Efficacy of Integrated Social Cognitive Remediation vs. Neurocognitive Remediation in Improving Functional Outcome in Schizophrenia: Concept and Design of a Multicenter, Single-Blind RCT (The ISST Study)

Wolfgang Wölwer, Nicole Frommann, Agnes Lowe, Daniel Kamp, Karolin Weide, Andreas Bechdolf, Anke Brockhaus-Dumke, Rene Hurlemann, Ana Muthesius, Stefan Klingberg, Martin Hellmich, Sabine Schmied, Andreas Meyer-Lindenberg, ISST study group, W Wölwer, S Abresch, N Frommann, A Lowe, D Kamp, P Ockenfelds, K Weide, F Pessanha, S Dinse Düsseldorf, A Philipsen, R Hurlemann, J Schultz, N Striepens, U Darrelmann, C Kloss, S Wasserthal, H Högenauer, N Schumacher Bonn, F Jessen, J Kambeitz, C Baldermann, A Muthesius, C Doll, H Schneegans, A Ferrari, G Kolb, T Haidl, D Zeus, T Pilgram, M Rohde, P Albert-Porcar, S Hölzer, M Hellmich, K Kuhr, K Rosenberger, D Kraus, S Schmied, U Bergmann, F Scheckenbach, A Montada Cologne, S Klingberg, D Wildgruber, U Hermanutz, J Richter, J Vonderschmitt, L Hölz Tübingen, A Bechdolf, K Leopold, S Siebert, F Seidel, E S Blanke Berlin, A Brockhaus-Dumke, X Solojenkina, B Klos, E Rosenbauer, S Cinar, L Herdt, F Henrich, S Neff Alzey, A Meyer-Lindenberg Mannheim, Wolfgang Wölwer, Nicole Frommann, Agnes Lowe, Daniel Kamp, Karolin Weide, Andreas Bechdolf, Anke Brockhaus-Dumke, Rene Hurlemann, Ana Muthesius, Stefan Klingberg, Martin Hellmich, Sabine Schmied, Andreas Meyer-Lindenberg, ISST study group, W Wölwer, S Abresch, N Frommann, A Lowe, D Kamp, P Ockenfelds, K Weide, F Pessanha, S Dinse Düsseldorf, A Philipsen, R Hurlemann, J Schultz, N Striepens, U Darrelmann, C Kloss, S Wasserthal, H Högenauer, N Schumacher Bonn, F Jessen, J Kambeitz, C Baldermann, A Muthesius, C Doll, H Schneegans, A Ferrari, G Kolb, T Haidl, D Zeus, T Pilgram, M Rohde, P Albert-Porcar, S Hölzer, M Hellmich, K Kuhr, K Rosenberger, D Kraus, S Schmied, U Bergmann, F Scheckenbach, A Montada Cologne, S Klingberg, D Wildgruber, U Hermanutz, J Richter, J Vonderschmitt, L Hölz Tübingen, A Bechdolf, K Leopold, S Siebert, F Seidel, E S Blanke Berlin, A Brockhaus-Dumke, X Solojenkina, B Klos, E Rosenbauer, S Cinar, L Herdt, F Henrich, S Neff Alzey, A Meyer-Lindenberg Mannheim

Abstract

Background: Although clinically effective treatment is available for schizophrenia, recovery often is still hampered by persistent poor psychosocial functioning, which in turn is limited by impairments in neurocognition, social cognition, and social behavioral skills. Although cognitive remediation has shown general efficacy in improving cognition and social functioning, effects still need to be improved and replicated in appropriately powered, methodologically rigorous randomized controlled trials (RCTs). Existing evidence indicates that effects can most likely be optimized by combining treatment approaches to simultaneously address both social cognitive and social behavioral processes.

Objectives: To assess whether Integrated Social Cognitive and Behavioral Skill Therapy (ISST) is more efficacious in improving functional outcome in schizophrenia than the active control treatment Neurocognitive Remediation Therapy (NCRT).

Methods: The present study is a multicenter, prospective, rater-blinded, two-arm RCT being conducted at six academic study sites in Germany. A sample of 180 at least partly remitted patients with schizophrenia are randomly assigned to either ISST or NCRT. ISST is a compensatory, strategy-based program that targets social cognitive processes and social behavioral skills. NCRT comprises mainly drill and practice-oriented neurocognitive training. Both treatments consist of 18 sessions over 6 months, and participants are subsequently followed up for another 6 months. The primary outcome is all-cause discontinuation over the 12-month study period; psychosocial functioning, quality of life, neurocognitive and social cognitive performance, and clinical symptoms are assessed as secondary outcomes at baseline before randomization (V1), at the end of the six-month treatment period (V6), and at the six-month follow-up (V12).

Discussion: This RCT is part of the German Enhancing Schizophrenia Prevention and Recovery through Innovative Treatments (ESPRIT) research network, which aims at using innovative treatments to enhance prevention and recovery in patients with schizophrenia. Because this study is one of the largest and methodologically most rigorous RCTs on the efficacy of cognitive remediation approaches in schizophrenia, it will not only help to identify the optimal treatment options for improving psychosocial functioning and thus recovery in patients but also allow conclusions to be drawn about factors influencing and mediating the effects of cognitive remediation in these patients.

Trial registration: ClinicalTrials.gov NCT02678858, German Study Register DRKS 00010033.

Keywords: cognitive remediation; functional outcome; recovery; schizophrenia; social cognition; social skills.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Wölwer, Frommann, Lowe, Kamp, Weide, Bechdolf, Brockhaus-Dumke, Hurlemann, Muthesius, Klingberg, Hellmich, Schmied and Meyer-Lindenberg.

Figures

Figure 1
Figure 1
Overview of the trial.

References

    1. Pinkham AE, Penn DL, Perkins DO, Lieberman J. Implications for the neural basis of social cognition for the study of schizophrenia. Am J Psychiatry. (2003) 160:815–24. 10.1176/appi.ajp.160.5.815
    1. Middelboe T, Mackeprang T, Hansson L, Werdelin G, Karlsson H, Bjarnason O, et al. . The Nordic Study on schizophrenic patients living in the community. Subjective needs and perceived help Eur Psychiatry. (2001) 16:207–14. 10.1016/S0924-9338(01)00566-1
    1. Corrigan PW, Reinke RR, Landsberger SA, Charate A, Toombs GA. The effects of atypical antipsychotic medications on psychosocial outcomes. Schizophr Res. (2003) 63:97–101. 10.1016/S0920-9964(02)00379-1
    1. Green MF, Horan WP, Lee J. Nonsocial and social cognition in schizophrenia: current evidence and future directions. World Psychiatry. (2019) 18:146–61. 10.1002/wps.20624
    1. Ramsay CE, Broussard B, Goulding SM, Cristofaro S, Hall D, Kaslow NJ, et al. . Life and treatment goals of individuals hospitalized for first-episode nonaffective psychosis. Psychiatry Res. (2011) 189:344–8. 10.1016/j.psychres.2011.05.039
    1. Hogarty GE, Flesher S, Ulrich R, Carter M, Greenwald D, Pogue-Geile M, et al. . Cognitive enhancement therapy for schizophrenia: effects of a 2-year randomized trial on cognition and behavior. Arch Gen Psychiatry. (2004) 61:866–76. 10.1001/archpsyc.61.9.866
    1. Mucci A, Galderisi S, Gibertoni D, Rossi A, Rocca P, Bertolino A, et al. . Factors associated with real-life functioning in persons with schizophrenia in a 4-year follow-up study of the Italian Network for Research on Psychoses. JAMA Psychiatry. (2021) 78:550–9. 10.1192/j.eurpsy.2021.135
    1. Frawley E, Cowman M, Lepage M, Donohoe G. Social and occupational recovery in early psychosis: a systematic review and meta-analysis of psychosocial interventions. Psychol Med. (2021) 2021:1–12. 10.1017/S003329172100341X
    1. Tsang HW, Leung AY, Chung RC, Bell M, Cheung WM. Review on vocational predictors: a systematic review of predictors of vocational outcomes among individuals with schizophrenia: an update since 1998. Aust N Z J Psychiatry. (2010) 44:495–504.
    1. Couture SM, Granholm EL, Fish SC. A path model investigation of neurocognition, theory of mind, social competence, negative symptoms and real-world functioning in schizophrenia. Schizophr Res. (2011) 125:152–60. 10.1016/j.schres.2010.09.020
    1. Kharawala S, Hastedt C, Podhorna J, Shukla H, Kappelhoff B, Harvey PD. The relationship between cognition and functioning in schizophrenia: a semi-systematic review. Schizophrenia Res: Cognition. (2022) 27:100217. 10.1016/j.scog.2021.100217
    1. Halverson TF, Orleans-Pobee M, Merrit C, Sheeran P, Fett AK, Penn DL. Pathways to functional outcomes in schizophrenia spectrum disorders: Meta-analysis of social cogintive and neurocognitive predictors. Neurosci Biobehav Rev. (2019) 105:212–9. 10.1016/j.neubiorev.2019.07.020
    1. Savla GN, Vella L, Armstrong CC, Penn DL, Twamley EW. Deficits in Domains of Social Cognition in Schizophrenia: A Meta-Analysis of the Empirical Evidence. Schizophr Bull. (2013) 39:979–92. 10.1093/schbul/sbs080
    1. Fett AK, Viechtbauer W, Dominguez MD, Penn DL, van Os J, Krabbendam L. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci Biobehav Rev. (2011) 35:573–88. 10.1016/j.neubiorev.2010.07.001
    1. Spiekermann A, Schulz M, Behrens J, Driessen M, Rahn E, Beblo T. Kognitive Leistungen und Adhärenzverhalten bei Patienten mit schizophrenen Psychosen. Fortschr Neurol Psychiatr. (2011) 79:73–82. 10.1055/s-0029-1245622
    1. Johansen R, Hestad K, Iversen VC, Agartz I, Sundet K, Andreassen OA, et al. . Cognitive and clinical factors are associated with service engagement in early-phase schizophrenia spectrum disorders. J Nerv Ment Dis. (2011) 199:176–82. 10.1097/NMD.0b013e31820bc2f9
    1. Gaebel W, Riesbeck M, Wolwer W, Klimke A, Eickhoff M, von Wilmsdorff M, et al. . Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia: 1-year results of a randomized controlled trial within the German Research Network on Schizophrenia. J Clin Psychiatry. (2007) 68:1763–74. 10.4088/JCP.v68n1116
    1. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry. (2011) 168:472–85. 10.1176/appi.ajp.2010.10060855
    1. Vita A, Barlati S, Ceraso A, Nibbio G, Ariu C, Deste G, et al. . Effectiveness, core elements, and moderators of response of cognitive remediation for schizophrenia: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. (2021) 78:848–58. 10.1001/jamapsychiatry.2021.0620
    1. Kurtz MM, Richardson CL. Social cognitive training for schizophrenia: a meta-analytic investigation of controlled research. Schizophr Bull. (2012) 38:1092–104. 10.1093/schbul/sbr036
    1. Kurtz MM, Gagen E, Rocha NB, Machado S, Penn DL. Comprehensive treatments for social cognitive deficits in schizophrenia: a critical review and effect-size analysis of controlled studies. Clin Psychol Rev. (2016) 43:80–9. 10.1016/j.cpr.2015.09.003
    1. Nijman SA, Veling W, van der Stouwe ECD, Pijnenborg GH. Social cognition training for people with a psychotic disorder: a network meta-analysis. Schizophr Bulletin. (2020) 46:1086–103. 10.1093/schbul/sbaa023
    1. Wölwer W, Frommann N, Halfmann S, Piaszek A, Streit M, Gaebel W. Remediation of impairments in facial affect recognition in schizophrenia: efficacy and specificity of a new training program. Schizophr Res. (2005) 80:295–303. 10.1016/j.schres.2005.07.018
    1. Luckhaus C, Frommann N, Stroth S, Brinkmeyer J, Wolwer W. Training of affect recognition in schizophrenia patients with violent offences: behavioral treatment effects and electrophysiological correlates. Soc Neurosci. (2013) 8:505–14. 10.1080/17470919.2013.820667
    1. Wölwer W, Frommann N. Social-cognitive remediation in schizophrenia: generalization of effects of the training of affect recognition (TAR). Schizophr Bull. (2011) 37:63–70. 10.1093/schbul/sbr071
    1. Vaskinn A, Løvgren A, Egeland MK, Feyer FK, Østefjells T, Andreassen OA, et al. . A randomized controlled trial of training of affect recognition (TAR) in schizophrenia shows lasting effects for theory of mind. Eur Arch Psychiatry Clin Neurosci. (2019) 269:611–20. 10.1007/s00406-019-00997-z
    1. Sachs G, Winklbaur B, Jagsch R, Lasser I, Kryspin-Exner I, Frommann N, et al. . Training of affect recognition (TAR) in schizophrenia - impact on functional outcome. Schizophr Res. (2012) 138:262–7. 10.1016/j.schres.2012.03.005
    1. Brekke J, Kay DD, Lee KS, Green MF. Biosocial pathways to functional outcome in schizophrenia. Schizophr Res. (2005) 80:213–25. 10.1016/j.schres.2005.07.008
    1. Kurtz MM, Mueser KT. A meta-analysis of controlled research on social skills training for schizophrenia. J Consult Clin Psychol. (2008) 76:491–504. 10.1037/0022-006X.76.3.491
    1. Yeo H, Yoon S, Lee J, Kurtz M, Choi K. A Meta-analysis of the effects of social-cognitive training in schizophrenia: Role of treatment characteristics and study quality. British J Clin Psychol. (2021) 61:37–57. 10.1111/bjc.12320
    1. Fiszdon JM, Reddy LF. Review of social cognitive treatments for psychosis. Clin Psychol Rev. (2012) 32:724–40. 10.1016/j.cpr.2012.09.003
    1. Horan W, Dolinsky M, Lee J, Kern R, Hellemann G, Sugar C, et al. . Social cognitive skills training for psychosis with community-based training exercieses: a randomized controlled trial. Schizophr Bulletin. (2018) 44:1254–66. 10.1093/schbul/sbx167
    1. Bowie CR, McGurk SR, Mausbach B, Patterson TL, Harvey PD. Combined cognitive remediation and functional skills training for schizophrenia: effects on cognition, functional competence, and real-world behavior. Am J Psychiatry. (2012) 169:710–8. 10.1176/appi.ajp.2012.11091337
    1. Eberle MC, Lee H, Travers-Podmaniczky G, Hesse K, Albrecht S, Klingberg S, et al. . STAR: Spielerisches Training affektiver Ressourcen - Das Manual (unpublished therapy manual). (2011).
    1. Medalia A, Saperstein A. The role of motivation for treatment success. Schizophr Bull. (2011) 37 Suppl 2:S122–8. 10.1093/schbul/sbr063
    1. Klingberg S, Wolwer W, Engel C, Wittorf A, Herrlich J, Meisner C, et al. . Negative symptoms of schizophrenia as primary target of cognitive behavioral therapy: results of the randomized clinical TONES study. Schizophr Bull. (2011) 37 Suppl 2:S98–110. 10.1093/schbul/sbr073
    1. Finauer G. Therapiemanuale für Neuropsychologische Rehabilitation: Kognitive und kompetenzorientierte Therapie für die Gruppen- und Einzelbehandlung. Heidelberg: Springer Medizin Verlag; (2007).
    1. Paquin K, Wilson AL, Cellard C, Lecomte T, Potvin S. A systematic review on improving cognition in schizophrenia: which is the more commonly used type of training, practice or strategy learning? BMC Psychiatry. (2014) 14:139. 10.1186/1471-244X-14-139
    1. Prikken M, Konings MJ, Lei WU, Begemann MJ, Sommer IE. The efficacy of computerized cognitive drill and practice training for patients with schizophrenia-spectrum disorder: a meta-analysis. Schizophr Res. (2019) 204:368–74. 10.1016/j.schres.2018.07.034
    1. Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al. . Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. (2008) 371:1085–97. 10.1016/S0140-6736(08)60486-9
    1. Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R, et al. . The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. (2009) 70 Suppl 4:1–46. 10.4088/JCP.7090su1cj
    1. Schimmelmann BG, Conus P, Schacht M, McGorry P, Lambert M. Predictors of service disengagement in first-admitted adolescents with psychosis. J Am Acad Child Adolesc Psychiatry. (2006) 45:990–9. 10.1097/01.chi.0000223015.29530.65
    1. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. . Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine. (2005) 353:1209–23. 10.1056/NEJMoa051688
    1. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, et al. . Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. (2007) 64:633–47. 10.1001/archpsyc.64.6.633
    1. Jeste SD, Patterson TL, Palmer BW, Dolder CR, Goldman S, Jeste DV. Cognitive predictors of medication adherence among middle-aged and older outpatients with schizophrenia. Schizophr Res. (2003) 63:49–58. 10.1016/S0920-9964(02)00314-6
    1. Choi J, Medalia A. Factors associated with a positive response to cognitive remediation in a community psychiatric sample. Psychiatr Serv. (2005) 56:602–4. 10.1176/appi.ps.56.5.602
    1. Llorca PM, Lancon C, Lancrenon S, Bayle FJ, Caci H, Rouillon F, et al. . The “Functional Remission of General Schizophrenia” (FROGS) scale: development and validation of a new questionnaire. Schizophr Res. (2009) 113:218–25. 10.1016/j.schres.2009.04.029
    1. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV social and occupational functioning assessment scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. (2000) 101:323–9. 10.1111/j.1600-0447.2000.tb10933.x
    1. Mausbach BT, Harvey PD, Goldman SR, Jeste DV, Patterson TL. Development of a brief scale of everyday functioning in persons with serious mental illness. Schizophr Bull. (2007) 33:1364–72. 10.1093/schbul/sbm014
    1. WHO . WHOQOL-BREF Introduction, Administration, Scoring and Generic Version of the Assessment - Field Trial Version. Geneva: WHO; (1996).
    1. Helmstaedter C, Lendt M, Lux S. VLMT Verbaler Lern- und Merkfähigkeitstest. Göttingen: Hogrefe; (2001).
    1. Wechsler D. Wechsler Adult Intelligence Scale—Revised. San Antonio, TX: The Psychological Corporation. (1981).
    1. Reitan R. A manual for the Administrating and Scoring of the Trail Making Test. Indianapolis: Indiana University Press. (1956).
    1. Ekman P, Friesen WV. Pictures of Facial Affect. Palo Alto, CA: Consulting Psychologists Press. (1976).
    1. Dziobek I, Fleck S, Kalbe E, Rogers K, Hassenstab J, Brand M, et al. . Introducing MASC: a movie for the assessment of social cognition. J Autism Dev Disord. (2006) 36:623–36. 10.1007/s10803-006-0107-0
    1. Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale: Manual. Toronto: Multi-Health Systems. (1992).
    1. Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the calgary depression scale. Br J Psychiatry Suppl. (1993) 22:39–44. 10.1192/S0007125000292581
    1. Derogatis LR, Melisaratos N. The brief symptom inventory: an introductory report. Psychol Med. (1983) 13:595–605. 10.1017/S0033291700048017
    1. Tait L, Birchwood M, Trower P. A new scale (SES) to measure engagement with community mental health services. J Ment Health. (2002) 11:191–8. 10.1080/09638230020023570-2
    1. Goodstadt MS, Cook G, Magid S, Gruson V. The drug attitudes scale (DAS): its development and evaluation. Int J Addict. (1978) 13:1307–17. 10.3109/10826087809039344
    1. Schulte D. Messung der therapieerwartung und therapieevaluation (PATHEV). Zeitschrift für Klinische Psychologie und Psychotherapie. (2005) 34:176–88. 10.1026/1616-3443.34.3.176
    1. Guy W. ECDEU Assessment Manual of Psychopharmacology: Publication ADM 76-338. Washington, DC: : US Department of Health, Education and Welfare. (1976).
    1. Galderisi S, Piegari G, Mucci A, Acerra A, Luciano L, Rabasca AF, et al. . Social skills and neurocognitive individualized training in schizophrenia: comparison with structured leisure activities. Eur Arch Psychiatry Clin Neurosci. (2010) 260:305–15. 10.1007/s00406-009-0078-1
    1. Lindenmayer J-P, McGurk SR, Khan A, Kaushik S, Thanju A, Hoffman L, et al. . Improving social cognition in schizophrenia: a pilot intervention combining computerized social cognition training with cognitive remediation. Schizophr Bull. (2013) 39:507–17. 10.1093/schbul/sbs120
    1. Galletly C, Castle D, Dark F, Humberstone V, Jablensky A, Killackey E, et al. . Royal Australian and New Zealand college of psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Australian & New Zealand. J Psychiatry. (2016) 50:410–72. 10.1177/0004867416641195
    1. Norman R, Lecomte T, Addington D, Anderson E. Canadian treatment guidelines on psychosocial treatment of schizophrenia in adults. Canadian J Psychiatry. (2017) 62:617–23. 10.1177/0706743717719894
    1. SIGN. Scottish Intercollegiate Guidelines Network (SIGN): Management of Schizophrenia. (2013). p. 27–28. Available online at:
    1. APA. Practice Guideline for the Treatment of Patients with Schizophrenia. 3rd ed. Washington DC: American Psychiatric Association Publishing (2021). Available online at:
    1. NICE . National Institute for Health & Clinical Excellence: Schizophrenia Core interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care (Update). London: National Institute for Clinical Excellence; (2010).
    1. Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW, et al. . The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull. (2010) 36:48–70. 10.1093/schbul/sbp115
    1. Bowie C, Bella M, Fiszdon J. Cognitive remediation for schizophrenia: an expert working group white paper on core techniques. Schizophr Res. (2020) 215:49–53. 10.1016/j.schres.2019.10.047

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