46 Chapter 2 Table 2. Continued Study Study design A priori design for risk factors N= n= Sleep outcome Age Steroid Sleep outcome Warris et al (2016)53 RCT Yes 47 47 6,0 (4.09.8) years Dex (6 mg/ m2/d) Sleep Note: Age reported as mean or range. Color-coding: red (lower quality), orange (medium quality), green (higher quality). Abbreviations: AUC: Area Under the Curve, CLIA: Chemiluminescence-based Immunoassay, Dex: Dexamethasone, DST: Dexamethasone Suppression Test, HR: High Risk, NS: Not Significant, All studies used a candidate gene approach, usually focusing on the glucocorticoid receptor gene (NR3C1; Supplemental Table 5). One study also included three other genes: the ATP-Binding Cassette B1 (ABCB1) gene, glutathione and glutathione-Stransferase (GST) gene and interleukin-10 (IL-10) gene.45 None of the studies adjusted for multiple testing or controlled for confounding variables. Furthermore, none of the studies included a replication cohort. One study used a validated questionnaire to measure APRs,4 the other studies used retrospectively collected toxicity data.39,40,44,45 The Bcl-1 polymorphism on the GR gene was studied in four patient cohorts,4,39,44,45 and only Kaymak Cihan et al. found a positive association between the homozygous CC genotype and the occurrence of depression symptoms during steroid treatment (Supplemental Table 5). This result has not been replicated in another cohort. The ER22/23EK and N363S GR gene polymorphisms were studied in respectively three4,39,45 and four patient cohorts4,39,40,44,45 of which none found a significant association with an APR outcome. The SNPs in the three additional genes described by Marino et al. (ABCB1, GST and IL-10) were studied in 36 patients; no significant association with the occurrence of neuropsychiatric signs was found.45 Other factors Several additional possible risk factors were identified during our literature search. Only a serum elevated monoamine oxidase was correlated with steroid-induced behavioral changes.49 However, monoamine oxidase changes appears to be an effect of stress, rather than a risk factor.57,58 Cortisol levels,4,53 adrenocorticotropic hormone
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