Chapter 1 Introduction
1.1 Background
Schizophrenia is a chronic and severe mental health disorder affecting millions of people globally.1 It is one of the leading causes of disability worldwide and we have seen an increasing trend over the last two decades.2 The extent of disability is partly attributed to the substantial impairment of cognitive functioning in schizophrenia.3–5 This indicates a potential treatment target for improving the years lived with disability due to schizophrenia.
Despite the efficacy of pharmacological interventions to ameliorate psychotic symptoms, there is little or no benefit of such medications for restoring cognition.6 Fortunately, a large body of evidence has been made available through meta-analyses of clinical trials, suggesting that cognitive remediation (a nonpharmacological intervention) provides, on average, consistent moderate improvements in cognitive and functional outcomes.7–10
Cognitive remediation has been defined as “an intervention targeting cognitive deficit (attention, memory, executive function, social cognition, or metacognition) using scientific principles of learning with the ultimate goal of improving functional outcomes. Its effectiveness is enhanced when provided in a context (formal or informal) that provides support and opportunity for improving everyday functioning.”11 Given its effectiveness and feasibility in clinical practice, this intervention has been widely accepted as a means of restoring cognitive deficits with the ultimate goal of improving daily functioning and quality of life in schizophrenia.
Nevertheless, there is still uncertainty regarding who may benefit the most from cognitive remediation therapy.12–14 Being able to reliably and accurately identify individuals’ characteristics that can predict cognitive remediation response or resistance (also known as moderators or treatment-effect interactions) in schizophrenia is of clinical importance as this would allow for better prognostication and treatment decisions, as well as optimal allocation of healthcare resources.15
Moderators of treatment effect indicate for whom or under what circumstances a treatment works.16 The treatment response, or lack thereof, depends on an individual’s value of the moderator so that identification of the moderator can help explain heterogeneity in treatment effect.17 A moderator that is a feature of an individual (e.g. male or female) or is a characteristic under which the treatment is delivered (e.g. inpatients or outpatients) suggests for whom or under what conditions the treatment may benefit the most, respectively.17
Systematic reviews on primary and secondary studies that investigated moderators of cognitive remediation effect in schizophrenia suggest quite a few baseline demographic, biologic, cognitive and functional, psychological, as well as illness-related characteristics.12,14 However, these studies tend to be at high risk of bias and underpowered.12 It is also not uncommon that they utilised suboptimal design or statistical approaches to investigating heterogeneity of treatment effects, such as little transparency on a priori specification (including the number and direction of potential moderators tested)18,19 or use of aggregate data and metaregression method in meta-analysis, which is prone to ecological bias.20,21 These limitations have likely led to the observed inconsistent and nonreproducible results.
When multiple trials are accessible, individual participant data meta-analysis that standardises analyses across trials may provide unbiased moderating effect-estimates by separating within-trial and between-trial information and more reliable findings due to increased statistical power.20,21 Therefore, individual participant data meta-analysis is considered the gold standard for identifying subgroup treatment effects.22
In the current study, six eligible trials were available from the Database of Cognitive Training and Remediation Studies (DoCTRS) and the Computerised Interactive Remediation of Cognition Training for Schizophrenia or CIRcuiTS Combined Data (CCD). Benefitting from the individual participant data meta-analysis approach, these data are invaluable resources for addressing the limitations encountered in previous studies for investigating moderators of cognitive remediation effect in schizophrenia.
1.2 Objective
The objective of this study was to identify moderators of cognitive remediation effect on cognitive functioning for patients with schizophrenia by means of individual participant data meta-analysis.
Reliable and accurate estimation of treatment-effect heterogeneity in cognitive remediation for schizophrenia would potentially help tailor clinical decision-making (precision medicine), improve prognosis of individuals with schizophrenia, enhance the design of future studies, and inform better diagnostic classification of disease.
References
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