Clozapine-resistant schizophrenia – non pharmacological augmentation methods

Joanna Gałaszkiewicz 1 , Krzysztof Rębisz 1 , Justyna Morylowska-Topolska 2 , Hanna Karakuła-Juchnowicz 1 ,  and Gustaw Kozak 1
  • 1 I Department of Psychiatry, Psychotherapy and Early Intervention, Medical University of Lublin
  • 2 Department of Clinical Neuropsychiatry, Medical University of Lublin


Clozapine is the drug of choice for drug-resistant schizophrenia, but despite its use, 30-40% patients fail to achieve satisfactory therapeutic effects. In such situations, augmentation attempts are made by both pharmacological and non-pharmacological methods. To date, most of the work has been devoted to pharmacological strategies, much less to augemantation of clozapine with electroconvulsive therapy (C+ECT), transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS).

Aim: The aim of the work is to present biological, non-pharmacological augmentation treatment methods with clozapine.

Material and methods: A review of the literature on non-pharmacological augmentation treatment methods with clozapine was made. PubMed database was searched using key words: drug-resistant schizophrenia, clozapine, ECT, transcranial magnetic stimulation, transcranial electrical stimulation and time descriptors: 1980-2017.

Results: Most studies on the possibility of increasing the efficacy of clozapine was devoted to combination therapy with clozapine + electric treatments. They have shown improved efficacy when using these two methods simultaneously from 37.5 to 100%. The only randomized trial so far has also confirmed the effectiveness of this procedure. Despite the described side effects of tachycardia or prolonged seizures, most studies indicate the safety and efficacy of combined use of clozapine and electroconvulsive therapy. Transcranial magnetic stimulation also appears to be a safe method in patients treated with clozapine. However, further research is needed before ECT can be included in standard TRS treatment algorithms. The data for combining transcranial electrical stimulation with clozapine, come only from descriptions of cases and need to be confirmed in controlled studies.

Conclusions: The results of studies on the possibility of increasing the effectiveness of clozapine using biological non-pharmacological treatment methods indicate a potentially beneficial effect of this type of methods in breaking the super-resistance in schizophrenia. Combination of clozapine and ECT can be considered as the most recommended strategy among these treatment methods.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 1988;24:62–67.

  • 2. Melzer HY. Defining treatment refractoriness in schizophrenia. Schizophr Bull 1990;16:563–565

  • 3. Meltzer HY. Dimensions of outcome with clozapine. Br J Psychiatry Suppl. 1992; (17):46-53

  • 4. Sommer IE, Begemann MJH, Temmerman A, Leucht S. Pharmacological Augmentation Strategies for Schizophrenia Patients With Insufficient Response to Clozapine: A Quantitative Literature Review. Schizophr. Bull. 38(5), 1003–1011 (2012)

  • 5. Henna Neto J, Elkis H. Clinical aspects of super-refractory schizophrenia: A 6-month cohort observational study. Rev Bras Psiquiatr. 2007 Sep;29(3):228-32

  • 6. Sinclair D, Adams CE. Treatment resistant schizophrenia: a comprehensive survey of randomised controlled trials. BMC Psychiatry 2014;14:253–260

  • 7. Miyamoto S, Jarskog LF, Fleischhacker WW. New therapeutic approaches for treatment-resistant schizophrenia: a look to the future. J. Psychiatr. Res. 58, 1–6 (2014)

  • 8. Muscatello MRA, 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. 15(16), 2329–2345 (2014)

  • 9. Miyamoto S, Jarskog LF, Fleischhacker WW. Schizophrenia: when clozapine fails. CurrOpin Psychiatry. 2015 May;28(3):243-8

  • 10. Vayisoğlu S, Yağcioğlu AE. Augmentation strategies in patients with schizophrenia who show partial response to clozapine treatment. Turk PsikiyatriDerg 2014;25(3):201–211

  • 11. Arumugham SS, Thirthalli J, Andrade C. Efficacy and safety of combining clozapine with electrical or magnetic brain stimulation in treatment-refractory schizophrenia Expert Rev ClinPharmacol. 2016 Sep;9(9):1245-52

  • 12. Chanpattana W, Kunigiri G, Kramer BA, Gangadhar BN. Survey of the practice of electroconvulsive therapy in teaching hospitals in India. J ECT 2005;21:100–104

  • 13. Braga RJ, Petrides G. The combined use of electroconvulsive therapy and antipsychotics in patients with schizophrenia. J ECT 2005;21:75–83

  • 14. Chanpattana W, Andrade C. ECT for treatment-resistant schizophrenia: a response from the far East to the UK. NICE report. J ECT 2006;22:4–12

  • 15. Chanpattana W, Kramer BA, Kunigiri G, Gangadhar BN, Kitphati R, Andrade C. A survey of the practice of electroconvulsive therapy in Asia. J ECT 2010;26:5–10

  • 16. Rayikanti R, Lentowicz I, Birbur B, Li L. Combined Antipsychotics and Electroconvulsive Therapy in an Acutely Psychotic Patient with Treatment-resistant Schizophrenia. Psychopharmacol Bull. 2017 May 15;47(2): 57-62

  • 17. Fink M. Clozapine and electroconvulsive therapy. Arch Gen Psychiatry 1990;47:290–291

  • 18. Klapheke MM. Clozapine, ECT, and Schizoaffective disorder, bipolar type. ConvulsTher 1991;7:36–39

  • 19. Klapheke MM. Follow-up on clozapine and ECT. ConvulsTher 1991;7:303–305

  • 20. Fink M. ECT and clozapine in schizophrenia. J ECT 1998;14:223–226

  • 21. Kaster TS, de Jesus D, Radhu N, Farzan F, Blumberger DM, Rajji TK et al. Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia. Schizophr. Res. 165(2–3), 157–162 (2015)

  • 22. Langguth B, Eichhammer P, Zowe M, Marienhagen J, Spiessl H, Hajak G. Neuronavigated transcranial magnetic stimulation and auditory hallucinations in a Schizophrenic patient: Monitoring of neuro-biological effects. Schizophr. Res. 84(1), 185–186 (2006)

  • 23. Přikryl R, Ustohal L, Kucerová HP, Cesková E. Effect of electroconvulsive therapy on cortical excitability in a patient with long-term remission of schizophrenia: a transcranial magnetic stimulation study. J. ECT. 27(1), e9–11 (2011)

  • 24. Daskalakis ZJ, George TP. Clozapine, GABA(B), and the treatment of resistant schizophrenia. Clin. Pharmacol. Ther. 86(4), 442–446 (2009)

  • 25. Grover S, Hazari N, Kate N. Combined use of clozapine and ECT: a review. ActaNeuropsychiatr. 2015 Jun;27(3):131-42

  • 26. Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry 2015;172:52–58

  • 27. Frankenberg FR, Suppes T, Mclean PE. Combined clozapine and electroconvulsive therapy. Convulsive Ther 1993;9:176–180

  • 28. 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 ClinNeurosci 2004;254:372–379

  • 29. Flamarique I, Castro-Fornieles J, Garrido JM, de la Serna E, Pons A, Bernardo M et al. Electroconvulsive therapy and clozapine in adolescents with schizophrenia spectrum disorders: is it a safe and effective combination? J ClinPsychopharmacol 2012;32:756–766.

  • 30. Kristensen D, Hageman I, Bauer J, JØrgensen MB, Correll CU. Antipsychotic polypharmacy in a treatment-refractory schizophrenia population receiving adjunctive treatment with electroconvulsive therapy. J ECT 2013;29:271–276

  • 31. Factor SA, Molho ES, Brown DL. Combined clozapine and electroconvulsive therapy for the treatment of drug-induced psychosis in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1995;7:304–307

  • 32. Bloch Y, Pollack M, Mor I. Should the administration of ECT during clozapine therapy be contraindicated? Br J Psychiatry 1996;169:253–254

  • 33. Kales HC, Dequardo JR, Tandon R. Combined electroconvulsive therapy and clozapine in treatmentresistant schizophrenia. ProgNeuropsychopharmacolBiol Psychiatry 1999;23:547–556

  • 34. Beale MD, Prichett JT, Kellner CH. Supraventricular tachycardia in a patient receiving ECT, clozapine, and caffeine. ConvulsTher 1994;10:228–231

  • 35. Cardwell BA, Nakai B. Seizure activity in combined clozapine and ECT: a retrospective view. ConvulsTher 1995;11:110–113

  • 36. Masoudzadeh A, Khailian AR. Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J BiolSci 2007;10:4287–4290

  • 37. Koen L, Van den Berg CE, Niehaus DJH. Combining ECT and clozapine in the treatment of clozapine-refractory schizophrenia and schizoaffective disorder – a pilot study. S AfrJ Psychiatry 2008;14:131–135

  • 38. Kales HC, Tandon R, Dequqrdo JR, Maixner D, Jibson M, Becks L. Combined electroconvulsive therapy and clozapine in schizophrenia. J Clin Psychiatry 1995;37:678

  • 39. James DV, Gray NS. Elective combined electroconvulsive and clozapine therapy. IntClinPsychopharmacol 1999; 14:69–72

  • 40. Bannour S, Bouhlel S, Krir MW, Amamou B, Ben Nasr S, El Kissi Y et al. Combination of maintenance electroconvulsive therapy and clozapine in treating a patient with refractory schizophrenia. J ECT 2014;30:e29–e30

  • 41. Vowels EC, Hitturlingappa S, Bastiampillai T. Combination clozapine and electroconvulsive therapy in a patient with schizophrenia and comorbid intellectual disability. Aust N Z J Psychiatry 2014;48:689–690

  • 42. Banatov R, Sirota P, Megged S. Neuroleptic-resistant schizophrenia treated with clozapine and ECT. ConvulsTher 1996;12:117–121

  • 43. Husni M, Haggarty J, Peat C. Clozapine does not increase ECT-seizure duration. Can J Psychiatry 1999;44:190–191

  • 44. Biedermann F, Pfaffenberger N, Baumgartner S, Kemmler G, Fleischhacker WW, Hofer A. Combined clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia: clinical and cognitive outcomes. J ECT 2011;27:e61–e62

  • 45. Pawełczyk T, Kołodziej-Kowalska E, Pawełczyk A, Rabe-Jabłońska J. Effectiveness and clinical predictors of response to combined ECT and antipsychotic therapy in patients with treatment-resistant schizophrenia and dominant negative symptoms. Psychiatry Res. 220(1-2), 175–180 (2014)

  • 46. Gazdag G, Kocsis-Ficzere N, Tolna J. The augmentation of clozapine treatment with electroconvulsive therapy. Ideggyógy. Szle. 59(7-8), 261–267 (2006)

  • 47. Grover S, Chakrabarti S, Hazari N, Avasthi A. Effectiveness of electroconvulsive therapy in patients with treatment resistant schizophrenia: A retrospective study. Psychiatry Res. 2017 Mar;249:349-353

  • 48. Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: A systematic review and meta-analysis. Schizophr. Res. 171(1-3), 215–224 (2016)

  • 49. Klapheke MM. Combining ECT and antipsychotic agents: benefits and risks. ConvulsTher 1993;9(4):241–255

  • 50. Varma S, Bishara D, Besag FMC, Taylor D. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther. Adv. Psychopharmacol. 1(2), 47–66 (2011)

  • 51. Whittaker R, Scott A, Gardner M. The prevalence of prolonged cerebral seizures at the first treatment in a course of electroconvulsive therapy. J. ECT. 23(1), 11–13 (2007).

  • 52. Merrill DB, Dec GW, Goff DC. Adverse cardiac effects associated with clozapine. J. Clin. Psychopharmacol. 25(1), 32–41 (2005).

  • 53. Masiar SJ, Johns CA. ECT following clozapine. Br J Psychiatry 1991;158:135–136.

  • 54. Safferman AZ, Munne R. Combining clozapine with ECT. ConvulsTher 1992;8:141–143

  • 55. Park S, Lee M. Successful electroconvulsive therapy and improvement of negative symptoms in refractory schizophrenia with clozapine-induced seizures: a case report. Psychiatr. Danub. 26(4), 360–362 (2014)

  • 56. Grubisha M, Gopalan P, Azzam PN. Takotsubo cardiomyopathy in a young man after maintenance electroconvulsive therapy and clozapine initiation: a case report. J ECT 2014;30:e40–41

  • 57. Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol. Psychiatry. 68(6), 568–577 (2010)

  • 58. Lefaucheur J-P, André-Obadia N, AntalA,Ayache SS, Baeken C, Benninger DH, Cantello RM et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol. 125(11), 2150–2206(2014)

  • 59. Zyss T, Rachel W, Datka W, Dudek D, Zięba A, Gorczyca P et al. Przezczaszkowa stymulacja magnetyczna w terapii psychiatrycznej. Prz. Lek. 72(7); 2015: 371-375

  • 60. Mäkelä J: A brief history of magnetic stimulation. BioMag Laboratory, HUSLAB, Helsinki University Central Hospital. Helsinki 2008

  • 61. Langguth B, Eichhammer P, Zowe M, Marienhagen J, Spiessl H, Hajak G. Neuronavigated transcranial magnetic stimulation and auditory hallucinations in a schizophrenic patient: Monitoring of neurobiological effects. Schizophr. Res. 84(1), 185–186 (2006)

  • 62. Otani VH, Shiozawa P, Cordeiro Q, Uchida RR. A systematic review and meta-analysis of the use of repetitive transcranial magnetic stimulation for auditory hallucinations treatment in refractory schizophrenic patients. Int J Psychiatry ClinPract. 2015;19(4):228-32

  • 63. Shi C, Yu X, Cheung EF, Shum DH, Chan RC. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: a meta-analysis. Psychiatry Res 2014; 215:505–513

  • 64. Rosa MO, Gattaz WF, Rosa MA, Rumi DO, Tavares H, Myczkowski M et al. Effects of repetitive transcranial magnetic stimulation on auditory hallucinations refractory to clozapine. J. Clin. Psychiatry. 68(10), 1528–1532 (2007)

  • 65. de Jesus DR, Gil A, Barbosa L, Lobato MI, Magalhães PV, Favalli GP et al. A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine. Psychiatry Res. 188(2), 203–207 (2011)

  • 66. d'Alfonso AAL, Aleman A, Kessels RPC, Schouten EA, Postma A,van Der Linden JA et al. Transcranial magnetic stimulation of left auditory cortex in patients with schizophrenia: effects on hallucinations and neurocognition. J Neuropsychiatry ClinNeurosci. 2002;14(1):77–79

  • 67. Eberle M-C, Wildgruber D, Wasserka B, Fallgatter AJ, Plewnia C. Relief From Chronic Intractable Auditory Hallucinations After Long-Term Bilateral Theta Burst Stimulation. Am. J. Psychiatry. 167(11), 1410–1410 (2010)

  • 68. Koops S, Dellen E van, Schutte MJL, Nieuwdorp W, Neggers SFW, Sommer IEC. Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial. Schizophr. Bull. 42(1), 250–257 (2016)

  • 69. Kim E-J, Yeo S, Hwang I, Park JI, Cui Y, Jin HM et al. Bilateral Repetitive Transcranial Magnetic Stimulation for Auditory Hallucinations in Patients with Schizophrenia: A Randomized Controlled, Cross-over Study. Clin. Psychopharmacol. Neurosci. Off. Sci. J. Korean Coll. Neuropsychopharmacol. 12(3), 222–228 (2014)

  • 70. Blumberger DM, Christensen BK, Zipursky RB, Moller B, Chen R, Fitzgerald PB et al. MRI-targeted repetitive transcranial magnetic stimulation of Heschl’s gyrus for refractory auditory hallucinations. Brain Stimulat. 5(4), 577–585 (2012)

  • 71. Thirthalli J, Bharadwaj B, Kulkarni S, Gangadhar BN, Kharawala S, Andrade C. Successful use of maintenance rTMS for 8 months in a patient with antipsychotic-refractory auditory hallucinations. Schizophr Res 2008; 100:351–352

  • 72. Barr MS, Farzan F, Tran LC, Fitzgerald PB, Daskalakis ZJ. A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia. Brain Stimulat. 5(3), 337–346 (2012)

  • 73. Fitzgerald PB, Herring S, Hoy K, McQueen S, Segrave R, Kulkarni J et al. A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia. Brain Stimulat. 1(1), 27–32 (2008)

  • 74. Schneider AL, Schneider TL, Stark H. Repetitive transcranial magnetic stimulation (rTMS) as an augmentation treatment for the negative symptoms of schizophrenia: a 4-week randomized placebo controlled study. Brain Stimulat. 1(2), 106–111 (2008)

  • 75. Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol. 120(12), 2008–2039 (2009)

  • 76. Zyss T. Przezczaszkowa stymulacja stałoprądowa. W: Zyss T, Zięba A, Dudek D, red. Najnowsze techniki neuromodulacyjne w terapii zaburzeń depresyjnych. Biblioteka Psychiatrii Polskiej. Kraków: Komitet Redakcyjno-Wydawniczy PTP; 2009, s. 161–181

  • 77. Koops S, Dellen E van, Schutte MJL, Nieuwdorp W, Neggers SFW, Sommer IEC. Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial. Schizophr. Bull. 42(1), 250–257 (2016).

  • 78. Nitsche MA, Niehaus L, Hoffmann KT, Hengst S, Liebetanz D, Paulus W et al. MRI study of human brain exposed to weak direct current stimulation of the frontal cortex. Clin. Neurophysiol. 2004; 115 (10): 2419–2423

  • 79. Nitsche MA, Doemkes S, Karaköse T, Antal A, Liebetanz D, Lang N et al. Shaping the effects of transcranial direct current stimulation of the human motor cortex. J Neurophysiol. 2007;97(4):3109-17

  • 80. Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA, Pascual-Leone A e al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int. J. Neuropsychopharmacol. 2008; 11 (2): 249–254. 71

  • 81. Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual-Leone A. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord. 2006; 8 (2): 203–204.72

  • 82. Nitsche MA, Boggio PS, Fregni F, Pascual-Leone A. Treatment of depression with transcranial direct current stimulation (tDCS): a review. Exp. Neurol. 2009; 219 (1): 14–19.73

  • 83. Zyss T. Przezczaszkowa stymulacja stałoprądowa tDCS i inne pokrewne techniki w terapii zaburzeń psychicznych. Psychiatr. Pol. 2010: 44 (4) s.505-518

  • 84. Caetano SC, Fonseca M, Olvera RL, Nicoletti M, Hatch JP, Stanley JA et al. Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients. Neurosc. Lett. 2005; 384 (3): 321–326

  • 85. Andrade C. Transcranial direct current stimulation for refractory auditory hallucinations in schizophrenia. J. Clin. Psychiatry. 74(11), e1054–1058 (2013)

  • 86. Brunelin J, Mondino M, Gassab L, Haesebaert F, Gaha L, Suaud-Chagny MF et al. Examining Transcranial DirectCurrent Stimulation (tDCS) as a Treatment for Hallucinations in Schizophrenia. Am. J. Psychiatry. 169(7), 719–724 (2012)

  • 87. Fröhlich F, Burrello TN, Mellin JM, Cordle AL, Lustenberger CM, Gilmore JH et al.. Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia. Eur. Psychiatry J. Assoc. Eur. Psychiatr. 33, 54–60 (2016)

  • 88. Jacks S, Kalivas B, Mittendorf A, Kindt C, Short EB. Transcranial Direct-Current Stimulation as an Adjunct to Electroconvulsive Therapy and Clozapine for Refractory Psychosis. Prim. Care Companion CNS Disord. [Internet]. 16(3) (2014). Available from:

  • 89. Cretaz E, Brunoni AR, Lafer B. Magnetic Seizure Therapy for Unipolar and Bipolar Depression: A Systematic Review. Neural Plast. Neural Plast. 2015, 2015, e521398 (2015)

  • 90. Magnetic Seizure Therapy (MST) for Treatment Resistant Depression, Schizophrenia and Obsessive Compulsive Disorder.


Journal + Issues