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Predictors and markers of clozapine response

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Abstract

Rationale

With other atypical antipsychotics now available, having predictors of clozapine response would be of considerable value, offering clinicians guidance in their decision as to when, and if, a trial of clozapine is warranted.

Objectives

The aim was to review existing evidence regarding identified predictors and markers of clozapine response.

Methods

Relevant studies were identified through PUBMED searches (1975–June 2004) and cross-referencing of reviews and included studies. The data were summarized under two main categories: clinical (general, neurological, cognitive/neuropsychological, clozapine levels) and biological (biochemical, endocrine, genetic, metabolic, morphological, dopamine D2 receptor occupancy). ‘Reliable’ predictors/markers were defined a priori as those with support of at least two independent reports that addressed overall response, with no contradictory findings to date. ‘Potential’ predictors/markers had the support of a single report that addressed overall response and at least one other evaluating treatment outcome but not directly addressing response status.

Results and conclusions

Higher baseline clinical symptoms and functioning in the previous years and low cerebrospinal homovanillic acid/5-hydroxyindoleacetic acid levels were identified as reliable. Three potential measures were identified: reduction of frontal cortex metabolic activity, reduction of caudate volume, and improvement in P50 sensory gating.

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References

  • Ackenheil M (1989) Clozapine-pharmacokinetic investigations and biochemical effects in man. Psychopharmacology (Berl) 99(Suppl):S32–S37

    Google Scholar 

  • Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982) Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17:639–654

    CAS  PubMed  Google Scholar 

  • Amminger GP, Resch F, Mutschlechner R, Friedrich MH, Ernst E (1997) Premorbid adjustment and remission of positive symptoms in first-episode psychosis. Eur Child Adolesc Psychiatry 6:212–218

    Google Scholar 

  • Arango C, Breier A, McMahon R, Carpenter WT Jr, Buchanan RW (2003) The relationship of clozapine and haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes. Am J Psychiatry 160:1421–1427

    Article  Google Scholar 

  • Arranz M, Collier D, Sodhi M, Ball D, Roberts G, Price J, Sham P, Kerwin R (1995) Association between clozapine response and allelic variation in 5-HT2A receptor gene. Lancet 346:281–282

    Google Scholar 

  • Arranz MJ, Collier DA, Munro J, Sham P, Kirov G, Sodhi M, Roberts G, Price J, Kerwin RW (1996) Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett 217:177–178

    Google Scholar 

  • Arranz MJ, Li T, Munro J, Liu X, Murray R, Collier DA, Kerwin RW (1998a) Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response. Pharmacogenetics 8:481–484

    Google Scholar 

  • Arranz MJ, Munro J, Owen MJ, Spurlock G, Sham PC, Zhao J, Kirov G, Collier DA, Kerwin RW (1998b) Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry 3:61–66

    Google Scholar 

  • Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA, Kerwin RW (1998c) Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 32:93–99

    Google Scholar 

  • Arranz MJ, Mancama D, Kerwin RW (2001) Neurotransmitter receptor variants and their influence on antipsychotic treatment. Int J Mol Med 7:27–30

    Google Scholar 

  • Bailer J, Brauer W, Rey ER (1996) Premorbid adjustment as predictor of outcome in schizophrenia: results of a prospective study. Acta Psychiatr Scand 93:368–377

    Google Scholar 

  • Banki CM (1978) Alterations of cerebral fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment. Psychopharmacology (Berl) 56:195–198

    Google Scholar 

  • Bilder RM, Wu H, Chakos MH, Bogerts B, Pollack S, Aronowitz J, Ashtari M, Degreef G, Kane JM, Lieberman JA (1994) Cerebral morphometry and clozapine treatment in schizophrenia. J Clin Psychiatry 55(suppl B):53–56

    Google Scholar 

  • Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA (2000) Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. NeuroReport 11:2017–2020

    Google Scholar 

  • Bolonna AA, Arranz MJ, Munro J, Osborne S, Petouni M, Martinez M, Kerwin RW (2000) No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response. Neurosci Lett 280:65–68

    Article  CAS  PubMed  Google Scholar 

  • Brier A, Buchanan RW, Waltrip RW II, Listwak S, Holmes C, Goldstein DS (1994) The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacology 10:1–7

    Google Scholar 

  • Bromet EJ, Jandorf L, Fennig S, Lavelle J, Kovasznay B, Ram R, Tanenberg-Karant M, Craig T (1996) The Suffolk County Mental Health Project: demographic, pre-morbid and clinical correlates of 6-month outcome. Psychol Med 26:953–962

    CAS  PubMed  Google Scholar 

  • Brown AS, Gewirtz G, Harkavy-Friedman J, Cooper T, Brebion G, Amador XF, Malaspina D, Gorman JM (1997) Effects of clozapine on plasma catecholamines and relation to treatment response in schizophrenia: a within-subject comparison with haloperidol. Neuropsychopharmacology 17:317–325

    Article  CAS  PubMed  Google Scholar 

  • Buchanan RW, Koeppl P, Breier A (1994a) Stability of neurological signs with clozapine treatment. Biol Psychiatry 36:198–200

    Google Scholar 

  • Buchanan RW, Holstein C, Breier A (1994b) The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance. Biol Psychiatry 36:717–725

    Google Scholar 

  • Buchsbaum MS, Wu JC, DeLisi LE, Holcomb HH, Hazlett E, Cooper-Langston K, Kessler R (1987) Positron emission tomography studies of basal ganglia and somatosensory cortex neuroleptic drug effects: differences between normal controls and schizophrenic patients. Biol Psychiatry 22:479–494

    Google Scholar 

  • Buchsbaum MS, Potkin SG, Marshall JF, Lottenberg S, Teng C, Heh CW, Tafalla R, Reynolds C, Abel L, Plon L et al (1992) Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia. Neuropsychopharmacology 6:155–163

    Google Scholar 

  • Buur-Rasmussen B, Brøsen K (1999) Cytochrome P450 and therapeutic drug monitoring with respect to clozapine. Eur Neuropsychopharmacol 9:453–459

    Google Scholar 

  • Carnahan RM, Lund BC, Perry PJ (2001) Ziprasidone, a new atypical antipsychotic drug. Pharmacotherapy 21:717–730

    Google Scholar 

  • Centorrino F, Baldessarini RJ, Kando JC, Frankenburg FR, Volpicelli SA, Flood JG (1994) Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. J Clin Psychopharmacol 14:119–125

    Google Scholar 

  • Centorrino F, Price BH, Tuttle M, Bahk W-M, Hennen J, Albert MJ, Baldessarini RJ (2002) EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry 159:109–115

    Google Scholar 

  • Chakos MH, Lieberman JA, Alvir J, Bilder R, Ashtari M (1995) Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine. Lancet 345:456–457

    Article  CAS  Google Scholar 

  • 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 158:518–526

    Article  Google Scholar 

  • Chen RY, Chen E, Ho WY (2000) A five-year longitudinal study of the regional cerebral metabolic changes of a schizophrenic patient from the first episode using Tc-99m HMPAO SPECT. Eur Arch Psychiatry Clin Neurosci 250:69–72

    Google Scholar 

  • Cohen RM, Nordahl TE, Semple WE, Andreason P, Litman RE, Pickar D (1997) The brain metabolic patterns of clozapine- and fluphenazine-treated patients with schizophrenia during a continuous performance task. Arch Gen Psychiatry 54:481–486

    CAS  PubMed  Google Scholar 

  • Cohen RM, Nordahl TE, Semple WE, Pickar D (1999) The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect. Neuropsychopharmacology 21:632–640

    Google Scholar 

  • Corson PW, Nopoulos P, Andreasen NC, Heckel D, Arndt S (1999) Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network. Biol Psychiatry 46:712–720

    Article  CAS  PubMed  Google Scholar 

  • Davidson M, Kahn RS, Stern RG, Hirschowitz J, Apter S, Knott P, Davis KL (1993) Treatment with clozapine and its effect on plasma homovanillic acid and norepinephrine concentrations in schizophrenia. Psychiatry Res 46:151–163

    Google Scholar 

  • Fabrazzo M, La Pia S, Monteleone P, Esposito G, Pinto A, De Simone L, Bencivenga R, Maj M (2002) Is the time course of clozapine response correlated to the time course of clozapine plasma levels? A one-year prospective study in drug-resistant patients with schizophrenia. Neuropsychopharmacology 27:1050–1055

    Article  CAS  PubMed  Google Scholar 

  • Fenton WS, Lee B (1993) Can clozapine response be predicted? A naturalistic pilot study. J Nerv Ment Dis 181:62–64

    PubMed  Google Scholar 

  • Fleischhacker WW (1999) Clozapine: a comparison with other novel antipsychotics. J Clin Psychiatry 60(Suppl 12):30–34

    Google Scholar 

  • Fleischhaker C, Schulz E, Remschmidt H (1998) Depressive symptoms and biogenic amines as predictors of treatment response in schizophrenic illnesses in childhood and adolescence. Z Kinder- Jugendpsychiatr Psychother 26:235–243

    Google Scholar 

  • Frazier JA, Giedd JN, Kaysen D, Albus K, Hamburger S, Alaghband-Rad J, Lenane MC, McKenna K, Breier A, Rapoport JL (1996) Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment. Am J Psychiatry 153:564–566

    Google Scholar 

  • Freudenreich O, Weiner RD, McEvoy JP (1997) Clozapine-induced electroencephalogram changes as a function of clozapine serum levels. Biol Psychiatry 42:132–137

    Google Scholar 

  • Friedman L, Knutson L, Shurell M, Meltzer HY (1991) Prefrontal sulcal prominence is inversely related to response to clozapine in schizophrenia. Biol Psychiatry 29:865–877

    Google Scholar 

  • Gallinat J, Riedel M, Juckel G, Sokullu S, Frodl T, Moukhtieva R, Mavrogiorgou P, Nissle S, Muller N, Danker-Hopfe H, Hegerl U (2001) P300 and symptom improvement in schizophrenia. Psychopharmacology (Berl) 158:55–65

    Google Scholar 

  • Geddes J, Freemantle N, Harrison P, Bebbington P (2000) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 321:1371–1376

    Article  CAS  PubMed  Google Scholar 

  • Glick ID, Zaninelli R, Hsu C, Young FK, Weiss L, Gunay I, Kumar V (2004) Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior. J Clin Psychiatry 65:679–685

    Google Scholar 

  • Goldberg TE, Greenberg RD, Griffin SJ, Gold JM, Kleinman JE, Pickar D, Schulz SC, Weinberger DR (1993) The effect of clozapine on cognition and psychiatric symptoms in patients with schizophrenia. Br J Psychiatry 162:43–48

    Google Scholar 

  • Grace J, Bellus SB, Raulin ML, Herz MI, Priest BL, Brenner V, Donnelly K, Smith P, Gunn S (1996) Long-term impact of clozapine and psychosocial treatment on psychiatric symptoms and cognitive functioning. Psychiatr Serv 47:41–45

    Google Scholar 

  • Green AI, Alam MY, Sobieraj JT, Pappalardo KM, Waternaux C, Salzman C, Schatzberg AF, Schildkraut JJ (1993) Clozapine response and plasma catecholamines and their metabolites. Psychiatry Res 46:139–149

    Google Scholar 

  • Gross A, Joutsiniemi SL, Rimon R, Appelberg B (2004) Clozapine-induced QEEG changes correlate with clinical response in schizophrenic patients: a prospective, longitudinal study. Pharmacopsychiatry 37:119–122

    Google Scholar 

  • Gutierrez B, Arranz MJ, Huezo-Diaz P, Dempster D, Matthiasson P, Travis M, Munro J, Osborne S, Kerwin RW (2002) Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Schizophr Res 58:93–97

    Google Scholar 

  • Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY (1993) Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 34:702–712

    Article  CAS  PubMed  Google Scholar 

  • Haring C, Neudorfer C, Schwitzer J, Hummer M, Saria A, Hinterhuber H, Fleischhacker WW (1994) EEG alterations in patients treated with clozapine in relation to plasma levels. Psychopharmacology (Berl) 114:97–100

    Google Scholar 

  • Hasegawa M, Gutierrez-Esteinou R, Way L, Meltzer HY (1993) Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol 13:383–390

    CAS  PubMed  Google Scholar 

  • Higashima M, Kawasaki Y, Urata K, Maeda Y, Sakai N, Mizukoshi C, Nagasawa T, Kamiya T, Yamaguchi N, Koshino Y, Matsuda H, Tsuji S, Sumiya H, Hisasda K (1996) Simultaneous observation of regional cerebral blood flow and event-related potential during performance of an auditory task. Brain Res Cogn Brain Res 4:289–296

    Google Scholar 

  • Hoff AL, Faustman WO, Wieneke M, Espinoza S, Costa M, Wolkowitz O, Csernansky JG (1996) The effects of clozapine on symptom reduction, neurocognitive function, and clinical management in treatment-refractory state hospital schizophrenic inpatients. Neuropsychopharmacology 15:361–369

    Google Scholar 

  • Honer WG, MacEwan GW, Kopala L, Altman S, Chisholm-Hay S, Singh K, Smith GN, Ehmann T, Ganesan S, Lang M (1995a) A clinical study of clozapine treatment and predictors of response in a Canadian sample. Can J Psychiatry 40:208–211

    Google Scholar 

  • Honer WG, Smith GN, Lapointe JS, MacEwan GW, Kopala L, Altman S (1995b) Regional cortical anatomy and clozapine response in refractory schizophrenia. Neuropsychopharmacology 13:85–87

    Google Scholar 

  • Hong CJ, Yu YW, Lin CH, Cheng CY, Tsai SJ (2001) Association analysis for NMDA receptor subunit 2B (GRIN2B) genetic variants and psychopathology and clozapine response in schizophrenia. Psychiatr Genet 11:219–222

    Google Scholar 

  • Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48:186–189

    Article  Google Scholar 

  • Honigfeld G, Patin J (1989) Predictors of response to clozapine therapy. Psychopharmacology (Berl) 99(Suppl):S64–S67

    Google Scholar 

  • Huezo-Diaz P, Arranz MJ, Munro J, Osborne S, Makoff A, Kerwin RW, Austin J, O’Donovan M (2004) An association of the neurotensin receptor gene with schizophrenia and clozapine response. Schizophr Res 66:193–195

    Google Scholar 

  • Kahn RS, Davidson M, Siever L, Gabriel S, Apter S, Davis KL (1993) Serotonin function and treatment response to clozapine in schizophrenic patients. Am J Psychiatry 150:1337–1342

    Google Scholar 

  • Kasper S, Resinger E (2003) Cognitive effects and antipsychotic treatment. Psychoneuroendocrinology 28(Suppl 1):27–38

    Google Scholar 

  • Kasper S, Tauscher J, Kufferle B, Barnas C, Hesselmann B, Asenbaum S, Podreka I, Brucke T (1998) Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol—a 123I-IBZM SPECT study. Psychopharmacology 136:367–373

    Google Scholar 

  • Kohn Y, Ebstein RP, Heresco-Levy U, Shapira B, Nemanov L, Gritsenko I, Avnon M, Lerer B (1997) Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol 7:39–43

    Google Scholar 

  • Konicki PE, Kwon KY, Steele V, White J, Fuller M, Jurjus GJ, Jaskiw GE (2001) Prefrontal cortical sulcal widening associated with poor treatment response to clozapine. Schizophr Res 48:173–176

    Google Scholar 

  • Koukkou M, Angst J, Zimmer D (1979) Paroxysmal EEG activity and psychopathology during the treatment with clozapine. Pharmakopsychiatr Neuro-psychopharmakol 12:173–183

    Google Scholar 

  • Kronig MH, Munne RA, Szymanski S, Safferman AZ, Pollack S, Cooper T, Kane JM, Lieberman JA (1995) Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 152:179–182

    CAS  PubMed  Google Scholar 

  • Kufferle B, Tauscher J, Asenbaum S, Vesely C, Prodreka I, Brucke T, Kasper S(1997) IBZM imaging of striatal dopamine-2 receptors in psychotic patients treated with novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol. Psychopharmacology (Berl) 133:323–328

    Google Scholar 

  • Kumari V, Soni W, Sharma T (1999) Normalization of information processing deficits in schizophrenia with clozapine. Am J Psychiatry 156:1046–1051

    CAS  PubMed  Google Scholar 

  • Lacroix D, Chaput Y, Rodriguez JP, Filion M, Morrison D, St-Denis P, Albert JM (1995) Quantified EEG changes associated with a positive clinical response to clozapine in schizophrenia. Prog Neuro-psychopharmacol Biol Psychiatry 19:861–876

    Google Scholar 

  • Lahdelma L, Ahokas A, Andersson LC, Suvisaari J, Hovatta I, Huttenen MO, Koskimies S (2001) Human leukocyte antigen-A1 predicts a good therapeutic response to clozapine with a low risk of agranulocytosis in patients with schizophrenia. J Clin Psychopharmacol 21:4–7

    Google Scholar 

  • Laurent A, Garcia-Larrea L, Dalery J, Terra JL, D’Amato T, Marie-Cardine M, Mauguiere F (1993) The P 300 potential in schizophrenia. Encephale 19:221–227

    Google Scholar 

  • Lauriello J, Mathalon DH, Rosenbloom M, Sullivan EV, Faustman WO, Ringo DL, Lim KO, Pfefferbaum A (1998) Association between regional brain volumes and clozapine response in schizophrenia. Biol Psychiatry 43:879–886

    Google Scholar 

  • Lee MA, Thompson PA, Meltzer HY (1994) Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 55(Suppl B):82–87

    Google Scholar 

  • Leo RJ, Regno PD (2000) Atypical antipsychotic use in the treatment of psychosis in primary care. Prim Care Companion J Clin Psychiatry 2:194–204

    Google Scholar 

  • Leucht S, Pitschel-Walz G, Abraham D, Kissling W (1999) Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 35:51–68

    Google Scholar 

  • Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A, Kronig M, Bookstein P, Kane JM (1994a) Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 151:1744–1752

    CAS  PubMed  Google Scholar 

  • Lieberman JA, Kane JM, Safferman AZ, Pollack S, Howard A, Szymanski S, Masiar SJ, Kronig MH, Cooper T, Novacenko H (1994b) Predictors of response to clozapine. J Clin Psychiatry 55(Suppl B):126–128

    Google Scholar 

  • Light GA, Geyer MA, Clementz BA, Cadenhead KS, Braff DL (2000) Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767–771

    Google Scholar 

  • Lin CH, Tsai SJ, Yu YW, Song HL, Tu PC, Sim CB, Hsu CP, Yang KH, Hong CJ (1999) No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population. NeuroReport 10:57–60

    Google Scholar 

  • Liu HC, Chang WH, Wei FC, Lin SK, Jann MW (1996) Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients. Ther Drug Monit 18:200–207

    Google Scholar 

  • Llorca PM, Lancon C, Disdier B, Farisse J, Sapin C, Auquier P (2002) Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations. J Psychiatry Neurosci 27:30–37

    Google Scholar 

  • Malhotra AK, Goldman D, Ozaki N, Rooney W, Clifton A, Buchanan RW, Brier A, Pickar D (1996a) Clozapine response and the 5HT2C Cys23Ser polymorphism. Neuroreport 7:2100–2102

    Google Scholar 

  • Malhotra AK, Goldman D, Ozaki N, Breier A, Buchanan R, Pickar D (1996b) Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine. Am J Psychiatry 153:1092–1094

    Google Scholar 

  • Malhotra AK, Goldman D, Buchanan RW, Rooney W, Clifton A, Kosmidis MH, Breier A, Pickar D (1998) The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response. Mol Psychiatry 3:72–75

    Google Scholar 

  • Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, Kerwin R (2002) Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett 333:207–211

    Article  CAS  PubMed  Google Scholar 

  • Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, Cola P, Howard A, Badri F, Nothen MM, Kalow W, Kennedy JL (1998) Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 19:123–132

    Google Scholar 

  • Masellis M, Basile VS, Özdemir V, Meltzer HY, Macciardi FM, Kennedy JL (2000) Pharmacogenetics of antipsychotic treatment: lessons learned from clozapine. Biol Psychiatry 47:252–266

    Google Scholar 

  • Masellis M, Basile VS, Meltzer HY, Lieberman JA, Sevy S, Goldman DA, Hamblin MW, Macciardi FM, Kennedy JL (2001) Lack of association between the T→C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Schizophr Res 47:49–58

    Google Scholar 

  • Mauri MC, Volonteri LS, Dell’Osso B, Regispani F, Papa P, Baldi M, Bareggi SR (2003) Predictors of clinical outcome in schizophrenic patients responding to clozapine. J Clin Psychopharmacol 23:660–664

    Article  CAS  PubMed  Google Scholar 

  • Mauri M, Volonteri LS, Fiorentini A, Invernizzi G, Nerini T, Baldi M, Bareggi SR (2004) Clinical outcome and plasma levels of clozapine and norclozapine in drug-resistant schizophrenic patients. Schizophr Res 66:197–198

    Google Scholar 

  • McGurk SR (1999) The effects of clozapine on cognitive functioning in schizophrenia. J Clin Psychiatry 60(Suppl 12):24–29

    Google Scholar 

  • Melkersson K, Dahl ML (2004) Adverse metabolic effects associated with atypical antipsychotics: literature review and clinical implications. Drugs 64:701–723

    CAS  PubMed  Google Scholar 

  • Meltzer HY (1996) Predictors of response to clozapine. Psychiatr Ann 26:385–389

    Google Scholar 

  • Meltzer HY (1989b) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99(Suppl):S18–S27

    Google Scholar 

  • Meltzer HY, McGurk S (1999) The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 25:233–255

    CAS  PubMed  Google Scholar 

  • Meltzer HY, Bastani B, Kwon KY, Ramirez LF, Burnett S, Sharpe J (1989a) A prospective study of clozapine in treatment-resistant schizophrenic patients. I. Preliminary report. Psychopharmacology (Berl) 99(Suppl):S68–S72

    Google Scholar 

  • Meltzer HY, Lee MA, Jayathilake K (2001) The blunted cortisol response to apomorphine and its relationship to treatment response in patients with schizophrenia. Neuropsychopharmacology 24:278–290

    Google Scholar 

  • Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, Bourgeois M, Chouinard G, Islam MZ, Kane J, Krishnan R, Lindenmayer JP, Potkin S (2003) Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 60:82–91

    CAS  PubMed  Google Scholar 

  • Miller DD, Fleming F, Holman TL, Perry PJ (1994) Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry 55(Suppl B):117–121

    PubMed  Google Scholar 

  • Nagamoto HT, Adler LE, Waldo MC, Freedman R (1989) Sensory gating in schizophrenics and normal controls: effects of changing stimulation interval. Biol Psychiatry 25:549–561

    Google Scholar 

  • Nagamoto HT, Adler LE, Hea RA, Griffith JM, McRae KA, Freedman R (1996) Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry 40:181–188

    Article  CAS  PubMed  Google Scholar 

  • Nagamoto HT, Adler LE, McRae KA, Huettl P, Cawthra E, Gerhardt G, Hea R, Griffith J (1999) Auditory P50 in schizophrenics on clozapine: improved gating parallels clinical improvement and changes in plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology 39:10–17

    Google Scholar 

  • Nair NP, Lal S, Cevantes P, Yassa R, Guyda H (1979) Effect of clozapine on apomorhine-induced growth hormone secretion and serum prolactin concentrations in schizophrenia. Neuropsychobiology 5:136–142

    CAS  PubMed  Google Scholar 

  • Nothen MM, Rietschel M, Erdmann J, Oberlander H, Moller HJ, Nober D, Propping P (1995) Genetic variation of the 5-HT2A receptor and response to clozapine. Lancet 346:908–909

    Google Scholar 

  • Olesen OV, Thomsen K, Jensen PN, Wulff CH, Rasmussen NA, Refshammer C, Sorensen J, Bysted M, Christensen J, Rosenberg R (1995) Clozapine serum levels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study. Psychopharmacology (Berl) 117:371–378

    Google Scholar 

  • Owen RR Jr, Beake BJ, Marby D, Dessain EC, Cole JO (1989) Response to clozapine in chronic psychotic patients. Psychopharmacol Bull 25:253–256

    Google Scholar 

  • Ozdemir V, Masellis M, Basile VS, Kalow W, Meltzer HY, Lieberman JA, Kennedy JL (1999) Variability in response to clozapine: potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. CNS Spectr 4:30–56

    Google Scholar 

  • Pallanti S, Quercioli L, Pazzagli A (1999) Basic symptoms and P300 abnormalities in young schizophrenic patients. Compr Psychiatry 40:363–371

    Google Scholar 

  • Perez-Gomez M, Junque C (1999) Clozapine: neuropsychological and neuroimaging studies. Actas Esp Psiquiatr 27:341–346

    Google Scholar 

  • 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 148:231–235

    CAS  PubMed  Google Scholar 

  • Pickar D, Owen RR, Litman RE, Konicki E, Gutierrez R, Rapaport MH (1992) Clinical and biologic response to clozapine in patients with schizophrenia. Crossover comparison with fluphenazine. Arch Gen Psychiatry 49:345–353

    CAS  PubMed  Google Scholar 

  • Pickar D, Owen RR Jr, Litman RE, Hsiao JK, Su TP (1994) Predictors of clozapine response in schizophrenia. J Clin Psychiatry 55(Suppl B):129–132

    PubMed  Google Scholar 

  • Pickar D, Su TP, Weinberger DR, Coppola R, Malhotra AK, Knable MB, Lee KS, Gorey J, Bartko JJ, Breier A, Hsiao J (1996) Individual variation in D2 dopamine receptor occupancy in clozapine-treated patients. Am J Psychiatry 153:1571–1578

    CAS  PubMed  Google Scholar 

  • Pillay SS, Stoll AL, Weiss MK, Tohen M, Zarate CA Jr, Banov MD, Cole JO (1996) EEG abnormalities before clozapine therapy predict a good clinical response to clozapine. Ann Clin Psychiatry 8:1–5

    Google Scholar 

  • Piscitelli SC, Frazier JA, McKenna K, Albus KE, Grothe DR, Gordon C, Rapoport JL (1995) Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry 56:535–536

    Google Scholar 

  • Potkin SG, Bera R, Gulasekaram B, Costa J, Hayes S, Jin Y, Richmond G, Carreon D, Sitanggan K, Gerber B, Telford J, Plon L, Plon H, Park L, Chang YJ, Oldroyd J, Cooper TB (1994a) Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 55(Suppl B):133–136

    Google Scholar 

  • Potkin SG, Buchsbaum MS, Jin Y, Tang C, Telford J, Friedman G, Lottenberg S, Najafi A, Gulasekaram B, Costa J, Richmond GM, Bunney WE Jr (1994b) Clozapine effects on glucose metabolic rate in striatum and frontal cortex. J Clin Psychiatry 55(Suppl B):63–66

    PubMed  Google Scholar 

  • Potkin SG, Basile VS, Jin Y, Masellis M, Badri F, Keator D, Wu JC, Alva G, Carreon DT, Bunney WE Jr, Fallon JH, Kennedy JL (2003) D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. Mol Psychiatry 8:109–113

    Article  CAS  PubMed  Google Scholar 

  • 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–S91

    Google Scholar 

  • Rao PA, Pickar D, Gejman PV, Ram A, Gershon ES, Gelernter J (1994) Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry 51:912–917

    Google Scholar 

  • Rietschel M, Naber D, Oberlander H, Holzbach R, Fimmers R, Eggermann K, Moller HJ, Propping P, Nothen MM (1996) Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology 15:491–496

    Google Scholar 

  • Rietschel M, Naber D, Fimmers R, Moller HJ, Propping P, Nothen MM (1997) Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. NeuroReport 8:1999–2003

    Google Scholar 

  • Risby ED, Epstein CM, Jewart RD, Nguyen BV, Morgan WN, Risch SC, Thrivikraman KV, Lewine RL (1995) Clozapine-induced EEG abnormalities and clinical response to clozapine. J Neuropsychiatry Clin Neurosci 7:466–470

    Google Scholar 

  • Risch SC, Lewine RRJ (1993) Low cerebrospinal fluid homovanillic acid-5-hydroxyindoleacetic acid ratio predicts clozapine efficacy: a replication. Arch Gen Psychiatry 50:670

    Google Scholar 

  • Robinson DG, Woerner MG, McMeniman M, Mendelowitz A, Bilder RM (2004) Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 161:473–479

    Google Scholar 

  • Rodriguez VM, Andree RM, Castejon MJ, Garcia EC, Delgado JL, Vila FJ (1996) SPECT study of regional cerebral perfusion in neuroleptic-resistant schizophrenic patients who responded or did not respond to clozapine. Am J Psychiatry 153:1343–1346

    CAS  PubMed  Google Scholar 

  • Rodriguez VM, Andree RM, Castejon MJ, Zamora ML, Alvaro PC, Delgado JL, Vila FJ (1997) Fronto-striato-thalamic perfusion and clozapine response in treatment-refractory schizophrenic patients. A 99 mTc-HMPAO study. Psychiatry Res 76:51–61

    PubMed  Google Scholar 

  • Rodriguez VM, Catalina ML, Garcia-Noblejas JA, Cuesta P (1998) Schizophrenic syndromes and clozapine response in treatment-resistant schizophrenia. Psychiatry Res 77:21–28

    Google Scholar 

  • Rosenheck R, Lawson W, Crayton J, Cramer J, Xu W, Thomas J, Stolar M, Charney D (1998) Predictors of differential response to clozapine and haloperidol. Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Biol Psychiatry 44:475–482

    Article  CAS  PubMed  Google Scholar 

  • Rosenheck R, Dunn L, Peszke M, Cramer J, Xu W, Thomas J, Charney D (1999) Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Am J Psychiatry 156:88–93

    Google Scholar 

  • Roth WT, Pfefferbaum A, Kelly AF, Berger PA, Kopell BS (1981) Auditory event-related potentials in schizophrenia and depression. Psychiatry Res 4:199–212

    Google Scholar 

  • Sarafoff M, Davis L, Ruther E (1979) Clozapine induced increase of human plasma norepinephrine. J Neural Transm 46:175–180

    Google Scholar 

  • Schall U, Catts SV, Chaturvedi S, Liebert B, Redenbach J, Karayanidis F, Ward PB (1998) The effect of clozapine therapy on frontal lobe dysfunction in schizophrenia: neuropsychology and event-related potential measures. Int J Neuropsychopharmacol 1:19–29

    Google Scholar 

  • Schall U, Catts SV, Karayanidis F, Ward PB (1999) Auditory event-related potential indices of fronto-temporal information processing in schizophrenia syndromes: valid outcome prediction of clozapine therapy in a three-year follow-up. Int J Neuropsychopharmacol 2:83–93

    Google Scholar 

  • Scharfetter J, Chaudhry HR, Hornik K, Fuchs K, Sieghart W, Kasper S, Aschauer HN (1999) Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 10:17–20

    Google Scholar 

  • Scheepers FE, Gispen-de Wied CC, Hulshoff Pol HE, Kahn RS (2001a) Effect of clozapine on caudate nucleus volume in relation to symptoms of schizophrenia. Am J Psychiatry 158:644–646

    Article  CAS  PubMed  Google Scholar 

  • Scheepers FE, Gispen-de Wied CC, Hulshoff Pol HE, van de Flier W, van der Linden JA, Kahn RS (2001b) The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics. Neuropsychopharmacology 24:47–54

    Article  CAS  PubMed  Google Scholar 

  • Schulz E, Fleischhaker C, Remschmidt HE (1996) Correlated changes in symptoms and neurotransmitter indices during maintenance treatment with clozapine or conventional neuroleptics in adolescents and young adults with schizophrenia. J Child Adolesc Psychopharmacol 6:119–131

    Google Scholar 

  • Schulz E, Fleischhaker C, Clement HW, Remschmidt H (1997) Blood biogenic amines during clozapine treatment of early-onset schizophrenia. J Neural Transm 104:1077–1089

    Google Scholar 

  • Simpson GM, Josiassen RC, Stanilla JK, de Leon J, Nair C, Abraham G, Odom-White A, Turner RM (1999) Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 156:1744–1750

    CAS  PubMed  Google Scholar 

  • Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK, Crocq MA, Gill M, Kerwin R (1995) Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gener (DRD4) in schizophrenic patients. Am J Med Genet 18:541–545

    Google Scholar 

  • Sodhi MS, Arranz MJ, Curtis D, Ball DM, Sham P, Roberts GW, Price J, Collier DA, Kerwin RW (1995) Association between clozapine response and allelic variation in the 5-HT2C receptor gene. NeuroReport 7:169–172

    Google Scholar 

  • Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia AG, Ventimiglia A, Perucca E (2000) Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology (Berl) 148:83–89

    Google Scholar 

  • Spivak B, Shabash E, Sheitman B, Weizman A, Mester R (2003) The effects of clozapine versus haloperidol on measures of impulsive aggression and suicidality in chronic schizophrenia patients: an open, nonrandomized, 6-month study. J Clin Psychiatry 64:755–760

    CAS  PubMed  Google Scholar 

  • Stahl SM, Grady MM (2004) A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 11:313–327

    Google Scholar 

  • Stern RG, Kahn RS, Davidson M, Nora RM, Davis KL (1994) Early response to clozapine in schizophrenia. Am J Psychiatry 151:1817–1818

    Google Scholar 

  • Stip E, Lussier I, Ngan E, Mendrek A, Liddle P (1999) Discriminant cognitive factors in responder and non-responder patients with schizophrenia. Eur Psychiatry 14:442–450

    Google Scholar 

  • Sumiyoshi T, Hasegawa M, Jayathilake K, Meltzer HY (1997) Prediction of short-term changes in symptom severity by baseline plasma homovanillic acid levels in schizophrenic patients receiving clozapine. Psychiatry Res 69:113–121

    Google Scholar 

  • Sumiyoshi T, Roy A, Kim C-H, Jayathilake K, Lee MA, Sumiyoshi C, Meltzer HY (2004) Prediction of changes in memory performance by plasma homovanillic acid levels in clozapine-treated patients with schizophrenia. Psychopharmacology 177:79–83

    Google Scholar 

  • Szymanski S, Lieberman J, Pollack S, Safferman A, Munne R, Umbricht D, Kane J, Kronig M, Chakos M, Cooper T (1995) Clozapine effects on neuroendocrine response to apomorphine challenge testing in chronic neuroleptic nonresponsive schizophrenia: preliminary findings. Biol Psychiatry 37:52–55

    Google Scholar 

  • Tauscher J, Kufferle B, Asenbaum S, Fischer P, Pezawas L, Barnas C, Tauscher-Wisniewski S, Brucke T, Kasper S (1999) In vivo 123I IBZM SPECT imaging of striatal dopamine-2 receptor occupancy in schizophrenic patients treated with olanzapine in comparison to clozapine and haloperidol. Psychopharmacology (Berl) 141:175–181

    Google Scholar 

  • Thorup M, Fog R (1977) Clozapine treatment of schizophrenic patients. Plasma concentration and coagulation factors. Acta Psychiatr Scand 55:123–126

    Google Scholar 

  • Tiihonen J, Nousiainen U, Hakola P, Leinonen E, Tuunainen A, Mervaala E, Paanila J (1991) EEG abnormalities associated with clozapine treatment. Am J Psych 148:1406

    Google Scholar 

  • Treves IA, Neufeld MY (1996) EEG abnormalities in clozapine-treated schizophrenic patients. Eur Neuropsychopharmacol 6:93–94

    Google Scholar 

  • Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Lai HC, Yang KH (2000) Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res 44:177–181

    Google Scholar 

  • Tsai SJ, Wang YC, Yu Younger WY, Lin CH, Yang KH, Hong CJ (2001) Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response. Schizophr Res 49:53–58

    Google Scholar 

  • Umbricht D, Javitt D, Novak G, Bates G, Pollack S, Lieberman J, Kane J (1998) Effects of clozapine on auditory evoked potentials in schizophrenia. Biol Psychiatry 44:716–725

    Google Scholar 

  • Umbricht DS, Wirshing WC, Wirshing DA, McMeniman M, Schooler NR, Marder SR, Kane JM (2002) Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia. J Clin Psychiatry 63:420–424

    PubMed  Google Scholar 

  • VanderZwaag C, McGee M, McEvoy JP, Freudenreich O, Wilson WH, Cooper TB (1996) Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 153:1579–1584

    CAS  PubMed  Google Scholar 

  • Vita A, Bressi S, Perani D, Invernizzi G, Giobbio GM, Dieci M, Garbarini M, Del Sole A, Fazio F (1995) High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naive schizophrenic patients. Am J Psychiatry 152:876–882

    Google Scholar 

  • Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT, Mohell N, Harvey SC, Lameh J, Nash N, Vanover KE, Olsson R, Jayathilake K, Lee M, Levey AI, Hacksell U, Burstein ES, Davis RE, Brann MR (2004) The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl) 177:207–216

    Google Scholar 

  • Yu YW, Tsai SJ, Lin CH, Hsu CP, Yang KH, Hong CJ (1999) Serotonin-6 receptor variant (C267T) and clinical response to clozapine. NeuroReport 10:1231–1233

    Google Scholar 

  • Zahn TP, Pickar D, Haier RJ (1994) Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia. Schizophr Res 13:133–144

    Article  Google Scholar 

  • Zarate CA Jr, Tohen M, Baldessarini RJ (1995) Clozapine in severe mood disorders. J Clin Psychiatry 56:411–417

    Google Scholar 

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  1. Centre for Addiction and Mental Health, Schizophrenia Program, 250 College Street, Toronto, Ontario, M5T 1R8, Canada

    Carmen Chung & Gary Remington

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Carmen Chung & Gary Remington

  3. Department of Psychiatry, University of Toronto, Ontario, Canada

    Gary Remington

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Chung, C., Remington, G. Predictors and markers of clozapine response. Psychopharmacology 179, 317–335 (2005). https://doi.org/10.1007/s00213-005-2174-x

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