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Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses

  • J. Lally (a1) (a2) (a3), O. Ajnakina (a1), M. Di Forti (a4), A. Trotta (a1), A. Demjaha (a1), A. Kolliakou (a5), V. Mondelli (a6) (a5), T. Reis Marques (a1), C. Pariante (a6) (a5), P. Dazzan (a1) (a6), S. S. Shergil (a1) (a2) (a6), O. D. Howes (a1) (a7), A. S. David (a1) (a6), J. H. MacCabe (a1) (a2), F. Gaughran (a1) (a2) and R. M. Murray (a1) (a2)...

Clozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.


This is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.


Seventy per cent (n = 56) of TR patients, and 23% of the total study population (n = 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25–4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44–9.56); and patients of male gender (OR 3.13 95% CI 1.35–7.23).


For the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

Corresponding author
*Address for correspondence: Dr J. Lally, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK. (Email:
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Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, Remington G (2011). An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. Journal of Clinical Psychiatry 72, 14391444.
Andreasen NC, Carpenter WT Jr., Kane JM, Lasser RA, Marder SR, Weinberger DR (2005). Remission in schizophrenia: proposed criteria and rationale for consensus. American Journal of Psychiatry 162, 441449.
Beck K, McCutcheon R, Bloomfield MA, Gaughran F, Reis Marques T, MacCabe J, Selvaraj S, Taylor D, Howes OD (2014). The practical management of refractory schizophrenia – the Maudsley Treatment REview and Assessment Team service approach. Acta Psychiatrica Scandinavica 130, 427438.
Carbon M, Correll CU (2014). Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues in clinical neuroscience 16, 505524.
Chouinard G (1991). Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophrenia Research 5, 2133.
Chouinard G, Chouinard VA (2008). Atypical antipsychotics: CATIE study, drug-induced movement disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes. Psychotherapy and Psychosomatics 77, 6977.
Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, McGuire PK (2014). Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biological Psychiatry 75, e11e13.
Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD (2012). Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. American Journal of Psychiatry 169, 12031210.
Di Forti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR, Handley R, Luzi S, Russo M, Paparelli A, Butt A, Stilo SA, Wiffen B, Powell J, Murray RM (2009). High-potency cannabis and the risk of psychosis. British Journal of Psychiatry 195, 488491.
Di Forti M, Sallis H, Allegri F, Trotta A, Ferraro L, Stilo SA, Marconi A, La Cascia C, Reis Marques T, Pariante C, Dazzan P, Mondelli V, Paparelli A, Kolliakou A, Prata D, Gaugrhan F, David AS, Morgan C, Sthal D, Khondoker M, MacCabe JH, Murray RM (2014). Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users. Schizophrenia Bulletin 40, 15091517.
Emsley R, Nuamah I, Hough D, Gopal S (2012). Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. Schizophrenia Research 138, 2934.
Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, Degenhardt F, Nothen MM, Collier DA, Ripke S, Naber D, Rietschel M (2015). Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Molecular Psychiatry 20, 150151.
Heinze G, Schemper M (2002). A solution to the problem of separation in logistic regression. Statistics in Medicine 21, 24092419.
Howes OD, Vergunst F, Gee S, McGuire P, Kapur S, Taylor D (2012). Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. British Journal of Psychiatry 201, 481485.
Iyo M, Tadokoro S, Kanahara N, Hashimoto T, Niitsu T, Watanabe H, Hashimoto K (2013). Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis. Journal of Clinical Psychopharmacology 33, 398404.
Kay SR, Fiszbein A, Opler LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Kolakowska T, Williams AO, Ardern M, Reveley MA, Jambor K, Gelder MG, Mandelbrote BM (1985). Schizophrenia with good and poor outcome. I: Early clinical features, response to neuroleptics and signs of organic dysfunction. British Journal of Psychiatry 146, 229239.
Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM (2014). Dose equivalents for second-generation antipsychotics: the minimum effective dose method. Schizophrenia Bulletin 40, 314326.
Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, Markwick A, Lloyd H, Jones PB (2006). Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophrenia Bulletin 32, 715723.
Lin CC, Wang YC, Chen JY, Liou YJ, Bai YM, Lai IC, Chen TT, Chiu HW, Li YC (2008). Artificial neural network prediction of clozapine response with combined pharmacogenetic and clinical data. Computer Methods and Programs in Biomedicine 91, 9199.
Malla A, Norman R, Schmitz N, Manchanda R, Bechard-Evans L, Takhar J, Haricharan R (2006). Predictors of rate and time to remission in first-episode psychosis: a two-year outcome study. Psychological Medicine 36, 649658.
Mallett R, Leff J, Bhugra D, Pang D, Zhao JH (2002). Social environment, ethnicity and schizophrenia. A case-control study. Social Psychiatry and Psychiatric Epidemiology 37, 329335.
Martin AK, Mowry B (2016). Increased rare duplication burden genomewide in patients with treatment-resistant schizophrenia. Psychological Medicine 46, 469476.
McCutcheon R, Beck K, Bloomfield MA, Marques TR, Rogdaki M, Howes OD (2015). Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms. Journal of Psychopharmacology 29, 892897.
McGuffin P, Farmer A, Harvey I (1991). A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Archives of General Psychiatry 48, 764770.
Meltzer HY (1997). Treatment-resistant schizophrenia–the role of clozapine. Current Medical Research and Opinion 14, 120.
Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL, Thompson PA (1997). Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. American Journal of Psychiatry 154, 475482.
Menezes NM, Arenovich T, Zipursky RB (2006). A systematic review of longitudinal outcome studies of first-episode psychosis. Psychological Medicine 36, 13491362.
Morgan C, Lappin J, Heslin M, Donoghue K, Lomas B, Reininghaus U, Onyejiaka A, Croudace T, Jones PB, Murray RM, Fearon P, Doody GA, Dazzan P (2014). Reappraising the long-term course and outcome of psychotic disorders: the AESOP-10 study. Psychological Medicine 44, 27132726.
NICE (2014). Psychosis and Schizophrenia in Adults: Treatment and Management (Clinical Guideline 178). Royal College of Psychiatrists: London.
Nielsen J, Nielsen RE, Correll CU (2012 a). Predictors of clozapine response in patients with treatment-refractory schizophrenia: results from a Danish Register Study. Journal of Clinical Psychopharmacology 32, 678683.
Nielsen J, Roge R, Schjerning O, Sorensen HJ, Taylor D (2012 b). Geographical and temporal variations in clozapine prescription for schizophrenia. European Neuropsychopharmacology 22, 818824.
Ortiz BB, Araujo Filho GM, Araripe Neto AG, Medeiros D, Bressan RA (2013). Is disorganized schizophrenia a predictor of treatment resistance? Evidence from an observational study. Revista Brasileira de Psiquiatria 35, 432434.
Revier CJ, Reininghaus U, Dutta R, Fearon P, Murray RM, Doody GA, Croudace T, Dazzan P, Heslin M, Onyejiaka A, Kravariti E, Lappin J, Lomas B, Kirkbride JB, Donoghue K, Morgan C, Jones PB (2015). Ten-year outcomes of first-episode psychoses in the MRC AESOP-10 study. Journal of Nervous and Mental Disease 203, 379386.
Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman JA (1999). Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. American Journal of Psychiatry 156, 544549.
Ropcke B, Eggers C (2005). Early-onset schizophrenia: a 15-year follow-up. European Child & Adolescent Psychiatry 14, 341350.
Sartorius N, Gulbinat W, Harrison G, Laska E, Siegel C (1996). Long-term follow-up of schizophrenia in 16 countries. A description of the International Study of Schizophrenia conducted by the World Health Organization. Social Psychiatry and Psychiatric Epidemiology 31, 249258.
Schennach R, Riedel M, Musil R, Moller HJ (2012). Treatment Response in First-episode Schizophrenia. Clinical Psychopharmacology and Neuroscience 10, 7887.
Schneider C, Papachristou E, Wimberley T, Gasse C, Dima D, MacCabe JH, Mortensen PB, Frangou S (2015). Clozapine use in childhood and adolescent schizophrenia: A nationwide population-based study. European Neuropsychopharmacology 25, 857863.
Singh SP, Cooper JE, Fisher HL, Tarrant CJ, Lloyd T, Banjo J, Corfe S, Jones P (2005). Determining the chronology and components of psychosis onset: The Nottingham Onset Schedule (NOS). Schizophrenia Research 80, 117130.
Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M (2014). Geographic and clinical variation in clozapine use in the United States. Psychiatric Services 65, 186192.
Stroup TS, Gerhard T, Crystal S, Huang C, Olfson M (2016). Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry 173, 166173.
Ucok A, Cikrikcili U, Karabulut S, Salaj A, Ozturk M, Tabak O, Durak R (2015). Delayed initiation of clozapine may be related to poor response in treatment-resistant schizophrenia. International Clinical Psychopharmacology 30, 290295.
Vanelle JM (1995). Treatment refractory schizophrenia [in French]. L'Encephale 21 (Spec. No. 3), 1321.
Vanelle JM, Olie JP, Levy-Soussan P (1994). New antipsychotics in schizophrenia: the French experience. Acta Psychiatrica Scandinavica (Suppl.) 380, 5963.
Vyas NS, Hadjulis M, Vourdas A, Byrne P, Frangou S (2007). The Maudsley early onset schizophrenia study. Predictors of psychosocial outcome at 4-year follow-up. European Child & Adolescent Psychiatry 16, 465470.
Wechsler D (1997). Wechsler Adult Intelligence Scale. The Psychological Corporation: San Antonio, TX.
Wechsler D (2001). Wechsler Test of Adult Reading: WTAR. Psychological Corporation: San Antonio, TX.
Wheeler A, Humberstone V, Robinson G (2009). Outcomes for schizophrenia patients with clozapine treatment: how good does it get? Journal of Psychopharmacology 23, 957965.
WHO (1992). The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva.
WHO (1994). Schedules for Clinical Assessment in Neuropsychiatry: Version 2: Manual. World Health Organization, Division of Mental Health: Geneva.
Wiersma D, Nienhuis FJ, Slooff CJ, Giel R (1998). Natural course of schizophrenic disorders: a 15-year followup of a Dutch incidence cohort. Schizophrenia Bulletin 24, 7585.
Wimberley T, Støvring H, Sørensen HJ, Horsdal HT, MacCabe JH, Gasse C (2016). Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry 3, 358366.
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