Download PDF
Pharmacopsychiatry
DOI: 10.1055/a-2421-2411
Original Paper

Early Treatment-Resistance in First Episode Psychosis

Piyumi Fernando
1   Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Schwaben, Universitätsklinikum Augsburg, Augsburg, Germany
,
Johanna Strauss
2   Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig Maximilians University, München, Germany
,
Elias Wagner
1   Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Schwaben, Universitätsklinikum Augsburg, Augsburg, Germany
,
Lisa Löhrs
2   Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig Maximilians University, München, Germany
,
Mattia Campana
2   Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig Maximilians University, München, Germany
,
Peter Falkai
2   Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Ludwig Maximilians University, München, Germany
,
Alkomiet Hasan
1   Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Schwaben, Universitätsklinikum Augsburg, Augsburg, Germany
3   DZPG (German Center for Mental Health), partner site München/Augsburg, Germany
,
Irina Papazova
1   Department of Psychiatry and Psychotherapy, Bezirkskrankenhaus Schwaben, Universitätsklinikum Augsburg, Augsburg, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Introduction Approximately 30% of individuals with schizophrenia experience treatment resistance (TR), with 70% exhibiting it from the onset. Most research fails to distinguish between acquired and innate resistance, with limited data on TR in first episode psychosis (FEP). However, FEP patients with TR experience progressively worse outcomes compared to those with initial response. To further understand these findings, clinical and demographic data of FEP patients with and without TR were compared in this naturalistic study.

Methods Information was extracted on FEP patients who were antipsychotic-naive at the time of admission from a retrospective database on F2x diagnosed patients admitted to the LMU psychiatric clinic between 2008 and 2018. Clozapine was used at discharge as a marker of TR in the FEP cohort. A similarly antipsychotic-naïve FEP control group without clozapine at discharge, was generated by matching for gender and age. Thirty clinical and demographic variables were analyzed to identify differences.

Results Two-hundred forty antipsychotic-naive FEPs were included: 33 with clozapine at discharge (TRC group), and 207 in the control group (non-TRC). Significant differences were observed in inpatient stay duration, chlorpromazine-equivalent dosage, number of antipsychotics, and anticholinergic medication at discharge.

Discussion The findings indicate that longer inpatient stay, an increased number of antipsychotics, and possibly a more extended prodrome may serve as markers for non-clozapine TR in FEP. Further research is necessary to establish the robustness of these variables as early-stage TR markers.

Keywords

treatment-resistance - psychosis - clozapine - schizophrenia - treatment-response

Supplementary Material



Publication History

Received: 26 February 2024
Received: 05 August 2024

Accepted: 16 September 2024

Article published online:
15 November 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Schennach-Wolff R, Jäger M, Mayr A. et al. Predictors of response and remission in the acute treatment of first-episode schizophrenia patients--is it all about early response?. Eur Neuropsychopharmacol 2011; 21: 370-378
    CrossrefPubMedSearch in Google Scholar
  • 2 Birchwood M, Todd P, Jackson C. Early intervention in psychosis. The critical period hypothesis. Br J Psychiatry Suppl 1998; 172: 53-59
    CrossrefPubMedSearch in Google Scholar
  • 3 Bozzatello P, Bellino S, Rocca P. Predictive factors of treatment resistance in first episode of psychosis: A systematic review. Front Psychiatry 2019; 10: 67
    CrossrefPubMedSearch in Google Scholar
  • 4 Iasevoli F, Giordano S, Balletta R. et al. 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. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65: 34-48
    CrossrefPubMedSearch in Google Scholar
  • 5 Kennedy JL, Altar CA, Taylor DL. et al. The social and economic burden of treatment-resistant schizophrenia: A systematic literature review. Int Clin Psychopharmacol 2014; 29: 63-76
    CrossrefPubMedSearch in Google Scholar
  • 6 Firth J, Siddiqi N, Koyanagi A. et al. The Lancet Psychiatry Commission: A blueprint for protecting physical health in people with mental illness. Lancet Psychiatry 2019; 6: 675-712
    CrossrefPubMedSearch in Google Scholar
  • 7 Howes OD, McCutcheon R, Agid O. et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry 2017; 174: 216-229
    CrossrefPubMedSearch in Google Scholar
  • 8 National Collaborating Centre for Mental Health (UK). Psychosis and Schizophrenia in Adults: Treatment and Management: Updated Edition 2014. London: National Institute for Health and Care Excellence (UK); 2014
    Search in Google Scholar
  • 9 Kane J, Honigfeld G, Singer J. et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789-796
    CrossrefPubMedSearch in Google Scholar
  • 10 Meltzer HY. Treatment-resistant schizophrenia – The role of clozapine. Current Medical Research and Opinion 1997; 14: 1-20
    CrossrefPubMedSearch in Google Scholar
  • 11 Potkin SG, Kane JM, Correll CU. et al. The neurobiology of treatment-resistant schizophrenia: Paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr 2020; 6: 1
    CrossrefPubMedSearch in Google Scholar
  • 12 Demjaha A, Lappin JM, Stahl D. et al. Antipsychotic treatment resistance in first-episode psychosis: Prevalence, subtypes and predictors. Psychol Med 2017; 47: 1981-1989
    CrossrefPubMedSearch in Google Scholar
  • 13 Lally J, Gaughran F, Timms P. et al. Treatment-resistant schizophrenia: Current insights on the pharmacogenomics of antipsychotics. Pharmgenomics Pers Med 2016; 9: 117-129
    CrossrefPubMedSearch in Google Scholar
  • 14 Stokes I, Griffiths SL, Jones R. et al. Prevalence of treatment resistance and clozapine use in early intervention services. BJPsych Open 2020; 6: e107
    CrossrefPubMedSearch in Google Scholar
  • 15 The Scottish First Episode Schizophrenia Study V. One-year follow-up The Scottish Schizophrenia Research Group. Br J Psychiatry 1988; 152: 470-476
    CrossrefPubMedSearch in Google Scholar
  • 16 Kopala LC, Fredrikson D, Good KP. et al. Symptoms in neuroleptic-naive, first-episode schizophrenia: Response to risperidone. Biol Psychiatry 1996; 39: 296-298
    CrossrefPubMedSearch in Google Scholar
  • 17 McCreadie RG. Managing the first episode of schizophrenia: The role of new therapies. Eur Neuropsychopharmacol 1996; 6: S3-S5
    CrossrefPubMedSearch in Google Scholar
  • 18 Robinson DG, Woerner MG, Alvir JM. et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156: 544-549
    CrossrefPubMedSearch in Google Scholar
  • 19 Lally J, Ajnakina O, Di Forti M. et al. Two distinct patterns of treatment resistance: Clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med 2016; 46: 3231-3240
    CrossrefPubMedSearch in Google Scholar
  • 20 Santesteban-Echarri O, Paino M, Rice S. et al. Predictors of functional recovery in first-episode psychosis: A systematic review and meta-analysis of longitudinal studies. Clin Psychol Rev 2017; 58: 59-75
    CrossrefPubMedSearch in Google Scholar
  • 21 Drake RJ, Husain N, Marshall M. et al. Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: A longitudinal analysis and modelling study. Lancet Psychiatry 2020; 7: 602-610
    CrossrefPubMedSearch in Google Scholar
  • 22 McCutcheon R, Beck K, D’Ambrosio E. et al. Antipsychotic plasma levels in the assessment of poor treatment response in schizophrenia. Acta Psychiatr Scand 2018; 137: 39-46
    CrossrefPubMedSearch in Google Scholar
  • 23 Legge SE, Dennison CA, Pardiñas AF. et al. Clinical indicators of treatment-resistant psychosis. Br J Psychiatry 2020; 216: 259-266
    CrossrefPubMedSearch in Google Scholar
  • 24 Griffiths SL, Birchwood M, Khan A. et al. Predictors of social and role outcomes in first episode psychosis: A prospective 12-month study of social cognition, neurocognition and symptoms. Early Interv Psychiatry 2021; 15: 993-1001
    CrossrefPubMedSearch in Google Scholar
  • 25 Alvarez-Jimenez M, Priede A, Hetrick SE. et al. Risk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies. Schizophr Res 2012; 139: 116-128
    CrossrefPubMedSearch in Google Scholar
  • 26 Weibell MA, Hegelstad WTV, Auestad B. et al. The effect of substance use on 10-year outcome in first-episode psychosis. Schizophr Bull 2017; 43: 843-851
    CrossrefPubMedSearch in Google Scholar
  • 27 Koutsouleris N, Kahn RS, Chekroud AM. et al. Multisite prediction of 4-week and 52-week treatment outcomes in patients with first-episode psychosis: A machine learning approach. Lancet Psychiatry 2016; 3: 935-946
    CrossrefPubMedSearch in Google Scholar
  • 28 Lally J, Ajnakina O, Stubbs B. et al. Remission and recovery from first-episode psychosis in adults: Systematic review and meta-analysis of long-term outcome studies. Br J Psychiatry 2017; 211: 350-358
    CrossrefPubMedSearch in Google Scholar
  • 29 Siskind D, Orr S, Sinha S. et al. Rates of treatment-resistant schizophrenia from first-episode cohorts: Systematic review and meta-analysis. Br J Psychiatry 2022; 220: 115-120
    CrossrefPubMedSearch in Google Scholar
  • 30 Agid O, Arenovich T, Sajeev G. et al. An algorithm-based approach to first-episode schizophrenia: Response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry 2011; 72: 1439-1444
    CrossrefPubMedSearch in Google Scholar
  • 31 Manschreck TC, Redmond DA, Candela SF. et al. Effects of clozapine on psychiatric symptoms, cognition, and functional outcome in schizophrenia. J Neuropsychiatry Clin Neurosci 1999; 11: 481-489
    CrossrefPubMedSearch in Google Scholar
  • 32 Asenjo Lobos C, Komossa K, Rummel-Kluge C. et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010; CD006633
    CrossrefPubMedSearch in Google Scholar
  • 33 Tiihonen J, Wahlbeck K, Lönnqvist J. et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: Observational follow-up study. BMJ 2006; 333: 224
    CrossrefPubMedSearch in Google Scholar
  • 34 Tiihonen J, Lönnqvist J, Wahlbeck K. et al. 11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). Lancet 2009; 374: 620-627
    CrossrefPubMedSearch in Google Scholar
  • 35 Meltzer HY, Alphs L, Green AI. et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 82-91
    CrossrefPubMedSearch in Google Scholar
  • 36 Meltzer HY. Suicide in schizophrenia, clozapine, and adoption of evidence-based medicine. J Clin Psychiatry 2005; 66: 530-533
    CrossrefPubMedSearch in Google Scholar
  • 37 Hennen J, Baldessarini RJ. Suicidal risk during treatment with clozapine: A meta-analysis. Schizophr Res 2005; 73: 139-145
    CrossrefPubMedSearch in Google Scholar
  • 38 Thien K, O’Donoghue B. Delays and barriers to the commencement of clozapine in eligible people with a psychotic disorder: A literature review. Early Interv Psychiatry 2019; 13: 18-23
    CrossrefPubMedSearch in Google Scholar
  • 39 Srihari VH, Tek C, Pollard J. et al. Reducing the duration of untreated psychosis and its impact in the U.S.: The STEP-ED study. BMC Psychiatry 2014; 14: 335
    CrossrefPubMedSearch in Google Scholar
  • 40 Marshall M, Lewis S, Lockwood A. et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: A systematic review. Arch Gen Psychiatry 2005; 62: 975-983
    CrossrefPubMedSearch in Google Scholar
  • 41 Lieberman JA. Managing anticholinergic side effects. Prim Care Companion J Clin Psychiatry 2004; 6: 20-23
    PubMedSearch in Google Scholar
  • 42 Gebhardt S, Schmidt P, Remschmidt H. et al. Effects of prodromal stage and untreated psychosis on subsequent psychopathology of schizophrenia: A path analysis. Psychopathology 2019; 52: 304-315
    CrossrefPubMedSearch in Google Scholar
  • 43 Balu DT. The NMDA receptor and schizophrenia: From pathophysiology to treatment. Adv Pharmacol 2016; 76: 351-382
    CrossrefPubMedSearch in Google Scholar
  • 44 Maia TV, Frank MJ. An integrative perspective on the role of dopamine in schizophrenia. Biol Psychiatry 2017; 81: 52-66
    CrossrefPubMedSearch in Google Scholar
  • 45 Cerveri G, Gesi C, Mencacci C. Pharmacological treatment of negative symptoms in schizophrenia: Update and proposal of a clinical algorithm. Neuropsychiatr Dis Treat 2019; 15: 1525-1535
    CrossrefPubMedSearch in Google Scholar
  • 46 Wimberley T, Støvring H, Sørensen HJ. et al. Predictors of treatment resistance in patients with schizophrenia: A population-based cohort study. Lancet Psychiatry 2016; 3: 358-366
    CrossrefPubMedSearch in Google Scholar
  • 47 Selten J-P, Veen ND, Hoek HW. et al. Early course of schizophrenia in a representative Dutch incidence cohort. Schizophr Res 2007; 97: 79-87
    CrossrefPubMedSearch in Google Scholar
  • 48 Austin SF, Mors O, Budtz-Jørgensen E. et al. Long-term trajectories of positive and negative symptoms in first episode psychosis: A 10 year follow-up study in the OPUS cohort. Schizophr Res 2015; 168: 84-91
    CrossrefPubMedSearch in Google Scholar
  • 49 Pelayo-Terán JM, Diaz FJ, Pérez-Iglesias R. et al. Trajectories of symptom dimensions in short-term response to antipsychotic treatment in patients with a first episode of non-affective psychosis. Psychol Med 2014; 44: 37-50
    CrossrefPubMedSearch in Google Scholar
  • 50 Díaz I, Pelayo-Terán JM, Pérez-Iglesias R. et al. Predictors of clinical remission following a first episode of non-affective psychosis: Sociodemographics, premorbid and clinical variables. Psychiatry Res 2013; 206: 181-187
    CrossrefPubMedSearch in Google Scholar
  • 51 Lasalvia A, Bonetto C, Lenzi J. et al. Predictors and moderators of treatment outcome in patients receiving multi-element psychosocial intervention for early psychosis: Results from the GET UP pragmatic cluster randomised controlled trial. Br J Psychiatry 2017; 210: 342-349
    CrossrefPubMedSearch in Google Scholar
  • 52 Verma S, Subramaniam M, Abdin E. et al. Symptomatic and functional remission in patients with first-episode psychosis. Acta Psychiatr Scand 2012; 126: 282-289
    CrossrefPubMedSearch in Google Scholar
  • 53 Lee BJ, Kim S-W, Kim JJ. et al. Defining treatment response, remission, relapse, and recovery in first-episode psychosis: A survey among Korean experts. Psychiatry Investig 2020; 17: 163-174
    CrossrefPubMedSearch in Google Scholar