Clozapine Combinations in Treatment-Resistant Schizophrenia Patients

  • Vladimir Lerner
  • Chanoch Miodownik


Schizophrenia is a severe disabling mental illness affecting about 1% of the population throughout the world. Antipsychotic medications (conventional and atypical antipsychotics) are the pharmacological basis for the cure of schizophrenia and schizoaffective patients, however not all patients are positively affected by this treatment. One fifth to one third of people suffering from schizophrenia is considered as treatment resistant. In other words, these people have persistent psychotic symptoms and poor functioning despite adequate treatment with conventional or novel antipsychotics.

To date one of the most effective medications is clozapine, which produces clinically significant improvement of symptoms in 30–50% of patients receiving it. However, from one-third to two thirds of schizophrenia patients still have persistent ‘positive’ symptoms despite adequate dosage and duration of clozapine monotherapy.

Among treatment-resistant schizophrenia patients with poor response to an adequate trial of clozapine monotherapy, 30–50% are treated with a combination of clozapine and second psychotropic medication.

Clinicians usually prescribe a combination of antipsychotics, in order to reach a greater or more rapid therapeutic response than has been achieved with antipsychotic monotherapy.

In this chapter, we present a summary of the literature concerning the combination of clozapine with different psychotropic medications or procedure in management of resistant schizophrenia and schizoaffective patients.


Negative Symptom Antipsychotic Medication Schizophrenia Patient Brief Psychiatric Rate Scale Brief Psychiatric Rate Scale Score 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Twice a day


Body mass index


Brief psychiatric rating scale


Clozapine-induced hypersalivation


Cytochrome P450 1A2


Electroconvulsive therapy




Extrapyramidal symptoms


Functional assessment for comprehensive treatment of schizophrenia


First-generation antipsychotics


Gamma aminobutiric acid


Global assessment scale


Health of the nation outcome scales (a new Italian version of the HoNOS)


High-density lipoprotein


Hamilton rating scale for depression


Low-density lipoprotein


Mini-mental status examination


Magnetic resonance imaging




N-Methyl-D-aspartate receptor


Positive and negative syndrome scale


Personal and social performance scale


Randomized controlled study


Scale for the assessment of negative symptoms


Scale for the assessment of positive symptoms


Second-generation antipsychotics


Selective serotonin re-uptake inhibitor


Treatment-resistant schizophrenia


White blood cells


  1. 1.
    Rossler W, Salize HJ, van Os J, Riecher-Rossler A (2005) Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol 15:399–409PubMedGoogle Scholar
  2. 2.
    Conley RR, Kelly DL (2001) Management of treatment resistance in schizophrenia. Biol Psychiatry 50:898–911PubMedGoogle Scholar
  3. 3.
    Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J (2004) Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161:1–56PubMedGoogle Scholar
  4. 4.
    Sheitman BB, Lieberman JA (1998) The natural history and pathophysiology of treatment resistant schizophrenia. J Psychiatr Res 32:143–150PubMedGoogle Scholar
  5. 5.
    McGlashan TH (1988) A selective review of recent North American long-term followup studies of schizophrenia. Schizophr Bull 14:515–542PubMedGoogle Scholar
  6. 6.
    Conley RR, Buchanan RW (1997) Evaluation of treatment-resistant schizophrenia. Schizophr Bull 23:663–674PubMedGoogle Scholar
  7. 7.
    Breier AF, Malhotra AK, Su TP, Pinals DA, Elman I, Adler CM, Lafargue RT, Clifton A, Pickar D (1999) Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Am J Psychiatry 156:294–298PubMedGoogle Scholar
  8. 8.
    Loebel AD, Lieberman JA, Alvir JM, Mayerhoff DI, Geisler SH, Szymanski SR (1992) Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 149:1183–1188PubMedGoogle Scholar
  9. 9.
    Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796PubMedGoogle Scholar
  10. 10.
    Suzuki T, Remington G, Mulsant BH, Uchida H, Rajji TK, Graff-Guerrero A, Mimura M, Mamo DC (2012) Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation. Psychiatry Res 197(1):1–6PubMedGoogle Scholar
  11. 11.
    Suzuki T, Uchida H, Nomura K, Takeuchi H, Nakajima S, Tanabe A, Yagi G, Watanabe K, Kashima H (2008) Novel rating scales for schizophrenia—targeted inventory on problems in schizophrenia (TIP-Sz) and functional assessment for comprehensive treatment of schizophrenia (FACT-Sz). Schizophr Res 106:328–336PubMedGoogle Scholar
  12. 12.
    Meltzer HY (1997) Treatment-resistant schizophrenia—the role of clozapine. Curr Med Res Opin 14:1–20PubMedGoogle Scholar
  13. 13.
    Pantelis C, Lambert TJ (2003) Managing patients with “treatment-resistant” schizophrenia. Med J Aust 178(Suppl):S62–S66PubMedGoogle Scholar
  14. 14.
    Barnes TR, McEvedy CJ (1996) Pharmacological treatment strategies in the non-responsive schizophrenic patient. Int Clin Psychopharmacol 11(Suppl 2):67–71PubMedGoogle Scholar
  15. 15.
    Dixon LB, Lehman AF, Levine J (1995) Conventional antipsychotic medications for schizophrenia. Schizophr Bull 21:567–577PubMedGoogle Scholar
  16. 16.
    Carpenter WT Jr (2007) Schizophrenia: disease, syndrome, or dimensions? Fam Process 46:199–206PubMedGoogle Scholar
  17. 17.
    Kirkpatrick B, Buchanan RW, Ross DE, Carpenter WT Jr (2001) A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry 58:165–171PubMedGoogle Scholar
  18. 18.
    Muscatello MR, Bruno A, Pandolfo G, Mico U, Bellinghieri PM, Scimeca G, Cacciola M, Campolo D, Settineri S, Zoccali R (2011) Topiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. J Psychopharmacol 25:667–674PubMedGoogle Scholar
  19. 19.
    Jalenques I (1996) Drug-resistant schizophrenia. Treatment options. CNS Drugs 5:8–23Google Scholar
  20. 20.
    Dencker SJ, Kulhaet F (1988) Treatment resistance in schizophrenia. Springer, Braunschweig/WiesbadenGoogle Scholar
  21. 21.
    Lawrie SM, Abukmeil SS, Chiswick A, Egan V, Santosh CG, Best JJ (1997) Qualitative cerebral morphology in schizophrenia: a magnetic resonance imaging study and systematic literature review. Schizophr Res 25:155–166PubMedGoogle Scholar
  22. 22.
    Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M (2003) Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 60:585–594PubMedGoogle Scholar
  23. 23.
    Jarema M, Choma M, Kozlowski P, Poniatowska R, Krawczyk R (1997) Cortical atrophy in MRI, mental status and neuroleptic treatment effect in schizophrenia. Psychiatr Pol 31:547–557PubMedGoogle Scholar
  24. 24.
    Sheppard C, Collins L, Fiorentino D, Fracchia J, Merlis S (1969) Polypharmacy in psychiatric treatment. I. Incidence at a state hospital. Curr Ther Res Clin Exp 11:765–774PubMedGoogle Scholar
  25. 25.
    Barnes TR, Paton C (2011) Antipsychotic polypharmacy in schizophrenia: benefits and risks. CNS Drugs 25:383–399PubMedGoogle Scholar
  26. 26.
    Gaebel W, Weinmann S, Sartorius N, Rutz W, McIntyre JS (2005) Schizophrenia practice guidelines: international survey and comparison. Br J Psychiatry 187:248–255PubMedGoogle Scholar
  27. 27.
    Marder SR, Essock SM, Miller AL, Buchanan RW, Davis JM, Kane JM, Lieberman J, Schooler NR (2002) The Mount Sinai conference on the pharmacotherapy of schizophrenia. Schizophr Bull 28:5–16PubMedGoogle Scholar
  28. 28.
    National Institute for Health and Clinical Excellence (2010) Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. Clinical guideline (updated 03 August, 2010). National Institute for Health and Clinical Excellence, LondonGoogle Scholar
  29. 29.
    Taylor D, Paton C, Kapur S (2009) The Maudsley prescribing guidelines, 10th edn. Informa Healthcare, LondonGoogle Scholar
  30. 30.
    Miller AL (2004) PORT treatment recommendations. Schizophr Bull 30:601–604PubMedGoogle Scholar
  31. 31.
    Stahl SM (1999) Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 60(Suppl 10):31–41PubMedGoogle Scholar
  32. 32.
    Biancosino B, Barbui C, Marmai L, Dona S, Grassi L (2005) Determinants of antipsychotic polypharmacy in psychiatric inpatients: a prospective study. Int Clin Psychopharmacol 20:305–309PubMedGoogle Scholar
  33. 33.
    Bret P, Bonnet F, Bret MC, Jaffre A (2002) Use of atypical antipsychotics in Charles perrens psychiatric hospital (Bordeaux) analysis of prescribing practices for amisulpride, clozapine, olanzapine and risperidone. Encéphale 28:329–342PubMedGoogle Scholar
  34. 34.
    Bret P, Bret MC, Queuille E (2009) Prescribing patterns of antipsychotics in 13 French psychiatric hospitals. Encéphale 35:129–138PubMedGoogle Scholar
  35. 35.
    Broekema WJ, de Groot IW, van Harten PN (2007) Simultaneous prescribing of atypical antipsychotics, conventional antipsychotics and anticholinergics—a European study. Pharm World Sci 29:126–130PubMedGoogle Scholar
  36. 36.
    De Hert M, Wampers M, Peuskens J (2006) Pharmacological treatment of hospitalised schizophrenic patients in Belgium. Int J Psychiatry Clin Pract 10:285–290Google Scholar
  37. 37.
    Florez Menendez G, Blanco Ramos M, Gomez-Reino Rodriguez I, Gayoso Diz P, Bobes Garcia J (2004) Polipharmacy in the antipsychotic prescribing in practices psychiatric out-patient clinic. Actas Esp Psiquiatr 32:333–339PubMedGoogle Scholar
  38. 38.
    Hamann J, Ruppert A, Auby P, Pugner K, Kissling W (2003) Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription database. Int Clin Psychopharmacol 18:237–242PubMedGoogle Scholar
  39. 39.
    Hemminki E (1977) Polypharmacy among psychiatric patients. Acta Psychiatr Scand 56:347–356PubMedGoogle Scholar
  40. 40.
    Heresco-Levy U, Brom D, Greenberg D (1993) Self-reported prescribing practices for schizophrenic patients among Israeli psychiatrists. Isr J Psychiatry Relat Sci 30:164–174PubMedGoogle Scholar
  41. 41.
    Paton C, Lelliott P, Harrington M, Okocha C, Sensky T, Duffett R (2003) Patterns of antipsychotic and anticholinergic prescribing for hospital inpatients. J Psychopharmacol 17:223–229PubMedGoogle Scholar
  42. 42.
    Tungaraza TE, Gupta S, Jones J, Poole R, Slegg G (2010) Polypharmacy and high-dose antipsychotic regimes in the community. The Psychiatrist 34:44–46Google Scholar
  43. 43.
    Yosselson-Superstine S, Sternik D, Liebenzon D (1979) Prescribing patterns in psychiatric hospitals in Israel. Acta Psychiatr Scand 60:477–482PubMedGoogle Scholar
  44. 44.
    Keks NA, Altson K, Hope J, Krapivensky N, Culhane C, Tanaghow A, Doherty P, Bootle A (1999) Use of antipsychosis and adjunctive medications by an inner urban community psychiatric service. Aust N Z J Psychiatry 33:896–901PubMedGoogle Scholar
  45. 45.
    Wheeler A, Humberstone V, Robinson G (2006) Trends in antipsychotic prescribing in schizophrenia in Auckland. Australas Psychiatry 14:169–174PubMedGoogle Scholar
  46. 46.
    Pai NB, Laidlaw M, Vella SC (2012) Augmentation of clozapine with another pharmacological agent: treatment for refractory schizophrenia in the ‘real world’. Acta Psychiatr Scand 126(1):40–46PubMedGoogle Scholar
  47. 47.
    Procyshyn RM, Kennedy NB, Tse G, Thompson B (2001) Antipsychotic polypharmacy: a survey of discharge prescriptions from a tertiary care psychiatric institution. Can J Psychiatry 46:334–339PubMedGoogle Scholar
  48. 48.
    Chong SA, Sachdev P, Mahendran R, Chua HC (2000) Neuroleptic and anticholinergic drug use in Chinese patients with schizophrenia resident in a state psychiatric hospital in Singapore. Aust N Z J Psychiatry 34:988–991PubMedGoogle Scholar
  49. 49.
    Sim K, Su A, Fujii S, Yang SY, Chong MY, Ungvari GS, Si T, Chung EK, Tsang HY, Chan YH, Heckers S, Shinfuku N, Tan CH (2004) Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in east Asia. Br J Clin Pharmacol 58:178–183PubMedGoogle Scholar
  50. 50.
    Ito C, Kubota Y, Sato M (1999) A prospective survey on drug choice for prescriptions for admitted patients with schizophrenia. Psychiatry Clin Neurosci 53(Suppl):S35–S40PubMedGoogle Scholar
  51. 51.
    Yoshimura R, Okamoto T, Nakamura J, Tateno M, Otsuka K, Takahashi H, Fujisawa D, Takamatsu T, Fujii S, Sato S, Inoue M, Sasaki H, Kuroki T, Shinfuku N (2006) Prescription pattern of antipsychotic drugs for schizophrenic inpatients in Japan: research on East Asia psychotropic prescription pattern-antipsychotics study. Psychiatry Clin Neurosci 60:778–779PubMedGoogle Scholar
  52. 52.
    Apiquian R, Fresan A, de la Fuente-Sandoval C, Ulloa RE, Nicolini H (2004) Survey on schizophrenia treatment in Mexico: perception and antipsychotic prescription patterns. BMC Psychiatry 4:12PubMedGoogle Scholar
  53. 53.
    Correll CU, Frederickson AM, Kane JM, Manu P (2007) Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res 89:91–100PubMedGoogle Scholar
  54. 54.
    Faries D, Ascher-Svanum H, Zhu B, Correll C, Kane J (2005) Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. BMC Psychiatry 5:26PubMedGoogle Scholar
  55. 55.
    Ganguly R, Kotzan JA, Miller LS, Kennedy K, Martin BC (2004) Prevalence, trends, and factors associated with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients, 1998–2000. J Clin Psychiatry 65:1377–1388PubMedGoogle Scholar
  56. 56.
    Kreyenbuhl J, Valenstein M, McCarthy JF, Ganoczy D, Blow FC (2006) Long-term combination antipsychotic treatment in VA patients with schizophrenia. Schizophr Res 84:90–99PubMedGoogle Scholar
  57. 57.
    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedGoogle Scholar
  58. 58.
    Tapp A, Wood AE, Secrest L, Erdmann J, Cubberley L, Kilzieh N (2003) Combination antipsychotic therapy in clinical practice. Psychiatr Serv 54:55–59PubMedGoogle Scholar
  59. 59.
    Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B (2001) Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 158:518–526PubMedGoogle Scholar
  60. 60.
    Frogley C, Taylor D, Dickens G, Picchioni M (2012) A systematic review of the evidence of clozapine’s anti-aggressive effects. Int J Neuropsychopharmacol 15(9):1351–1371PubMedGoogle Scholar
  61. 61.
    Munro J, O’Sullivan D, Andrews C, Arana A, Mortimer A, Kerwin R (1999) Active monitoring of 12,760 clozapine recipients in the UK and Ireland. Beyond pharmacovigilance. Br J Psychiatry 175:576–580PubMedGoogle Scholar
  62. 62.
    Bredbacka PE, Paukkala E, Kinnunen E, Koponen H (1993) Can severe cardiorespiratory dysregulation induced by clozapine monotherapy be predicted? Int Clin Psychopharmacol 8:205–206PubMedGoogle Scholar
  63. 63.
    Subramanian S, Völlm BA (2012) Clozapine dose for schizophrenia (Protocol). The Cochrane Library Issue 1
  64. 64.
    Perry PJ, Miller DD, Arndt SV, Cadoret RJ (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 148:231–235PubMedGoogle Scholar
  65. 65.
    Potkin SG, Bera R, Gulasekaram B, Costa J, Hayes S, Jin Y, Richmond G, Carreon D, Sitanggan K, Gerber B et al (1994) Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 55(Suppl B):133–136PubMedGoogle Scholar
  66. 66.
    Porcelli S, Balzarro B, Serretti A (2011) Clozapine resistance: augmentation strategies. Eur Neuropsychopharmacol 22(3):165–182PubMedGoogle Scholar
  67. 67.
    Sernyak MJ, Rosenheck R (2004) Clinicians’ reasons for antipsychotic coprescribing. J Clin Psychiatry 65:1597–1600PubMedGoogle Scholar
  68. 68.
    Nielsen J, Damkier P, Lublin H, Taylor D (2011) Optimizing clozapine treatment. Acta Psychiatr Scand 123:411–422PubMedGoogle Scholar
  69. 69.
    Miller AE (2005) Psychiatric management of treatment-resistant schizophrenia. In: The American Psychiatric Association, annual meeting, May 21–26, Atlanta, GA, Forum #4Google Scholar
  70. 70.
    Kane JM, Leucht S, Carpenter D, Docherty JP (2003) The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry 64(Suppl 12):5–19PubMedGoogle Scholar
  71. 71.
    Cipriani A, Boso M, Barbui C (2009) Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev Jul 8;(3):CD006324Google Scholar
  72. 72.
    Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S (2009) Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 35:443–457PubMedGoogle Scholar
  73. 73.
    Taylor DM, Smith L (2009) Augmentation of clozapine with a second antipsychotic—a meta-analysis of randomized, placebo-controlled studies. Acta Psychiatr Scand 119:419–425PubMedGoogle Scholar
  74. 74.
    Muscatello MR, Bruno A, Pandolfo G, Mico U, Scimeca G, Di Nardo F, Santoro V, Spina E, Zoccali RA (2011) Effect of aripiprazole augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. Schizophr Res 127:93–99PubMedGoogle Scholar
  75. 75.
    Weiner E, Conley RR, Ball MP, Feldman S, Gold JM, Kelly DL, Wonodi I, McMahon RP, Buchanan RW (2010) Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology 35:2274–2283PubMedGoogle Scholar
  76. 76.
    Ito H, Koyama A, Higuchi T (2005) Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 187:243–247PubMedGoogle Scholar
  77. 77.
    Mace S, Taylor D (2005) A prescription survey of antipsychotic use in England and Wales following the introduction of NICE guidance. Int J Psychiatry Clin Pract 9:124–129Google Scholar
  78. 78.
    Taylor D, Mir S, Mace S, Whiskey E (2002) Co-prescribing of atypical and typical antipsychotics—prescribing sequence and documented outcome. Psychiatr Bull 26:170–172Google Scholar
  79. 79.
    Buckley P, Miller A, Olsen J, Garver D, Miller DD, Csernansky J (2001) When symptoms persist: clozapine augmentation strategies. Schizophr Bull 27:615–628PubMedGoogle Scholar
  80. 80.
    Chen CK, Shiah IS, Yeh CB, Mao WC, Chang CC (2005) Combination treatment of clozapine and topiramate in resistant rapid-cycling bipolar disorder. Clin Neuropharmacol 28:136–138PubMedGoogle Scholar
  81. 81.
    Compton AD, Slemmer JE, Drew MR, Hyman JM, Golden KM, Balster RL, Wiley JL (2001) Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats. Neuropharmacology 40:289–297PubMedGoogle Scholar
  82. 82.
    Dardennes RM, Al Anbar NN, Rouillon F (2010) Successful augmentation of clozapine-resistant treatment of schizophrenia with clonidine. Prog Neuropsychopharmacol Biol Psychiatry 34:724–725PubMedGoogle Scholar
  83. 83.
    Diaz P, Bhaskara S, Dursun SM, Deakin B (2005) Double-blind, placebo-controlled, crossover trial of clozapine plus glycine in refractory schizophrenia negative results. J Clin Psychopharmacol 25:277–278PubMedGoogle Scholar
  84. 84.
    Doruk A, Uzun O, Ozsahin A (2008) A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol 23:223–227PubMedGoogle Scholar
  85. 85.
    Gazdag G, Kocsis-Ficzere N, Tolna J (2006) The augmentation of clozapine treatment with electroconvulsive therapy. Ideggyogy Sz 59:261–267PubMedGoogle Scholar
  86. 86.
    Hahn MK, Remington G, Bois D, Cohn T (2010) Topiramate augmentation in clozapine-treated patients with schizophrenia: clinical and metabolic effects. J Clin Psychopharmacol 30:706–710PubMedGoogle Scholar
  87. 87.
    Havaki-Kontaxaki BJ, Ferentinos PP, Kontaxakis VP, Paplos KG, Soldatos CR (2006) Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia. Clin Neuropharmacol 29:52–56PubMedGoogle Scholar
  88. 88.
    Hrdlicka M (2002) Combination of clozapine and maprotiline in refractory psychotic depression. Eur Psychiatry 17:484PubMedGoogle Scholar
  89. 89.
    Kalyoncu A, Mirsal H, Pektas O, Unsalan N, Tan D, Beyazyurek M (2005) Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect? J Psychopharmacol 19:301–305PubMedGoogle Scholar
  90. 90.
    Kanaan RA, Kerwin RW (2006) Lithium and clozapine rechallenge: a retrospective case analysis. J Clin Psychiatry 67:756–760PubMedGoogle Scholar
  91. 91.
    Keller S, Drexler H, Lichtenberg P (2009) Very high-dose clozapine and electroconvulsive therapy combination treatment in a patient with schizophrenia. J ECT 25:280–281PubMedGoogle Scholar
  92. 92.
    Kelly DL, Conley RR, Feldman S, Yu Y, McMahon RP, Richardson CM (2006) Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia. Psychiatr Q 77:81–95PubMedGoogle Scholar
  93. 93.
    Kreinin A, Miodownik C, Libov I, Shestakova D, Lerner V (2009) Moclobemide treatment of clozapine-induced hypersalivation: pilot open study. Clin Neuropharmacol 32:151–153PubMedGoogle Scholar
  94. 94.
    Pavlovic ZM (2008) Augmentation of clozapine’s antiaggressive properties with lamotrigine in a patient with chronic disorganized schizophrenia. J Clin Psychopharmacol 28:119–120PubMedGoogle Scholar
  95. 95.
    Risch SC, Horner MD, McGurk SR, Palecko S, Markowitz JS, Nahas Z, DeVane CL (2007) Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study. Schizophr Res 93:131–135PubMedGoogle Scholar
  96. 96.
    Stryjer R, Strous R, Bar F, Shaked G, Shiloh R, Rozencwaig S, Grupper D, Buchman N, Kotler M, Rabey JM, Weizman A (2004) Donepezil augmentation of clozapine monotherapy in schizophrenia patients: a double blind cross-over study. Hum Psychopharmacol 19:343–346PubMedGoogle Scholar
  97. 97.
    Tiihonen J, Wahlbeck K, Kiviniemi V (2009) The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res 109:10–14PubMedGoogle Scholar
  98. 98.
    Zink M, Englisch S, Knopf U, Kuwilsky A, Dressing H (2007) Augmentation of clozapine with valproic acid for clozapine-induced obsessive-compulsive symptoms. Pharmacopsychiatry 40:202–203PubMedGoogle Scholar
  99. 99.
    Zoccali R, Muscatello MR, Bruno A, Cambria R, Mico U, Spina E, Meduri M (2007) The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res 93:109–116PubMedGoogle Scholar
  100. 100.
    Potter WZ, Ko GN, Zhang LD, Yan WW (1989) Clozapine in China: a review and preview of US/PRC collaboration. Psychopharmacology (Berl) 99(Suppl):S87–S91Google Scholar
  101. 101.
    Mowerman S, Siris SG (1996) Adjunctive loxapine in a clozapine-resistant cohort of schizophrenic patients. Ann Clin Psychiatry 8:193–197PubMedGoogle Scholar
  102. 102.
    Friedman J, Ault K, Powchik P (1997) Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biol Psychiatry 42:522–523PubMedGoogle Scholar
  103. 103.
    Friedman JI, Lindenmayer JP, Alcantara F, Bowler S, Parak M, White L, Iskander A, Parrella M, Adler DN, Tsopelas ND, Tsai WY, Novakovick V, Harvey PD, Davis KL (2011) Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology 36:1289–1295PubMedGoogle Scholar
  104. 104.
    Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman-Etrog P, Modai I, Khaikin M, Weizman A (1997) Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry 171:569–573PubMedGoogle Scholar
  105. 105.
    Shiloh R, Zemishlany Z, Aizenberg D, Weizman A (1997) Sulpiride adjunction to clozapine in treatment-resistant schizophrenic patients: a preliminary case series study. Eur Psychiatry 12:152–155PubMedGoogle Scholar
  106. 106.
    Stubbs JH, Haw CM, Staley CJ, Mountjoy CQ (2000) Augmentation with sulpiride for a schizophrenic patient partially responsive to clozapine. Acta Psychiatr Scand 102:390–393, discussion 393–4PubMedGoogle Scholar
  107. 107.
    Liu Q, Li X, Zhang Y (1996) A control study of clozapine in combination with sulpiride in alleviating the negative symptoms of schizophrenia. Chin J Psychiatry 29:87–90Google Scholar
  108. 108.
    Si S, Yuan C (1999) A comparative trial of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Shandong Arch Psychiatry 12:17–20Google Scholar
  109. 109.
    Wang C, Qin T, Lin Y, Zhao X (1994) A clinical effect and following-up study about sulpiride and clozapine for 105 cases of the schizophrenia type. Xinxiang Med Stud 11:148–151Google Scholar
  110. 110.
    Xao H (1999) A double-blind comparative study of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Sichuan Ment Health 12:250–251Google Scholar
  111. 111.
    Zhu Y, Zhang S, Zhang D (1999) A controlled trial comparing chlorimipramine and sulpiride as adjunct to clozapine in the treatment of negative symptoms of schizophrenia. J Clin Psychol Med 9:204–205Google Scholar
  112. 112.
    Zou G, Huang Y, Zou S, Yang Y (2003) A comparative trial of the beneficial effects of sulpiride combined with clozapine in the treatment of refractory schizophrenia. J Yichun Univ 25:94–96Google Scholar
  113. 113.
    Wang J, Omori IM, Fenton M, Soares B (2011) Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev 2010 Jan 20;(1):CD008125Google Scholar
  114. 114.
    Cubala WJ, Wichowicz HM, Landowski J (2007) Refractory schizophrenia treated with clozapine combined with zuclopenthixol. Prog Neuropsychopharmacol Biol Psychiatry 31:781–783PubMedGoogle Scholar
  115. 115.
    Rajarethinam R, Gilani S, Tancer M, DeQuardo J (2003) Augmentation of clozapine partial responders with conventional antipsychotics. Schizophr Res 60:97–98PubMedGoogle Scholar
  116. 116.
    Mossaheb N, Sacher J, Wiesegger G, Klein N, Spindelegger CJ, Asenbaum S, Dudczak R, Kasper S (2006) Haloperidol in combination with clozapine in treatment-refractory patients with schizophrenia. Eur Neuropsychopharmacol 16(suppl 4):416Google Scholar
  117. 117.
    Jia Z, Zhang Z, Jin S (2000) A controlled trial for comparing clozapine combined with pipothiazine palmitate to clozapine alone in the treatment of negative symptoms in schizophrenic patients. Herald Med 19:142–143Google Scholar
  118. 118.
    Zhu H, Deng D (2002) A study of clozapine combined with or without pipotiazine palmitate in refractory schizophrenia. J Clin Psychol Med 12:15–17Google Scholar
  119. 119.
    Cooke C, de Leon J (1999) Adding other antipsychotics to clozapine. J Clin Psychiatry 60:710PubMedGoogle Scholar
  120. 120.
    Grohmann R, Ruther E, Sassim N, Schmidt LG (1989) Adverse effects of clozapine. Psychopharmacology (Berl) 99(Suppl):S101–S104Google Scholar
  121. 121.
    Peacock L, Gerlach J (1994) Clozapine treatment in Denmark: concomitant psychotropic medication and hematologic monitoring in a system with liberal usage practices. J Clin Psychiatry 55:44–49PubMedGoogle Scholar
  122. 122.
    Barbui C, Signoretti A, Mule S, Boso M, Cipriani A (2009) Does the addition of a second antipsychotic drug improve clozapine treatment? Schizophr Bull 35:458–468PubMedGoogle Scholar
  123. 123.
    Kontaxakis VP, Ferentinos PP, Havaki-Kontaxaki BJ, Roukas DK (2005) Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review. Eur Psychiatry 20:409–415PubMedGoogle Scholar
  124. 124.
    Taylor DM, Smith L, Gee SH, Jimmi N (2011) Augmentation of clozapine with a second antipsychotic—a meta-analysis. Acta Psychiatr Scand 125(1):15–24PubMedGoogle Scholar
  125. 125.
    Tamminga CA (2002) Partial dopamine agonists in the treatment of psychosis. J Neural Transm 109:411–420PubMedGoogle Scholar
  126. 126.
    Bolonna AA, Kerwin RW (2005) Partial agonism and schizophrenia. Br J Psychiatry 186:7–10PubMedGoogle Scholar
  127. 127.
    Rivas-Vasquez RA (2003) Aripiprazole: a novel antipsychotic with dopamine stabilising properties. Prof Psychol Res Pr 34:108–111Google Scholar
  128. 128.
    Clarke LA, Lindenmayer JP, Kaushik S (2006) Clozapine augmentation with aripiprazole for negative symptoms. J Clin Psychiatry 67:675–676PubMedGoogle Scholar
  129. 129.
    Lim S, Bowers MB (2007) Augmentation of clozapine treatment with aripiprazole. J Clin Psychiatry 68:798–799PubMedGoogle Scholar
  130. 130.
    Masopust J, Tuma I, Libiger J (2008) Adjunctive aripiprazole decreased metabolic side effects of clozapine treatment. Neuro Endocrinol Lett 29:435–437PubMedGoogle Scholar
  131. 131.
    Pigato G, Toffanin T, Perini GI (2009) Is a high dosage aripiprazole-clozapine combination an effective strategy for treatment-resistant schizophrenic patients? a case report. Prog Neuropsychopharmacol Biol Psychiatry 33:153–155PubMedGoogle Scholar
  132. 132.
    Rocha FL, Hara C (2006) Benefits of combining aripiprazole to clozapine: three case reports. Prog Neuropsychopharmacol Biol Psychiatry 30:1167–1169PubMedGoogle Scholar
  133. 133.
    Ziegenbein M, Sieberer M, Calliess IT, Kropp S (2005) Combination of clozapine and aripiprazole: a promising approach in treatment-resistant schizophrenia. Aust N Z J Psychiatry 39:840–841PubMedGoogle Scholar
  134. 134.
    Ziegenbein M, Wittmann G, Kropp S (2006) Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia: a clinical observation. Clin Drug Investig 26:117–124PubMedGoogle Scholar
  135. 135.
    Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, Katsanou MN (2007) Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: an open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry 31:373–377PubMedGoogle Scholar
  136. 136.
    Karunakaran K, Tungaraza TE, Harborne GC (2007) Is clozapine-aripiprazole combination a useful regime in the management of treatment-resistant schizophrenia? J Psychopharmacol 21:453–456PubMedGoogle Scholar
  137. 137.
    Benedetti A, Di Paolo A, Lastella M, Casamassima F, Candiracci C, Litta A, Ciofi L, Danesi R, Lattanzi L, Del Tacca M, Cassano GB (2010) Augmentation of clozapine with aripiprazole in severe psychotic bipolar and schizoaffective disorders: a pilot study. Clin Pract Epidemiol Ment Health 6:30–35PubMedGoogle Scholar
  138. 138.
    Millar H, Felter C, Landsberg W (2008) The effects of aripiprazole in combination with clozapine: patient functioning results from a double-blind, 16-week study in patients with schizophrenia. J Psychopharmacol 22:A17Google Scholar
  139. 139.
    Fleischhacker WW, Heikkinen ME, Olie JP, Landsberg W, Dewaele P, McQuade RD, Loze JY, Hennicken D, Kerselaers W (2010) 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 13:1115–1125PubMedGoogle Scholar
  140. 140.
    Barbui C, Accordini S, Nose M, Stroup S, Purgato M, Girlanda F, Esposito E, Veronese A, Tansella M, Cipriani A (2011) Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol 31:266–273PubMedGoogle Scholar
  141. 141.
    Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, Kim YS (2008) Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 69:720–731PubMedGoogle Scholar
  142. 142.
    De Risio A, Pancheri A, Simonetti G, Giannarelli D, Stefanutto L, Gentile B (2011) Add-on of aripiprazole improves outcome in clozapine-resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35:1112–1116PubMedGoogle Scholar
  143. 143.
    Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, Shaughnessy RA (2005) Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 162:130–136PubMedGoogle Scholar
  144. 144.
    Owens DG (1994) Extrapyramidal side effects and tolerability of risperidone: a review. J Clin Psychiatry 55(Suppl):29–35PubMedGoogle Scholar
  145. 145.
    Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, Ertugrul A, Jayathilake K, Gogus A, Tunca Z, Meltzer HY (2005) A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry 66:63–72PubMedGoogle Scholar
  146. 146.
    Honer W, MacEwan GW, Williams R, Falkai P, McKenna PJ, Pomarol-Clotet E, Chen EY, Leung SP, Wong J, Stip E (2005) A randomized, placebo-controlled, double-blind trial of augmentation of clozapine with risperidone. Schizophr Bull 31:487Google Scholar
  147. 147.
    Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R (2006) Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med 354:472–482PubMedGoogle Scholar
  148. 148.
    de Groot IW, Heck AH, van Harten PN (2001) Addition of risperidone to clozapine therapy in chronically psychotic inpatients. J Clin Psychiatry 62:129–130PubMedGoogle Scholar
  149. 149.
    Henderson DC, Goff DC (1996) Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry 57:395–397PubMedGoogle Scholar
  150. 150.
    Taylor CG, Flynn SW, Altman S, Ehmann T, MacEwan GW, Honer WG (2001) An open trial of risperidone augmentation of partial response to clozapine. Schizophr Res 48:155–158PubMedGoogle Scholar
  151. 151.
    Adesanya A, Pantelis C (2000) Adjunctive risperidone treatment in patients with ‘clozapine-resistant schizophrenia’. Aust N Z J Psychiatry 34:533–534PubMedGoogle Scholar
  152. 152.
    McCarthy RH, Terkelsen KG (1995) Risperidone augmentation of clozapine. Pharmacopsychiatry 28:61–63PubMedGoogle Scholar
  153. 153.
    Morera AL, Barreiro P, Cano-Munoz JL (1999) Risperidone and clozapine combination for the treatment of refractory schizophrenia. Acta Psychiatr Scand 99:305–306, discussion 306–7PubMedGoogle Scholar
  154. 154.
    Patel JK, Salzman C, Green AI, Tsuang MT (1997) Chronic schizophrenia: response to clozapine, risperidone, and paroxetine. Am J Psychiatry 154:543–546PubMedGoogle Scholar
  155. 155.
    Raskin S, Katz G, Zislin Z, Knobler HY, Durst R (2000) Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand 101:334–336PubMedGoogle Scholar
  156. 156.
    Tyson SC, Devane CL, Risch SC (1995) Pharmacokinetic interaction between risperidone and clozapine. Am J Psychiatry 152:1401–1402PubMedGoogle Scholar
  157. 157.
    Beauchemin MA, Millaud F, Nguyen KA (2002) A case of neuroleptic malignant syndrome with clozapine and risperidone. Can J Psychiatry 47:886PubMedGoogle Scholar
  158. 158.
    Kontaxakis VP, Havaki-Kontaxaki BJ, Stamouli SS, Christodoulou GN (2002) Toxic interaction between risperidone and clozapine: a case report. Prog Neuropsychopharmacol Biol Psychiatry 26:407–409PubMedGoogle Scholar
  159. 159.
    Senechal A, Landry P, Deschamps R, Lessard M (2002) Neutropenia in a patient treated with clozapine in combination with other psychotropic drugs. Encéphale 28:567–569PubMedGoogle Scholar
  160. 160.
    Godleski LS, Sernyak MJ (1996) Agranulocytosis after addition of risperidone to clozapine treatment [letter]. Am J Psychiatry 153:735–736PubMedGoogle Scholar
  161. 161.
    Koreen AR, Lieberman JA, Kronig M, Cooper TB (1995) Cross-tapering clozapine and risperidone [letter]. Am J Psychiatry 152:1690PubMedGoogle Scholar
  162. 162.
    Chong SA, Tan CH, Lee HS (1996) Hoarding and clozapine-risperidone combination [letter]. Can J Psychiatry Revue Canadienne DePsychiatrie 41:315–316Google Scholar
  163. 163.
    Chong SA, Tan CH, Lee HS (1997) Atrial ectopics with clozapine-risperidone combination. J Clin Psychopharmacol 17:130–131PubMedGoogle Scholar
  164. 164.
    Agelink MW, Kavuk I, Ak I (2004) Clozapine with amisulpride for refractory schizophrenia. Am J Psychiatry 161:924–925PubMedGoogle Scholar
  165. 165.
    Allouche G, Joober R, Vanelle JM, Brochier T, Olie JP (1994) Sequence in prescribing neuroleptics: a therapeutic alternative in refractory schizophrenia? Encéphale 20:777–780PubMedGoogle Scholar
  166. 166.
    Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G (2008) Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry 41:24–28PubMedGoogle Scholar
  167. 167.
    Cook B, Hoogenboom G (2004) Combined use of amisulpride and clozapine for patients with treatment-resistant schizophrenia. Australas Psychiatry 12:74–76PubMedGoogle Scholar
  168. 168.
    Croissant B, Hermann D, Olbrich R (2005) Reduction of side effects by combining clozapine with amisulpride: case report and short review of clozapine-induced hypersalivation—a case report. Pharmacopsychiatry 38:38–39PubMedGoogle Scholar
  169. 169.
    Genc Y, Taner E, Candansayar S (2007) Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single-blind randomized study. Adv Ther 24:1–13PubMedGoogle Scholar
  170. 170.
    George S, Cowan C (2005) Effectiveness of amisulpride augmentation of clozapine in a non-responder to either drug alone: a case report. Acta Psychiatr Scand 111:163PubMedGoogle Scholar
  171. 171.
    Kampf P, Agelink MW, Naber D (2005) Augmentation of clozapine with amisulpride: a promising therapeutic approach to refractory schizophrenic symptoms. Pharmacopsychiatry 38:39–40PubMedGoogle Scholar
  172. 172.
    Kreinin A, Miodownik C, Sokolik S, Shestakova D, Libov I, Bergman J, Lerner V (2010) Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation. World J Biol Psychiatry 12(8):620–626PubMedGoogle Scholar
  173. 173.
    Kreinin A, Novitski D, Weizman A (2006) Amisulpride treatment of clozapine-induced hypersalivation in schizophrenia patients: a randomized, double-blind, placebo-controlled cross-over study. Int Clin Psychopharmacol 21:99–103PubMedGoogle Scholar
  174. 174.
    Lerner V, Bergman J, Borokhov A, Loewenthal U, Miodownik C (2005) Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy. Clin Neuropharmacol 28:66–71PubMedGoogle Scholar
  175. 175.
    Munro J, Matthiasson P, Osborne S, Travis M, Purcell S, Cobb AM, Launer M, Beer MD, Kerwin R (2004) Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine. Acta Psychiatr Scand 110:292–298PubMedGoogle Scholar
  176. 176.
    Zink M, Knopf U, Henn FA, Thome J (2004) Combination of clozapine and amisulpride in treatment-resistant schizophrenia—case reports and review of the literature. Pharmacopsychiatry 37:26–31PubMedGoogle Scholar
  177. 177.
    Gupta S, Sonnenberg SJ, Frank B (1998) Olanzapine augmentation of clozapine. Ann Clin Psychiatry 10:113–115PubMedGoogle Scholar
  178. 178.
    Rhoads E (2000) Polypharmacy of 2 atypical antipsychotics. J Clin Psychiatry 61:678–680PubMedGoogle Scholar
  179. 179.
    Nielsen J, Emborg C, Gydesen S, Dybbro J, Aagaard J, Haderup K, Glyngdal P, Fabricius S, Thode D, Lublin H, Andersen T, Damkier P, Taylor D (2012) Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol 32:173–178PubMedGoogle Scholar
  180. 180.
    Nielsen RE, Levander S, Thode D, Nielsen J (2012) Effects of sertindole on cognition in clozapine-treated schizophrenia patients. Acta Psychiatr Scand 126(1):31–39PubMedGoogle Scholar
  181. 181.
    Kaye NS (2003) Ziprasidone augmentation of clozapine in 11 patients. J Clin Psychiatry 64:215–216PubMedGoogle Scholar
  182. 182.
    Ziegenbein M, Kropp S, Kuenzel HE (2005) Combination of clozapine and ziprasidone in treatment-resistant schizophrenia: an open clinical study. Clin Neuropharmacol 28:220–224PubMedGoogle Scholar
  183. 183.
    Zink M, Mase E, Dressing H (2004) Ziprasidone-augmentation of clozapine. Psychiatr Prax 31:259–261PubMedGoogle Scholar
  184. 184.
    Zink M, Mase E, Dressing H (2004) Combination of ziprasidone and clozapine in treatment-resistant schizophrenia. Hum Psychopharmacol 19:271–273PubMedGoogle Scholar
  185. 185.
    Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384PubMedGoogle Scholar
  186. 186.
    Dursun SM, Deakin JF (2001) Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol 15:297–301PubMedGoogle Scholar
  187. 187.
    Tiihonen J, Hallikainen T, Ryynanen OP, Repo-Tiihonen E, Kotilainen I, Eronen M, Toivonen P, Wahlbeck K, Putkonen A (2003) Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 54:1241–1248PubMedGoogle Scholar
  188. 188.
    Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Thompson TR, Volavka J, Webster EL (2007) Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol 27:582–589PubMedGoogle Scholar
  189. 189.
    McIlwain ME, Harrison J, Wheeler AJ, Russell BR (2011) Pharmacotherapy for treatment-resistant schizophrenia. Neuropsychiatr Dis Treat 7:135–149PubMedGoogle Scholar
  190. 190.
    Arnone D (2005) Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4:5PubMedGoogle Scholar
  191. 191.
    Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE (2000) An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 41(Suppl 1):S3–S9PubMedGoogle Scholar
  192. 192.
    Afshar H, Roohafza H, Mousavi G, Golchin S, Toghianifar N, Sadeghi M, Talaei M (2009) Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol 23:157–162PubMedGoogle Scholar
  193. 193.
    Arif H, Buchsbaum R, Weintraub D, Pierro J, Resor SR Jr, Hirsch LJ (2009) Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs. Epilepsy Behav 14:202–209PubMedGoogle Scholar
  194. 194.
    Lee S, Sziklas V, Andermann F, Farnham S, Risse G, Gustafson M, Gates J, Penovich P, Al-Asmi A, Dubeau F, Jones-Gotman M (2003) The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia 44:339–347PubMedGoogle Scholar
  195. 195.
    Thompson PJ, Baxendale SA, Duncan JS, Sander JW (2000) Effects of topiramate on cognitive function. J Neurol Neurosurg Psychiatry 69:636–641PubMedGoogle Scholar
  196. 196.
    Behdani F, Hebrani P, Rezaei Ardani A, Rafee E (2011) Effect of topiramate augmentation in chronic schizophrenia: a placebo-controlled trial. Arch Iran Med 14:270–275PubMedGoogle Scholar
  197. 197.
    Fayek M, Kingsbury SJ, Simpson G (2002) Treatment-resistant schizophrenia: making the determination. Psychiatric Times 19:
  198. 198.
    Bender S, Linka T, Wolstein J, Gehendges S, Paulus HJ, Schall U, Gastpar M (2004) Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol 7:59–63PubMedGoogle Scholar
  199. 199.
    Small JG, Klapper MH, Malloy FW, Steadman TM (2003) Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol 23:223–228PubMedGoogle Scholar
  200. 200.
    Bryois C, Ferrero F (1993) Clinical observation of 11 patients under clozapine-lithium association. Eur Psychiatry 8:213–218Google Scholar
  201. 201.
    Moldavsky M, Stein D, Benatov R, Sirota P, Elizur A, Matzner Y, Weizman A (1998) Combined clozapine-lithium treatment for schizophrenia and schizoaffective disorder. Eur Psychiatry 13:104–106PubMedGoogle Scholar
  202. 202.
    Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523–533PubMedGoogle Scholar
  203. 203.
    Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828PubMedGoogle Scholar
  204. 204.
    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 56:29–36PubMedGoogle Scholar
  205. 205.
    Potkin SG, Jin Y, Bunney BG, Costa J, Gulasekaram B (1999) Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry 156:145–147PubMedGoogle Scholar
  206. 206.
    Goff DC, Henderson DC, Evins AE, Amico E (1999) A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 45:512–514PubMedGoogle Scholar
  207. 207.
    Goff DC, Tsai G, Manoach DS, Flood J, Darby DG, Coyle JT (1996) D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry 153:1628–1630PubMedGoogle Scholar
  208. 208.
    Tsai GE, Yang P, Chung LC, Tsai IC, Tsai CW, Coyle JT (1999) D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 156:1822–1825PubMedGoogle Scholar
  209. 209.
    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 60:645–649PubMedGoogle Scholar
  210. 210.
    Goff DC, Lamberti JS, Leon AC, Green MF, Miller AL, Patel J, Manschreck T, Freudenreich O, Johnson SA (2008) A placebo-controlled add-on trial of the ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 33:465–472PubMedGoogle Scholar
  211. 211.
    Goff DC, Leahy L, Berman I, Posever T, Herz L, Leon AC, Johnson SA, Lynch G (2001) A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 21:484–487PubMedGoogle Scholar
  212. 212.
    Horrobin DF (1998) The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 30:193–208PubMedGoogle Scholar
  213. 213.
    Peet M, Horrobin DF (2002) A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 36:7–18PubMedGoogle Scholar
  214. 214.
    Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ (2002) Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 159:1596–1598PubMedGoogle Scholar
  215. 215.
    Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M (2001) A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 158:2071–2074PubMedGoogle Scholar
  216. 216.
    de Lucena D, Fernandes BS, Berk M, Dodd S, Medeiros DW, Pedrini M, Kunz M, Gomes FA, Giglio LF, Lobato MI, Belmonte-de-Abreu PS, Gama CS (2009) 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 70:1416–1423PubMedGoogle Scholar
  217. 217.
    Lu ML, Lane HY, Chen KP, Jann MW, Su MH, Chang WH (2000) Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry 61:594–599PubMedGoogle Scholar
  218. 218.
    Silver H, Kushnir M, Kaplan A (1996) Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. Biol Psychiatry 40:671–674PubMedGoogle Scholar
  219. 219.
    Lu ML, Lane HY, Lin SK, Chen KP, Chang WH (2004) Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry 65:766–771PubMedGoogle Scholar
  220. 220.
    Hindmarch I, Hashimoto K (2010) Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Hum Psychopharmacol 25:193–200PubMedGoogle Scholar
  221. 221.
    Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A (1996) Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 153:1625–1627PubMedGoogle Scholar
  222. 222.
    Spina E, Avenoso A, Facciola G, Fabrazzo M, Monteleone P, Maj M, Perucca E, Caputi AP (1998) Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Int Clin Psychopharmacol 13:141–145PubMedGoogle Scholar
  223. 223.
    Delle Chiaie R, Salviati M, Fiorentini S, Biondi M (2007) Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol 15:563–568PubMedGoogle Scholar
  224. 224.
    Zoccali R, Muscatello MR, Cedro C, Neri P, La Torre D, Spina E, Di Rosa AE, Meduri M (2004) The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol 19:71–76PubMedGoogle Scholar
  225. 225.
    Berk M, Gama CS, Sundram S, Hustig H, Koopowitz L, D’Souza R, Malloy H, Rowland C, Monkhouse A, Monkhouse A, Bole F, Sathiyamoorthy S, Piskulic D, Dodd S (2009) Mirtazapine add-on therapy in the treatment of schizophrenia with atypical antipsychotics: a double-blind, randomised, placebo-controlled clinical trial. Hum Psychopharmacol 24:233–238PubMedGoogle Scholar
  226. 226.
    Bloch Y, Pollack M, Mor I (1996) Should the administration of ECT during clozapine therapy be contraindicated? Br J Psychiatry 169:253–254PubMedGoogle Scholar
  227. 227.
    Kupchik M, Spivak B, Mester R, Reznik I, Gonen N, Weizman A, Kotler M (2000) Combined electroconvulsive-clozapine therapy. Clin Neuropharmacol 23:14–16PubMedGoogle Scholar
  228. 228.
    Frankenburg FR, Suppes T, McLean PE (1993) Combined clozapine and electroconvulsive therapy. Convuls Ther 9:176–180PubMedGoogle Scholar
  229. 229.
    Kho KH, Blansjaar BA, de Vries S, Babuskova D, Zwinderman AH, Linszen DH (2004) Electroconvulsive therapy for the treatment of clozapine nonresponders suffering from schizophrenia—an open label study. Eur Arch Psychiatry Clin Neurosci 254:372–379PubMedGoogle Scholar
  230. 230.
    Masoudzadeh A, Khalilian AR (2007) Comparative study of clozapine, electroshock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J Biol Sci 10:4287–4290PubMedGoogle Scholar
  231. 231.
    Benatov R, Sirota P, Megged S (1996) Neuroleptic-resistant schizophrenia treated with clozapine and ECT. Convuls Ther 12:117–121PubMedGoogle Scholar
  232. 232.
    Bhatia SC, Bhatia SK, Gupta S (1998) Concurrent administration of clozapine and ECT: a successful therapeutic strategy for a patient with treatment-resistant schizophrenia. J ECT 14:280–283PubMedGoogle Scholar
  233. 233.
    Cardwell BA, Nakai B (1995) Seizure activity in combined clozapine and ECT: a retrospective view. Convuls Ther 11:110–113PubMedGoogle Scholar
  234. 234.
    Kales HC, Dequardo JR, Tandon R (1999) Combined electroconvulsive therapy and clozapine in treatment-resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 23:547–556PubMedGoogle Scholar
  235. 235.
    Kumar S, Goswami U, Behera D, Khastgir U (2003) ECT and clozapine combination producing delirium: a case report. Indian J Psychiatry 45:193PubMedGoogle Scholar
  236. 236.
    Landy DA (1991) Combined use of clozapine and electroconvulsive therapy. Convuls Ther 7:218–221PubMedGoogle Scholar
  237. 237.
    Masiar SJ, Johns CA (1991) ECT following clozapine. Br J Psychiatry 158:135–136PubMedGoogle Scholar
  238. 238.
    Safferman AZ, Munne R (1992) Combining clozapine with ECT. Convuls Ther 8:141–143PubMedGoogle Scholar
  239. 239.
    McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK (2006) Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 163:600–610PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Ministry of Health, Faculty of Health SciencesBen Gurion University of the Negev and Be’er Sheva Mental Health CenterBe’er-ShevaIsrael

Personalised recommendations