Skip to main content Accessibility help
×
Home

Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies

  • S. E. Smart (a1), A. P. Kępińska (a1), R. M. Murray (a1) and J. H. MacCabe (a1)

Abstract

Treatment-resistant schizophrenia, affecting approximately 20–30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies
      Available formats
      ×

Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

Author for correspondence: Sophie E Smart, E-mail: sophie.smart@kcl.ac.uk

References

Hide All
Addington, AM and Rapoport, JL (2009) The genetics of childhood-onset schizophrenia: when madness strikes the prepubescent. Current Psychiatry Reports 11, 156161.
Andrews, A, Knapp, M, McCrone, P, Parsonage, M. and Trachtenberg, M (2012) Effective Interventions in Schizophrenia: the Economic Case. A Report Prepared for the Schizophrenia Commission. Rethink Mental Illness: London.
Byrne, M, Agerbo, E and Mortensen, PB (2018) Family history of psychiatric disorders and age at first contact in schizophrenia: an epidemiological study. The British Journal of Psychiatry 181, s19s25.
Cannon-Spoor, HE, Potkin, SG and Wyatt, RJ (1982) Measurement of premorbid adjustment in chronic schizophrenia. Schizophrenia Bulletin 8, 470484.
Carbon, M and Correll, CU (2014) Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues in Clinical Neuroscience 16, 505524.
Chan, SKW, Chang, WC, Lee, EHM, Wong, GHY, Hui, CLM, Chen, EYH and Sham, PC (2014) Predictors of treatment resistant schizophrenia-spectrum disorder: 10-year retrospective study of first-episode psychosis. Early Intervention in Psychiatry 8, 78.
Conley, RR and Kelly, DL (2001) Management of treatment resistance in schizophrenia. Biological Psychiatry 50, 898911.
de Bartolomeis, A, Balletta, R, Giordano, S, Buonaguro, EF, Latte, G. and Iasevoli, F (2013) Differential cognitive performances between schizophrenic responders and non-responders to antipsychotics: correlation with course of the illness, psychopathology, attitude to the treatment and antipsychotics doses. Psychiatry Research 210, 387395.
de Bartolomeis, A, Prinzivalli, E, Callovini, G, D'Ambrosio, L, Altavilla, B, Avagliano, C and Iasevoli, F (2018) Treatment resistant schizophrenia and neurological soft signs may converge on the same pathology: evidence from explanatory analysis on clinical, psychopathological, and cognitive variables. Progress in Neuro-Psychopharmacology & Biological Psychiatry 81, 356366.
Demjaha, A, Lappin, JM, Stahl, D, Patel, MX, MacCabe, JH, Howes, OD, Heslin, M, Reininghaus, UA, Donoghue, K, Lomas, B, Charalambides, M, Onyejiaka, A, Fearon, P, Jones, P, Doody, G, Morgan, C, Dazzan, P and Murray, RM (2017) Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychological Medicine 47, 19811989.
Farooq, S, Agid, O, Foussias, G and Remington, G (2013) Using treatment response to subtype schizophrenia: proposal for a new paradigm in classification. Schizophrenia Bulletin 39, 11691172.
Frank, J, Lang, M, Witt, SH, Strohmaier, J, Rujescu, D, Cichon, S, Degenhardt, F, Nöthen, MM, Collier, DA, Ripke, S, Naber, D and Rietschel, M (2014) Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Molecular Psychiatry 20, 150.
Gillespie, AL, Samanaite, R, Mill, J, Egerton, A and MacCabe, JH (2017) Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry 17, 12.
Hall, RC (1995) Global assessment of functioning: a modified scale. Psychosomatics 36, 267275.
Hilker, R, Helenius, D, Fagerlund, B, Skytthe, A, Christensen, K, Werge, TM, Nordentoft, M and Glenthøj, B (2017) Is an early Age at illness onset in schizophrenia associated with increased genetic susceptibility? Analysis of data from the nationwide Danish Twin register. EBioMedicine 18, 320326.
Horsdal, HT, Wimberley, T, Benros, ME and Gasse, C (2017 a) C-reactive protein levels and treatment resistance in schizophrenia—A Danish population-based cohort study. Human Psychopharmacology: Clinical and Experimental 32, e2632-n/a.
Horsdal, HT, Wimberley, T, Köhler-Forsberg, O, Baandrup, L and Gasse, C (2017 b) Association between global functioning at first schizophrenia diagnosis and treatment resistance. Early Intervention in Psychiatry 12, 11981202.
Howes, OD, Vergunst, F, Gee, S, McGuire, P, Kapur, S and Taylor, D (2012) Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. The British Journal of Psychiatry 201, 481485.
Howes, OD, McCutcheon, R, Agid, O, de Bartolomeis, A, van Beveren, NJ, Birnbaum, ML, Bloomfield, MA, Bressan, RA, Buchanan, RW, Carpenter, WT, Castle, DJ, Citrome, L, Daskalakis, ZJ, Davidson, M, Drake, RJ, Dursun, S, Ebdrup, BH, Elkis, H, Falkai, P, Fleischacker, W, Gadelha, A, Gaughran, F, Glenthoj, BY, Graff-Guerrero, A, Hallak, JE, Honer, WG, Kennedy, J, Kinon, BJ, Lawrie, SM, Lee, J, Leweke, F, MacCabe, JH, McNabb, CB, Meltzer, H, Moller, H-J, Nakajima, S, Pantelis, C, Marques, TR, Remington, G, Rossell, SL, Russell, BR, Siu, CO, Suzuki, T, Sommer, IE, Taylor, D, Thomas, N, Ucok, A, Umbricht, D, Walters, JT, Kane, J and Correll, CU (2017) Treatment-resistant schizophrenia: treatment response and resistance in psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. The American Journal of Psychiatry 174, 216229.
Iasevoli, F, Giordano, S, Balletta, R, Latte, G, Formato, MV, Prinzivalli, E, De Berardis, D, Tomasetti, C and de Bartolomeis, A (2016) Treatment resistant schizophrenia is associated with the worst community functioning among severely-ill highly-disabling psychiatric conditions and is the most relevant predictor of poorer achievements in functional milestones. Progress in Neuro-Psychopharmacology & Biological Psychiatry 65, 3448.
Immonen, J, Jääskeläinen, E, Korpela, H and Miettunen, J (2017) Age at onset and the outcomes of schizophrenia: a systematic review and meta-analysis. Early Intervention in Psychiatry 11, 453460.
Jablensky, A, McNeil, TF and Morgan, VA (2017) Barbara fish and a short history of the neurodevelopmental hypothesis of schizophrenia. Schizophrenia Bulletin 43, 11581163.
Joober, R, Rouleau, GA, Lal, S, Dixon, M, O'Driscoll, G, Palmour, R, Annable, L, Bloom, D, Lalonde, P, Labelle, A and Benkelfat, C (2002) Neuropsychological impairments in neuroleptic-responder vs. -nonresponder schizophrenic patients and healthy volunteers. Schizophrenia Research 53, 229238.
Kane, J, Honigfeld, G, Singer, J and Meltzer, H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry 45, 789796.
Kay, SR, Fiszbein, A and Opler, LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Kennedy, JL, Altar, CA, Taylor, DL, Degtiar, I and Hornberger, JC (2014) The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. International Clinical Psychopharmacology 29, 6376.
Killaspy, H, Marston, L, Omar, RZ, Green, N, Harrison, I, Lean, M, Holloway, F, Craig, T, Leavey, G and King, M (2013) Service quality and clinical outcomes: an example from mental health rehabilitation services in England. The British Journal of Psychiatry 202, 2834.
Kim, JS, Park, CM, Choi, JA, Park, E, Tchoe, HJ, Choi, M, Suh, JK, Kim, YH, Won, SH, Chung, YC, Bae, KY, Lee, SK, Park, SC and Lee, SH (2017) The association between season of birth, age at onset, and clozapine use in schizophrenia. Acta Psychiatrica Scandinavica 136, 445454.
Kravariti, E, Demjaha, A, Zanelli, J, Ibrahim, F, Wise, C, MacCabe, JH, Reichenberg, A, Pilecka, I, Morgan, K, Fearon, P, Morgan, C, Doody, GA, Donoghue, K, Jones, PB, Kacar, AS, Dazzan, P, Lappin, J and Murray, RM (2018) Neuropsychological function at first episode in treatment-resistant psychosis: findings from the AESOP-10 study. Psychological Medicine 111. https://doi.org/10.1017/ S0033291718002957
Lally, J, Ajnakina, O, Di Forti, M, Trotta, A, Demjaha, A, Kolliakou, A, Mondelli, V, Marques, T, Pariante, C, Dazzan, P, Shergil, S, Howes, O, David, A, MacCabe, J, Gaughran, F and Murray, R (2016) Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychological Medicine 46, 32313240.
Lee, J, Takeuchi, H, Fervaha, G, Sin, GL, Foussias, G, Agid, O, Farooq, S and Remington, G (2015) Subtyping schizophrenia by treatment response: antipsychotic development and the central role of positive symptoms. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie 60, 515522.
Liberati, A, Altman, DG, Tetzlaff, J, Mulrow, C, Gøtzsche, PC, Ioannidis, JPA, Clarke, M, Devereaux, PJ, Kleijnen, J and Moher, D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine 6, e1000100.
Lin, AS, Chang, SS, Lin, SH, Peng, YC, Hwu, HG and Chen, WJ (2015) Minor physical anomalies and craniofacial measures in patients with treatment-resistant schizophrenia. Psychological Medicine 45, 18391850.
Martin, AK and Mowry, B (2015) 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 and Howes, OD (2015) Treatment resistant or resistant to treatment? Antipsychotic plasma levels in patients with poorly controlled psychotic symptoms. Journal of Psychopharmacology 29, 892897.
McGuire, P and Dazzan, P (2017) Does neuroimaging have a role in predicting outcomes in psychosis? World Psychiatry 16, 209210.
Meltzer, HY, Rabinowitz, J, Lee, MA, Cola, PA, Ranjan, R, Findling, RL and Thompson, PA (1997) Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. American Journal of Psychiatry 154, 475482.
Murray, RM, Bhavsar, V, Tripoli, G. and Howes, O (2017) 30 years on: how the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis. Schizophrenia Bulletin 43, 11901196.
Nakajima, S, Takeuchi, H, Plitman, E, Fervaha, G, Gerretsen, P, Caravaggio, F, Chung, JK, Iwata, Y, Remington, G and Graff-Guerrero, A (2015) Neuroimaging findings in treatment-resistant schizophrenia: a systematic review: lack of neuroimaging correlates of treatment-resistant schizophrenia. Schizophrenia Research 164, 164175.
NICE (2014) Psychosis and Schizophrenia in Adults: Treatment and Management: Updated Edition 2014. In National Institute for Health and Clinical Excellence: Guidance National Collaborating Centre for Mental Health: London.
Shmueli, G (2010) To explain or to predict? Statistical Science 25, 289310.
Siskind, D, McCartney, L, Goldschlager, R and Kisely, S (2016) Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. British Journal of Psychiatry 209, 385392.
Sorensen, HJ, Foldager, L, Roge, R, Pristed, SG, Andreasen, JT and Nielsen, J (2014) An association between autumn birth and clozapine treatment in patients with schizophrenia: a population-based analysis. Nordic Journal of Psychiatry 68, 428432.
Steyerberg, EW, Vickers, AJ, Cook, NR, Gerds, T, Gonen, M, Obuchowski, N, Pencina, MJ and Kattan, MW (2010) Assessing the performance of prediction models: a framework for some traditional and novel measures. Epidemiology 21, 128138.
Suzuki, T, Remington, G, Mulsant, BH, Rajji, TK, Uchida, H, Graff-Guerrero, A and Mamo, DC (2011) Treatment resistant schizophrenia and response to antipsychotics: a review. Schizophrenia Research 133, 5462.
Suzuki, T, Remington, G, Mulsant, BH, Uchida, H, Rajji, TK, Graff-Guerrero, A, Mimura, M and Mamo, DC (2012) Defining treatment-resistant schizophrenia and response to antipsychotics: a review and recommendation. Psychiatry Research 197, 16.
Taylor, DM (2017) Clozapine for treatment-resistant schizophrenia: still the gold standard? CNS Drugs 31, 177180.
Üçok, A, Çıkrıkçılı, U, Ergül, C, Tabak, Ö, Salaj, A, Karabulut, S and Correll, CU (2016) Correlates of clozapine use after a first episode of schizophrenia: results from a long-term prospective study. CNS Drugs 30, 9971006.
Walter, S and Elwood, J (1975) A test for seasonality of events with a variable population at risk. Journal of Epidemiology & Community Health 29, 1821.
Warnez, S. and Alessi-Severini, S. (2014) Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry 14, 102102.
Wimberley, T, Pedersen, CB, MacCabe, JH, Støvring, H, Astrup, A, Sørensen, HJ, Horsdal, HT, Mortensen, PB and Gasse, C (2016 a) Inverse association between urbanicity and treatment resistance in schizophrenia. Schizophrenia Research 174, 150155.
Wimberley, T, Støvring, H, Sørensen, HJ, Horsdal, HT, MacCabe, JH and Gasse, C (2016 b) Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. The Lancet Psychiatry 3, 358366.
Wimberley, T, Gasse, C, Meier, SM, Agerbo, E, MacCabe, JH and Horsdal, HT (2017) Polygenic risk score for schizophrenia and treatment-resistant schizophrenia. Schizophrenia Bulletin 43, 10641069.
World Health Organization (1993) The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization.
Yoshimura, B, Yada, Y, So, R, Takaki, M and Yamada, N (2017) The critical treatment window of clozapine in treatment-resistant schizophrenia: secondary analysis of an observational study. Psychiatry Research 250, 6570.

Keywords

Type Description Title
WORD
Supplementary materials

Smart et al. supplementary material
Smart et al. supplementary material

 Word (82 KB)
82 KB

Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies

  • S. E. Smart (a1), A. P. Kępińska (a1), R. M. Murray (a1) and J. H. MacCabe (a1)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed