Considering medication exposure in genomic association studies of cognition in psychotic disorders
Abstract
Cognitive dysfunction is a core feature of psychosis-spectrum illnesses, and the characterization of related genetic mechanisms may provide insights regarding the disease pathophysiology. Substantial efforts have been made to determine the genetic component of cognitive symptoms, without clear success. Illness-related moderators and environmental factors such as medications hinder the detection of genomic association with cognition. Polypharmacy is common in psychotic disorders, and the cumulative effects of medication regimens can confound gene–cognition associations. A review of the relative contributions of important pharmacological and genetic relationships identifies that the effects of medications on cognition in psychotic disorders may be at least, if not more, impactful than individual genes, thus underscoring the importance of accounting for medication exposure in gene–cognition association studies.
References
- 1. A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia. Schizophr. Res. 113(2-3), 167–175 (2009).
- 2. Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the bipolar-schizophrenia network on intermediate phenotypes (B-SNIP) study. Am. J. Psychiatry 170(11), 1275–1284 (2013).
- 3. . Characteristics of the MATRICS consensus cognitive battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr. Res. 125(2-3), 161–168 (2011).
- 4. . Cognitive impairment in schizophrenia. Handb. Exp. Pharmacol. (213), 11–37 (2012).
- 5. Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch. Gen. Psychiatry 64(11), 1242–1250 (2007).
- 6. A three-stage genome-wide association study of general cognitive ability: hunting the small effects. Behav. Genet. 40(6), 759–767 (2010).
- 7. . Genome-wide association studies and human disease: from trickle to flood. JAMA 302(18), 2028–2029 (2009).
- 8. . Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert Rev. Neurother. 10(1), 43–57 (2010).
- 9. Cognitive burden of anticholinergic medications in psychotic disorders. Schizophr. Res. 190, 129–135 (2017).
- 10. . The anticholinergic drug scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J. Clin. Pharmacol. 46(12), 1481–1486 (2006).
- 11. The cognitive impact of anticholinergics: a clinical review. Clin. Interv. Aging 4, 225–233 (2009).
- 12. . Long-term anticholinergic use and the aging brain. Alzheimers. Dement. 9(4), 377–385 (2013).
- 13. Association of anticholinergic burden with cognitive and functional status in a cohort of hospitalized elderly: comparison of the anticholinergic cognitive burden scale and anticholinergic risk scale: results from the REPOSI study. Drugs Aging 30(2), 103–112 (2013).
- 14. . Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36(1), 52–73 (2011).
- 15. . Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol. Psychiatry 48(5), 381–388 (2000).
- 16. . Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am. J. Psychiatry 158(6), 918–925 (2001).
- 17. . Altered hippocampal muscarinic M4, but not M1, receptor expression from subjects with schizophrenia. Biol. Psychiatry 61(10), 1161–1170 (2007).
- 18. . Investigation of m1/m4 muscarinic receptors in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression disorder. Neuropsychopharmacology 29(3), 619–625 (2004).
- 19. . Serum levels of anticholinergic drugs and impaired recent memory in chronic schizophrenic patients. Am. J. Psychiatry 139(11), 1460–1462 (1982).
- 20. . Effects of anticholinergic medication on memory in schizophrenia. Schizophr. Res. 3(2), 127–129 (1990).
- 21. . The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia. Am. J. Psychiatry 166(9), 1055–1062 (2009).
- 22. . Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia. Psychiatry Res. 204(2-3), 61–67 (2012).
- 23. . Association of anticholinergic load with impairment of complex attention and memory in schizophrenia. Am. J. Psychiatry 161(1), 116–124 (2004).
- 24. Antipsychotic medications: linking receptor antagonism to neuropsychological functioning in first episode psychosis. J. Int. Neuropsychol. Soc. 18(4), 717–727 (2012).
- 25. The impact of medication anticholinergic burden on cognitive performance in people with schizophrenia. J. Clin. Psychopharmacol. 37(6), 651–656 (2017).
- 26. Anticholinergic burden and cognition in older patients with schizophrenia. J. Clin. Psychiatry 78(9), e1284–e1290 (2017).
- 27. Is cognitive impairment associated with antipsychotic dose and anticholinergic equivalent loads in first-episode psychosis? Psychol. Med. 48(13), 2247–2256 (2018).
- 28. The effect of anticholinergic burden on cognitive and daily living functions in patients with schizophrenia. Asian J. Psychiatr. 46, 111–117 (2019).
- 29. Anticholinergic medication burden-associated cognitive impairment in schizophrenia. Am. J. Psychiatry 178(9), 838–847 (2021).
- 30. . Impact of anticholinergics on the aging brain: a review and practical application. Aging health 4(3), 311–320 (2008).
- 31. . The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch. Intern. Med. 168(5), 508–513 (2008).
- 32. Relationships between a new cultured cell-based serum anticholinergic activity assay and anticholinergic burden scales or cognitive performance in older adults. Am. J. Geriatr. Psychiatry 29(12), 1239–1252 (2021).
- 33. . Measures of anticholinergic drug exposure, serum anticholinergic activity, and all-cause postdischarge mortality in older hospitalized patients with hip fractures. Am. J. Geriatr. Psychiatry 21(8), 785–793 (2013).
- 34. . Anticholinergic drug use, serum anticholinergic activity, and adverse drug events among older people: a population-based study. Drugs Aging 30(5), 321–330 (2013).
- 35. . Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC Geriatr. 15, 31 (2015).
- 36. The impact of anticholinergic burden on functional capacity in persons with schizophrenia across the adult life span. Schizophr. Bull. 47(1), 249–257 (2021).
- 37. . Influence of antipsychotic and anticholinergic loads on cognitive functions in patients with schizophrenia. Schizophr. Res. Treatment 2016, 8213165 (2016).
- 38. . The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J. Psychopharmacol. 20(3), 335–346 (2006).
- 39. . A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol. Psychiatry 55(10), 1013–1022 (2004).
- 40. . The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr. Bull. 25(2), 201–222 (1999).
- 41. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST). Am. J. Psychiatry 166(6), 675–682 (2009).
- 42. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry 64(6), 633–647 (2007).
- 43. . Emerging 5-HT receptor antagonists for the treatment of schizophrenia. Expert Opin. Emerg. Drugs 25(2), 189–200 (2020).
- 44. . 5-HT6 receptor antagonists: potential efficacy for the treatment of cognitive impairment in schizophrenia. Curr. Pharm. Des. 21(26), 3739–3759 (2015).
- 45. . Serotonergic mechanisms as targets for existing and novel antipsychotics. Handb. Exp. Pharmacol. (212), 87–124 (2012).
- 46. The effect of antipsychotics on the cognitive performance of individuals with psychotic disorders: network meta-analyses of randomized controlled trials. Neurosci. Biobehav. Rev. 126, 265–275 (2021).
- 47. . Psychopharmacologic and clinical correlates of attention in chronic schizophrenia. Am. J. Psychiatry 142(4), 497–499 (1985).
- 48. . Relationships between medication treatments and neuropsychological test performance in schizophrenia. Psychiatry Res. 37(3), 297–308 (1991).
- 49. Antipsychotic medication and cognitive function in schizophrenia. Schizophr. Res. 86(1-3), 138–146 (2006).
- 50. . Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with schizophrenia and schizoaffective disorder. J. Psychopharmacol. 24(7), 1037–1044 (2010).
- 51. Doubtful association of antipsychotic polypharmacy and high dosage with cognition in chronic schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 34(7), 1333–1341 (2010).
- 52. . Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use. PLOS ONE 3(9), e3150 (2008).
- 53. . Pharmacological treatment effects on eye movement control. Brain Cogn. 68(3), 415–435 (2008).
- 54. . Effects of sertraline on autonomic and cognitive functions in healthy volunteers. Psychopharmacology 168(3), 293–298 (2003).
- 55. . SSRIs and cognitive performance in a working sample. Hum. Psychopharmacol. 20(8), 561–572 (2005).
- 56. . Commonly prescribed drugs associate with cognitive function: a cross-sectional study in UK Biobank. BMJ Open 6(11), e012177 (2016).
- 57. . Cognitive side effects of anticonvulsants. J. Clin. Psychiatry 62(Suppl. 14), 27–33 (2001).
- 58. Serum concentrations of mood stabilizers are associated with memory, but not other cognitive domains in psychosis spectrum disorders; explorative analyses in a naturalistic setting. Int. J. Bipolar. Disord. 4(1), 24 (2016).
- 59. Long-term benzodiazepine prescription during maintenance therapy of individuals with psychosis spectrum disorders-associations with cognition and global functioning. Clin. Neuropharmacol. 44(3), 89–93 (2021).
- 60. Benzodiazepines: risks and benefits. A reconsideration. J. Psychopharmacol. 27(11), 967–971 (2013).
- 61. . Concomitant medication of psychoses in a lifetime perspective. Hum. Psychopharmacol. 26(4-5), 322–331 (2011).
- 62. Impact of polygenic risk for coronary artery disease and cardiovascular medication burden on cognitive impairment in psychotic disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 113, 110464 (2022).
- 63. . Chemistry of the adaptive mind. Philos. Trans. A Math. Phys. Eng. Sci. 362(1825), 2871–2888 (2004).
- 64. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98(12), 6917–6922 (2001).
- 65. . The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav. 5(4), 311–328 (2006).
- 66. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol. Psychiatry 52(7), 701–707 (2002).
- 67. Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin card sorting test. Arch. Gen. Psychiatry 59(7), 662–663 (2002).
- 68. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch. Gen. Psychiatry 60(9), 889–896 (2003).
- 69. . Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol. Psychiatry 10(3), 229, 287–298 (2005).
- 70. . Association study of a functional catechol-O-methyltransferase genetic polymorphism with age of onset, cognitive function, symptomatology and prognosis in chronic schizophrenia. Neuropsychobiology 49(4), 196–200 (2004).
- 71. Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis. Schizophr. Res. 202, 212–216 (2018).
- 72. Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. Psychopharmacology 232(1), 145–154 (2015).
- 73. Catechol-O-methyltransferase genotype differentially contributes to the flexibility and stability of cognitive sets in patients with psychotic disorders and their first-degree relatives. Schizophr. Res. 223, 236–241 (2020).
- 74. . Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin card sort test in schizophrenia and healthy controls. Mol. Psychiatry 12(5), 502–509 (2007).
- 75. . Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2(1), 24–32 (2001).
- 76. The BDNF Val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2), 257–269 (2003).
- 77. . Effect of the BDNF Val66Met genotype on episodic memory in schizophrenia. Schizophr. Res. 77(2-3), 355–356 (2005).
- 78. Association between BDNF Val66met genotype and episodic memory. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B(1), 73–75 (2005).
- 79. . A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci. Biobehav. Rev. 51, 15–30 (2015).
- 80. . Association between BDNF Val66Met polymorphism and cognitive performance in antipsychotic-naïve patients with schizophrenia. J. Mol. Neurosci. 47(3), 505–510 (2012).
- 81. Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum. Genet. 131(7), 1187–1195 (2012).
- 82. . Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch. Gen. Psychiatry 63(7), 731–740 (2006).
- 83. . The cognitive genetics of neuropsychiatric disorders. Curr. Top. Behav. Neurosci. 12, 579–613 (2012).
- 84. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat. Commun. 9(1), 2098 (2018).
- 85. GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium. Mol. Psychiatry 22(3), 336–345 (2017).
- 86. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510), 421–427 (2014).
- 87. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat. Genet. 43(10), 977–983 (2011).
- 88. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat. Genet. 43(10), 969–976 (2011).
- 89. Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia. Schizophr. Res. 201, 393–399 (2018).
- 90. Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 183(3), 181–194 (2020).
- 91. Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders. Neuropsychopharmacology 46(10), 1802–1810 (2021).
- 92. Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol. Psychiatry 19(2), 168–174 (2014).
- 93. Predicting cognitive executive functioning with polygenic risk scores for psychiatric disorders. Behav. Genet. 47(1), 11–24 (2017).
- 94. Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls. Transl. Psychiatry 8(1), 78 (2018).
- 95. The relationship between polygenic risk scores and cognition in schizophrenia. Schizophr. Bull. 46(2), 336–344 (2020).
- 96. . Polygenic risk scores shed light on the relationship between schizophrenia and cognitive functioning: review and meta-analysis. J. Clin. Med. Res. 9(2), 341 (2020).
- 97. Epigenetics of schizophrenia. Psychiatry Res. 305, 114218 (2021).
- 98. Altered neural signaling and immune pathways in peripheral blood mononuclear cells of schizophrenia patients with cognitive impairment: a transcriptome analysis. Brain Behav. Immun. 53, 194–206 (2016).
- 99. . Uncovering molecular biomarkers that correlate cognitive decline with the changes of hippocampus' gene expression profiles in Alzheimer's disease. PLOS ONE 5(4), e10153 (2010).
- 100. Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function. Mol. Psychiatry 26(11), 6926–6936 (2021).
- 101. The search for new biomarkers for cognition in schizophrenia. Schizophr. Res. Cogn. 2(4), 172–178 (2015).
- 102. . Inflammation subtypes and translating inflammation-related genetic findings in schizophrenia and related psychoses: a perspective on pathways for treatment stratification and novel therapies. Harv. Rev. Psychiatry 30(1), 59–70 (2022).
- 103. . Distinct effects of inflammation on cytochrome P450 regulation and drug metabolism: lessons from experimental models and a potential role for pharmacogenetics. Genes 11(12), 1509 (2020).