Unraveling the Influence of Age, IQ, Education, and Negative Symptoms
                    on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree
                    Analysis

Xenia M. Hart; Yasue Mitsukura; Robert R. Bies; Hiroyuki Uchida

doi:10.1055/a-2258-0379

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2024; 57(02): 53-60
DOI: 10.1055/a-2258-0379

Original Paper

Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis

Xenia M. Hart

¹Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

,

Yasue Mitsukura

²Department of System Design Engineering, Faculty of Science and Technology, Keio University Japan

,

Robert R. Bies

³Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA

,

Hiroyuki Uchida

¹Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

› Author Affiliations

Abstract

Introduction The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D₂ receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before.

Methods This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D₂ receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia.

Results The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26).

Conclusions These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D₂ occupancy.

Keywords

schizophrenia - dopamine antagonists - cognitive impairment - cognition - CATIE

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References

References
1 Sakurai H, Bies RR, Stroup ST. et al. Dopamine D₂ receptor occupancy and cognition in schizophrenia: Analysis of the CATIE data. Schizophr Bull 2013; 39: 564-574
2 Keefe RS, Silva SG, Perkins DO. et al. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: A review and meta-analysis. Schizophr Bull 1999; 25: 201-222
3 Minzenberg MJ, Poole JH, Benton C. et al. Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am J Psychiatry 2004; 161: 116-124
4 Hoff AL, Sakuma M, Wieneke M. et al. Longitudinal neuropsychological follow-up study of patients with first-episode schizophrenia. Am J Psychiatry 1999; 156: 1336-1341
5 Dickinson D, Zaidman SR, Giangrande EJ. et al. Distinct polygenic score profiles in schizophrenia subgroups with different trajectories of cognitive development. Am J Psychiatry 2020; 177: 298-307
6 Akiyama K, Saito S, Saito A. et al. Predictive value of premorbid IQ, negative symptoms, and age for cognitive and social functions in Japanese patients with schizophrenia: A study using the Japanese version of the brief assessment of cognition in schizophrenia. Psychiatry Res 2016; 246: 663-671
7 Lieberman JA, Stroup TS, McEvoy JP. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209-1223
8 Bigos KL, Pollock BG, Coley KC. et al. Sex, race, and smoking impact olanzapine exposure. J Clin Pharmacol 2008; 48: 157-165
9 Feng Y, Pollock BG, Coley K. et al. Population pharmacokinetic analysis for risperidone using highly sparse sampling measurements from the CATIE study. Br J Clin Pharmacol 2008; 66: 629-639
10 Wessels AM, Bies RR, Pollock BG. et al. Population pharmacokinetic modeling of ziprasidone in patients with schizophrenia from the CATIE study. J Clin Pharmacol 2011; 51: 1587-1591
11 Uchida H, Takeuchi H, Graff-Guerrero A. et al. Predicting dopamine D₂ receptor occupancy from plasma levels of antipsychotic drugs: A systematic review and pooled analysis. J Clin Psychopharmacol 2011; 31: 318-325
12 Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm 1977; 5: 445-479
13 Cha TA, Beall E, Irvine B. et al. At least five related, but distinct, hepatitis C viral genotypes exist. Proc Natl Acad Sci U S A 1992; 89: 7144-7148
14 Nakajima S, Uchida H, Bies RR. et al. Dopamine D_2/3 receptor occupancy following dose reduction is predictable with minimal plasma antipsychotic concentrations: An open-label clinical trial. Schizophr Bull 2016; 42: 212-219
15 R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing; Vienna, Austria: 2022
16 Kuhn M. Building Predictive Models in R Using the caret Package. J Stat Softw 2008; 28: 1-26
17 Hothorn T, Zeileis A. Partykit: A modular toolkit for recursive partytioning in R. J Mach Learn Res 2015; 16: 3905-3909
18 Wesner K, Hiemke C, Bergemann N. et al. Therapeutic reference range for olanzapine in schizophrenia: Systematic review on blood concentrations, clinical effects, and dopamine receptor occupancy. J Clin Psychiatry 2023; 84: 22r14626
19 Ventura J, Hellemann GS, Thames AD. et al. Symptoms as mediators of the relationship between neurocognition and functional outcome in schizophrenia: A meta-analysis. Schizophr Res 2009; 113: 189-199
20 Wykes T, Huddy V, Cellard C. et al. A meta-analysis of cognitive remediation for schizophrenia: Methodology and effect sizes. Am J Psychiatry 2011; 168: 472-485
21 Kurtz MM, Müser KT. A meta-analysis of controlled research on social skills training for schizophrenia. J Consult Clin Psychol 2008; 76: 491-504
22 Green MF, Kern RS, Heaton RK. Longitudinal studies of cognition and functional outcome in schizophrenia: Implications for MATRICS. Schizophr Res 2004; 72: 41-51
23 Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2006; 2: 531-536
24 Bhana N, Foster RH, Olney R. et al. Olanzapine: An updated review of its use in the management of schizophrenia. Drugs 2001; 61: 111-161
25 Schoretsanitis G, de Leon J, Haen E. et al. Pharmacokinetics of risperidone in different application forms - Comparing long-acting injectable and oral formulations. Eur Neuropsychopharmacol 2018; 28: 130-137
26 Schmidt AW, Lebel LA, Howard HR. et al. Ziprasidone: A novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol 2001; 425: 197-201

Supplementary Material

Supplementary Material