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What Can We Do If Clozapine Fails? Pharmacologic Choices and Differential Outcomes

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Treatment–Refractory Schizophrenia

Abstract

What to do when clozapine therapy (or other medications) does not work … or, more often, doesn’t work well enough? This is a real clinical conundrum. Moreover, clinicians struggle daily with the dilemma of distilling information on appropriate augmentation strategies from studies of groups of patients and thereupon extrapolating that information to the individual patient in their practice. This is a complicated equation at the time when the clinician and/or the patient conclude that clozapine therapy has reached its plateau and other options are called for. This chapter will detail the range of options as well as some considerations for selecting one choice over another for given patient scenarios.

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References

  • Akdede BB, Anil Yagcioglu AE, Alptekin K, Turgut TI, Tumuktu M, Yazici MK, Jayathilake K, Tunca Z, Gogus A, Meltzer HY (2006) A double · blind study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. J Clin Psychiatry 67:1912–1919

    Article  CAS  PubMed  Google Scholar 

  • Anil YagcJoglu AE, Kivircik Akdede BB, Turgut T, Tumuklu M, YazicJ 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 66:63–72

    Article  Google Scholar 

  • 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 41:24–28

    Article  CAS  PubMed  Google Scholar 

  • Bachmann CJ, Lehr D, Theisen FM, Preiss M (2009) Aripiprazole as an adjunct to clozapine therapy in adolescents with early onset schizophrenia: a retrospective chart review. Pharmacopsychiatry 42:153–157

    Article  CAS  PubMed  Google Scholar 

  • Barr MS, Farzan F, Rajji TK, Voineskos AN, Blumberger DM, Arenovich T, Fitzgerald PB, Daskalakis ZJ (2013) Can repetitive magnetic stimulation improve cognition in schizophrenia? Pilot data from a randomized controlled trial. Biol Psychiatry 73:510–517

    Article  PubMed  Google Scholar 

  • Bender S, Linka T, Wolstein J, Gehendges S, Paulus HJ, SchaU U, Gastpar M (2004) Safety and efficacy of combined clozapine-lithium pharmacotherapy. Int J Neuropsychopharmacol 7:59–63

    Article  CAS  PubMed  Google Scholar 

  • Benedetti A, Di Paolo A, Lastella M, Casamassima F, Candiracci C, Litta A, Cfofi 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 6:30–35

    Article  PubMed Central  PubMed  Google Scholar 

  • Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jesperson S, Little J, Conus P, Cuenod M, Do KQ, Bush AI (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia – double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64:361–368

    Article  CAS  PubMed  Google Scholar 

  • 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 24:233–238

    Article  CAS  PubMed  Google Scholar 

  • Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A (1996) Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 153:1625–1627

    CAS  PubMed  Google Scholar 

  • Carpenter WT Jr, Conley RR, Buchanan RW, Breier A, Tamminga CA (1995) Patient response and resource management: another view of clozapine treatment of schizophrenia. Am J Psychiatry 152:827–832

    PubMed  Google Scholar 

  • Castle DJ, Keks N, Newton R, Schweitzer I, Coplov D, Paoletti N, Burrows GD, Tiller J (2013) Pharmacological approaches to the management of schizophrenia: Ten years on. Aust Psychiatry 21:329–334

    Google Scholar 

  • Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B (2001) Effectiveness of second generation anti psychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 158:518–526

    Article  CAS  PubMed  Google Scholar 

  • 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 69:720–731

    Article  CAS  PubMed  Google Scholar 

  • Conley RR, Carpenter WT Jr, Tamminga CA (1997) Time to clozapine response in a standardized trial. Am J Psychiatry 154:1243–1247

    CAS  PubMed  Google Scholar 

  • de Groot IW, Heck AH, van Harten PN (2001) Addition of risperidone to clozapine therapy in chronicaUy psychotic inpatients. J Clin Psychiatry 62:129–130

    Article  PubMed  Google Scholar 

  • 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 70:1416–1423

    Article  PubMed  Google Scholar 

  • Delle Chiaie R, Salviatl M, Fiorentini S, Biondi M (2007) Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. Exp Clin Psychopharmacol 15:563–568

    Article  CAS  PubMed  Google Scholar 

  • 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 25:277–278

    Article  PubMed  Google Scholar 

  • 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 15:297–301

    Article  CAS  PubMed  Google Scholar 

  • 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 159:1596–1598

    Article  PubMed  Google Scholar 

  • Engllsch S, Esser A, Enning F, Hohmann S, Schanz H, Zink M (2010) Augmentation with pregabalin in schizophrenia. J Clin Psychopharmacol 30:437–440

    Article  Google Scholar 

  • Evins AE, Fitzgerald SM, Wine LO, Rosselli R, Goff DC (2000) Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 157:826–828

    Article  CAS  PubMed  Google Scholar 

  • 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 158:2071–2074

    Article  CAS  PubMed  Google Scholar 

  • Flamarique I, Castro-Fornieles J, Garrido JM, De la Serna E, Pons A, Bernardo M, Baeza I (2012) Electroconvulsive therapy and clozapine in adolescents with schizophrenia spectrum disorders: is it a safe and effective combination? J Clin Psychopharmacol 32:756–766

    Article  CAS  PubMed  Google Scholar 

  • Freudenreich O, Goff DC (2002) Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 106:323–330

    Article  CAS  PubMed  Google Scholar 

  • Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC (2007) Risperadone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res 92:920–994

    Google Scholar 

  • Freudenreich O, Henderson DC, Macklin EA, Evins AE, Fan X, Cather C, Walsh JP, Goff DC (2009) Modafinil for clozapine treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry 70:1674–1680

    Article  CAS  PubMed  Google Scholar 

  • Goff DC, Henderson DC, Evins AE, Amico E (1999) A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. BioI Psychiatry 45:512–514

    Article  CAS  Google Scholar 

  • 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 21:484–487

    Article  CAS  PubMed  Google Scholar 

  • 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 27:582–589

    Article  CAS  PubMed  Google Scholar 

  • 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 33:465–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Henderson DC, Goff DC (1996) Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry 57:395–397

    CAS  PubMed  Google Scholar 

  • Henderson DC, Kunkel L, Nguyen DO, Borba CP, Daley TB, Louie PM, Freudenrefch O, Cather C, Evins AE, Goff DC (2006) An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatry Scand 113:142–147

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 354:472–482

    Article  CAS  PubMed  Google Scholar 

  • 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 162:130–136

    Article  PubMed  Google Scholar 

  • Kampf P, Agelink MW, Naber D (2005) Augmentation of clozapine with amisutpride: a promising therapeutic approach to refractory schizophrenic symptoms. Pharmacopsychiatry 38:39–40

    Article  CAS  PubMed  Google Scholar 

  • Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796

    Article  CAS  PubMed  Google Scholar 

  • 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 77:81–95

    Article  PubMed  Google Scholar 

  • Kremer I, Vass A, Gorelik I, Bar G, Blanaru M, Javitt DC, HerescoLevy U (2004) Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. BioI Psychiatry 56:441–446

    Article  CAS  Google Scholar 

  • Kulkarni J, Hayes E, Gavrilidis E (2012) Hormones in schizophrenia. Curr Opin Psychiatry 25:89–95

    Article  PubMed  Google Scholar 

  • Kupchik M, Spivak B, Mester R, Resnik I, Gonen N, Weizman A, Kotler M (2000) Combined electroconvulsive-clozapine therapy. Clin Neuropsychopharmacol 23:14–16

    Article  CAS  Google Scholar 

  • Kuwilsky A, Krumm B, Englisch S, Dressing H, Zink M (2010) Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry 43:216–220

    Article  CAS  PubMed  Google Scholar 

  • Lan GX, Li ZC, Li L (2006) A randomized, placebo-controlled trial of combined citalopram and clozapine in the treatment of negative symptoms of schizophrenia. Chin Ment Health J 20:696–698

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lerner V, Bergman J, Borokhov A, Loewenthal U, Mlodownlk C (2005) Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy. Clin Neuropharmacol 28:66–71

    Article  CAS  PubMed  Google Scholar 

  • Lu ML, Lane HY, Chen KP, Jann MW, Su MH, Chang WH (2000) Ftuvoxamine reduces the clozaplne dosage needed in refractory schizophrenic patients. J Clin Psychiatry 61:594–599

    Article  CAS  PubMed  Google Scholar 

  • Masoudzadeh A, Khalilian AR (2007) Comparative study of clozapine, electroschock and the combination of ECT with clozapine in treatment-resistant schizophrenic patients. Pak J Biol Sci 10:4287–4290

    Article  CAS  PubMed  Google Scholar 

  • 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 BioI Psychiatry 31:373–377

    CAS  Google Scholar 

  • 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 110:292–298

    Article  CAS  PubMed  Google Scholar 

  • Muscatello M, Bruno A, Pandolfo G, Mico U, BeUinghieri P, Sdmeca G, Cacciola M, Campolo D, Settineri S, Zoccati R (2011) Topiramate augmentation of clozapine in schizophrenia: a double-blind, placebo-controlled study. J Psychopharmacol 25(5):667–674

    Article  CAS  PubMed  Google Scholar 

  • Papanastasiou E, Stone JM, Shergill S (2013) When drugs don’t work: the potential of glutamatergic antipsychotics in schizophrenia. Br J Psychiatry 202:91–93

    Article  PubMed  Google Scholar 

  • 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 36:7–18

    Article  PubMed  Google Scholar 

  • Pompili M, et al (2013) Indications for electroconvulsive therapy in schizophrenia: a systematic review. Schiz Res. doi:10.1016/j.schres.2013.02.005

  • Porcelli S, Balzarro B, Serretti A (2012) Clozapine resistance: augmentation strategies. Eur Neuropsychopharm 22:165–182

    Article  CAS  Google Scholar 

  • 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 156:145–147

    CAS  PubMed  Google Scholar 

  • 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 171:569–573

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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 23:223–228

    CAS  PubMed  Google Scholar 

  • Sommer IE, Begemann MJH, Temmerman A, Leucht S (2012) Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 38:1003–1011

    Article  PubMed Central  PubMed  Google Scholar 

  • 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 13:141–145

    Article  CAS  PubMed  Google Scholar 

  • Taylor EG, Flynn SW, Altman S, Ehmann T, MacEwan GW, Honer WG (2001) An open trial of risperidone augmentation of partial response to clozapine. Schizophr Res 48:155–158

    Article  CAS  PubMed  Google Scholar 

  • Tiihonen J, Hallikafnen 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. BioI Psychiatry 54:1241–1248

    Article  CAS  Google Scholar 

  • Tiihonen J, Hatonen P, Wahlbeck K, Repo-Tiihonen E, Hyvarinen S, Eronen M, Putkonen H, Takata P, Mehtonen OP, Puck M, Oksanen J, Koskelainen P, Joffe G, Aer J, HaUikainen T, Ryynanen OP, Tupala E (2005) Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 66:1012–1015

    Article  CAS  PubMed  Google Scholar 

  • Tiihonen J, Suokas J, Suvisaari J, Haukka J, Korhonen P (2012) Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry 69:476–483

    Article  CAS  PubMed  Google Scholar 

  • Tsai GE, Yang P, Chung LE, Tsai IC, Tsai CW, Coyle JT (1999) D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 156:1822–1825

    CAS  PubMed  Google Scholar 

  • Weiner E, Conley RR, BaU MP, Feldman S, Gold JM, Kelly DL, Wooodi I, McMahon RP, Buchanan RW (2010) Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology 35:2274–2283

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Williams L, Newton G, Roberts K, Finlayson S, Brabbins C (2002) Clozapine-resistant schizophrenia: a positive approach. Br J Psychiatry 181:184–187

    Article  PubMed  Google Scholar 

  • Wilson WH (1996) Time required for initial improvement during clozapine treatment of refractory schizophrenia. Am J Psychiatry 153:951–952

    CAS  PubMed  Google Scholar 

  • Ziegenbein M, Wittmann G, Kropp S (2006) Aripiprazole augmentation of clozapine in treatment-resistant schizophrenia: a clinical observation. Clin Drug Investig 26:117–124

    Article  CAS  PubMed  Google Scholar 

  • 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 37:26–31.

    Article  CAS  PubMed  Google Scholar 

  • Zink M, Kuwilsky A, Krumm B, Dressing H (2009) Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Psychopharmacol 23:305–314

    Article  CAS  PubMed  Google Scholar 

  • 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 dozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study. Int Clin Psychopharmacol 19:71–76

    Article  PubMed  Google Scholar 

  • Zoccali R, MuscateUo 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 93:109–116

    Article  CAS  PubMed  Google Scholar 

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Castle, D.J., Keks, N. (2014). What Can We Do If Clozapine Fails? Pharmacologic Choices and Differential Outcomes. In: Buckley, P., Gaughran, F. (eds) Treatment–Refractory Schizophrenia. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-45257-4_7

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