, De Berardis D, Di Giannantonio M. Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: a review. J Biol Regul Homeost Agents. 2012;26(3):347–56.PubMedGoogle Scholar
  161. 161.
    Kelly DL, Vyas G, Richardson CM, Koola M, McMahon RP, Buchanan RW, et al. Adjunct minocycline to clozapine treated patients with persistent schizophrenia symptoms. Schizophr Res. 2011;133(1–3):257–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Kelly DL, Sullivan KM, McEvoy JP, McMahon RP, Wehring HJ, Gold JM, et al. Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms. J Clin Psychopharmacol. 2015;35(4):374–81.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Wehring HJ, Elsobky T, McEvoy JP, Vyas G, Richardson CM, McMahon RP, et al. Adjunctive minocycline in clozapine-treated patients with schizophrenia: analyzing the effects of minocycline on clozapine plasma levels. Psychiatry Q. 2018;89(1):73–80.CrossRefGoogle Scholar
  164. 164.
    Diaz P, Bhaskara S, Dursun SM, Deakin B. Double-blind, placebo-controlled, crossover trial of clozapine plus glycine in refractory schizophrenia negative results. J Clin Psychopharmacol. 2005;25(3):277–8.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000;157(5):826–8.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Javitt DC, Silipo G, Cienfuegos A, Shelley AM, Bark N, Park M, et al. Adjunctive high-dose glycine in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2001;4(4):385–91.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Doruk A, Uzun O, Ozsahin A. A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2008;23(4):223–7.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Sanghani SN, Petrides G, Kellner CH. Electroconvulsive therapy (ECT) in schizophrenia: a review of recent literature. Curr Opin Psychiatry. 2018;31:213–22.PubMedGoogle Scholar
  169. 169.
    Rosenquist PB, Miller B, Pillai A. The antipsychotic effects of ECT: a review of possible mechanisms. J ECT. 2014;30(2):125–31.PubMedCrossRefGoogle Scholar
  170. 170.
    Ahmed S, Khan AM, Mekala HM, Venigalla H, Ahmed R, Etman A, et al. Combined use of electroconvulsive therapy and antipsychotics (both clozapine and non-clozapine) in treatment resistant schizophrenia: a comparative meta-analysis. Heliyon. 2017;3(11):e00429.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Zheng W, Cao XL, Ungvari GS, Xiang YQ, Guo T, Liu ZR, et al. Electroconvulsive therapy added to non-clozapine antipsychotic medication for treatment resistant schizophrenia: meta-analysis of randomized controlled trials. PLoS One. 2016;11(6):e0156510.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Klapheke MM. Clozapine, ECT, and schizoaffective disorder, bipolar type. Convuls Ther. 1991;7(1):36–9.PubMedGoogle Scholar
  173. 173.
    Safferman AZ, Munne R. Combining clozapine with ECT. Convuls Ther. 1992;8(2):141–3.PubMedGoogle Scholar
  174. 174.
    Green AI, Zalma A, Berman I, DuRand CJ, Salzman C. Clozapine following ECT: a two-step treatment. J Clin Psychiatry. 1994;55(9):388–90.PubMedGoogle Scholar
  175. 175.
    Benatov R, Sirota P, Megged S. Neuroleptic-resistant schizophrenia treated with clozapine and ECT. Convuls Ther. 1996;12(2):117–21.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Grover S, Hazari N, Kate N. Combined use of clozapine and ECT: a review. Acta Neuropsychiatr. 2015;27(3):131–42.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Cardwell BA, Nakai B. Seizure activity in combined clozapine and ECT: a retrospective view. Convuls Ther. 1995;11(2):110–3.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Tang WK, Ungvari GS. Efficacy of electroconvulsive therapy combined with antipsychotic medication in treatment-resistant schizophrenia: a prospective, open trial. J ECT. 2002;18(2):90–4.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Tang WK, Ungvari GS. Efficacy of electroconvulsive therapy in treatment-resistant schizophrenia: a prospective open trial. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(3):373–9.CrossRefGoogle Scholar
  180. 180.
    Kho KH, Blansjaar BA, de Vries S, Babuskova D, Zwinderman AH, Linszen DH. Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia – an open label study. Eur Arch Psychiatry Clin Neurosci. 2004;254(6):372–9.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Masoudzadeh A, Khalilian AR. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatmentresistant schizophrenic patients. Pak J Biol Sci. 2007;10(23):4287–90.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry. 2015;172(1):52–8.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Kim HS, Kim SH, Lee NY, Youn T, Lee JH, Chung S, et al. Effectiveness of electroconvulsive therapy augmentation on clozapine-resistant schizophrenia. Psychiatry Investig. 2017;14(1):58–62.PubMedCrossRefPubMedCentralGoogle Scholar
  184. 184.
    Cotovio G, Velosa A, Oliveira-Maia AJ, Barahona-Correa B. Clozapine-resistant schizophrenia treated with ultra-brief pulse, unilateral electroconvulsive therapy. J ECT. 2017;33(1):e3–4.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Grover S, Chakrabarti S, Hazari N, Avasthi A. Effectiveness of electroconvulsive therapy in patients with treatment resistant schizophrenia: a retrospective study. Psychiatry Res. 2017;249:349–53.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Kales HC, Dequardo JR, Tandon R. Combined electroconvulsive therapy and clozapine in treatment-resistant schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 1999;23(3):547–56.CrossRefGoogle Scholar
  187. 187.
    Remington G, Saha A, Chong SA, Shammi C. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs. 2005;19(10):843–72.PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Barber S, Olotu U, Corsi M, Cipriani A. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2017;3:CD006324.PubMedPubMedCentralGoogle Scholar
  189. 189.
    Barnes TR, McEvedy CJ, Nelson HE. Management of treatment resistant schizophrenia unresponsive to clozapine. Br J Psychiatry Suppl. 1996;31:31–40.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Domenico De Berardis
    • 1
    • 2
    Email author
  • Michele Fornaro
    • 3
    • 4
  • Annalisa Anastasia
    • 4
  • Federica Vellante
    • 2
  • Alessandro Valchera
    • 3
    • 5
  • Marilde Cavuto
    • 6
  • Giampaolo Perna
    • 7
    • 8
    • 9
  • Marco Di Nicola
    • 10
  • Gianluca Serafini
    • 11
  • Alessandro Carano
    • 12
  • Maurizio Pompili
    • 13
  • Laura Orsolini
    • 3
    • 14
  • Carmine Tomasetti
    • 15
  • Gabriella Di Emidio
    • 16
  • Giovanni Martinotti
    • 2
    • 14
  • Massimo Di Giannantonio
    • 2
  1. 1.National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and TreatmentHospital “G. Mazzini”TeramoItaly
  2. 2.Department of Neuroscience, Imaging and Clinical ScienceUniversity “G. D’Annunzio”ChietiItaly
  3. 3.Polyedra Research GroupTeramoItaly
  4. 4.Department of Neuroscience, Reproductive Science and OdontostomatologySchool of Medicine ‘Federico II’ NaplesNaplesItaly
  5. 5.Villa S. Giuseppe Hospital, Hermanas HospitalariasAscoli PicenoItaly
  6. 6.Department of Theory, Analysis, Composition and DirectionMusic Conservatory “L. Canepa”SassariItaly
  7. 7.Department of Clinical NeurosciencesHermanas Hospitalarias, FoRiPsi, Villa San Benedetto MenniComoItaly
  8. 8.Department of Psychiatry and NeuropsychologyUniversity of MaastrichtMaastrichtThe Netherlands
  9. 9.Department of Psychiatry and Behavioral Sciences, Leonard Miller School of MedicineUniversity of MiamiCoral GablesUSA
  10. 10.Institute of Psychiatry and PsychologyCatholic University of Sacred HeartRomeItaly
  11. 11.Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of PsychiatryUniversity of GenoaGenoaItaly
  12. 12.NHS, Department of Mental Health, Psychiatric Service of Diagnosis and TreatmentHospital “Madonna Del Soccorso”San Benedetto del TrontoItaly
  13. 13.Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea HospitalSapienza University of RomeRomeItaly
  14. 14.Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, College Lane CampusUniversity of HertfordshireHatfieldUK
  15. 15.NHS, Department of Mental Health, Psychiatric Service of Diagnosis and TreatmentHospital of GiulianovaTeramoItaly
  16. 16.NHS, Department of Mental Health, Psychiatric Service of Diagnosis and TreatmentMental Health Center of GiulianovaTeramoItaly

Personalised recommendations