This study examines the association between insulin resistance, schizophrenia polygenic risk, and treatment outcomes in first-episode, antipsychotic-naive patients with schizophrenia.Funding/Support: This work was supported by grants from the Stanley Medical Research Institute (Dr Bahn)

Bahn, Sabine

Crespo Facorro, Benedicto

Lago, Santiago G.

Papiol, Sergi

Suárez Pinilla, Paula

Tomasik, Jakub

Vázquez Bourgon, Javier

JAMA Psychiatry

English

UCrea

14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 1/10JAMA Psychiatry. 2019 Aug; 76(8): 864–867.Published online 2019 Apr 3.doi: 10.1001/jamapsychiatry.2019.0304: 10.1001/jamapsychiatry.2019.0304PMCID: PMC6583823PMID: 30942838Association of Insulin Resistance With Schizophrenia Polygenic RiskScore and Response to Antipsychotic TreatmentJakub Tomasik, PhD,  Santiago G. Lago, PhD,  Javier Vázquez-Bourgon, MD, PhD,  Sergi Papiol, PhD,Paula Suárez-Pinilla, MD, PhD,  Benedicto Crespo-Facorro, MD, PhD,  and Sabine Bahn, MD, PhDDepartment of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, EnglandUniversity Hospital Marqués de Valdecilla, IDIVAL, Department of Psychiatry, School of Medicine, University ofCantabria, Santander, SpainCentro de Investigación Biomédica en Red de Salud Mental, Santander, SpainValdecilla Biomedical Research Institute, Santander, SpainCentro de Investigación Biomédica en Red de Salud Mental, Barcelona, SpainInstitute of Psychiatric Phenomics and Genomics, University Hospital, Ludwig Maximilian University, Munich,GermanyDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University, Munich,GermanyCorresponding author.Article InformationCorresponding Author: Sabine Bahn, MD, PhD, Department of Chemical Engineering and Biotechnology,University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, England (sb209@cam.ac.uk).Accepted for Publication: January 6, 2019.Published Online: April 3, 2019. doi:10.1001/jamapsychiatry.2019.0304Author Contributions: Dr Tomasik had full access to all the data in the study and takes responsibility for theintegrity of the data and the accuracy of the data analysis. Drs Crespo-Facorro and Bahn contributed equally to thiswork.Study concept and design: Tomasik, Lago, Crespo-Facorro, Bahn.Acquisition, analysis, or interpretation of data: All authors.Drafting the manuscript: Tomasik, Lago, Bahn.Critical revision of the manuscript for important intellectual content: All authors.Statistical analysis: Tomasik.Administrative, technical, or material support: Crespo-Facorro, Bahn.Study supervision: Crespo-Facorro, Bahn.Conflict of Interest Disclosures: Dr Tomasik was a consultant for Psynova Neurotech, Ltd, until April 2016. DrLago was part funded by Psynova Neurotech Ltd until October 2015. Dr Bahn is a director of Psynova NeurotechLtd and Psyomics Ltd. No other disclosures were reported.Funding/Support: This work was supported by grants from the Stanley Medical Research Institute (Dr Bahn).Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.1 1 2,3,4 5,6,72,3 2,3,4 11234567JAMA Psychiatry14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 2/10Additional Contributions: We are grateful to the individuals who participated in the study for sample donation andthe technical and clinical support staff at the affiliated institutions for collection of samples, clinical data, andtechnical support. Participants were not compensated by the funding sponsor for their contribution.Received 2018 Oct 9; Accepted 2019 Jan 6.Copyright 2019 American Medical Association. All Rights Reserved.This study examines the association between insulin resistance, schizophrenia polygenic risk, andtreatment outcomes in first-episode, antipsychotic-naive patients with schizophrenia.Patients with schizophrenia show an increased risk of impaired glucose metabolism,  yet the mechanismbehind this association remains unknown. Multiple studies have attempted to identify the determinants ofinsulin resistance (IR) in schizophrenia, with evidence suggesting that it cannot be fully explained bydisease duration, symptom severity, medication effects, obesity, or hormonal stress axis activation, andother interacting factors are likely involved.  While family and genome-wide association studies havesuggested a shared genetic vulnerability between schizophrenia and abnormal glucose metabolism,  to ourknowledge, a direct link between schizophrenia genetic risk and insulin resistance has not beeninvestigated. Here, we examine the association between IR, schizophrenia polygenic risk, and treatmentoutcomes in first-episode, antipsychotic-naive patients with schizophrenia and matched healthy individualswhile controlling for demographic, lifestyle, and clinical factors.MethodsFirst-episode, antipsychotic-naive patients with schizophrenia and matched unaffected control individuals(58 patients with schizophrenia and 58 control individuals; Table) were recruited at the University HospitalMarqués de Valdecilla (Santander, Spain) as described previously.  The study procedures were approvedby the medical faculty ethical committee, and written informed consent was obtained from all studyparticipants. Schizophrenia polygenic risk scores (PRS) were calculated based on 108 genome-widesignificant schizophrenia loci  from the Illumina Infinium PsychArray Bead-Chip genotyping dataimputed using IMPUTE2/SHAPEIT. The updated Homeostasis Model Assessment (HOMA2)  was usedto infer IR, β cell function, and insulin sensitivity from clinical measurements of fasting serum glucose andinsulin levels. Switching antipsychotic medication at least once during the initial 12 months of treatmentwas used as a heuristic long-term treatment outcome measure. All statistical tests were 2-sided and aredescribed in figure legends. A P value of less than .05 was considered significant. Analyses wereconducted in R, version 3.5.0 (R Foundation).ResultsConsistent with previous reports,  patients with schizophrenia showed increased baseline HOMA2-IR(mean difference [MD] [SE], 0.68 [0.25]; P = .004), HOMA2 β-cell function (MD [SE], 32.2 [13.1]; P = .02), and fasting insulin levels (MD [SE], 5.5 [2.1] μIU/mL [to convert to picomoles per liter, multiplyby 6.945]; P = .004), whereas HOMA2 insulin sensitivity (MD [SE], −19.6 [15.5]; P = .20) and fastingglucose levels (MD [SE], 0.6 [2.0] mg/dL [to convert to millimoles per liter, multiply by 0.0555]; P = .76)did not differ significantly from control values (Table). After adjusting for covariates, HOMA2-IRremained significantly increased in patients with schizophrenia (MD [SE], 0.82 [0.25]; P < .001, adjustedfor body mass index; Figure, A). The HOMA2-IR was positively associated with schizophrenia PRS inpatients with schizophrenia (β [SE], 3.74 [1.68]; P = .02, adjusted for age; Figure, B) but not in the controlgroup (adjusted β [SE], 0.29 [0.40]; P = .45), where body mass index was the most significant risk factor(adjusted β [SE], 0.071 [0.018]; P < .001). Baseline HOMA2-IR was significantly associated withswitching antipsychotic medication during the initial 12 months of treatment, with an adjusted odds ratio(OR) of 1.77 (95% CI, 1.10-3.52; P = .02, adjusted for ethnicity; Figure, C). Of the 41 patients for whomcomplete follow-up information was available, all 8 patients who at baseline satisfied the fasting insulin1123451614/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 3/10criteria for IR (≥25 μIU/mL)  required changing medication within the first year of treatment.Schizophrenia PRS was not significantly associated with medication switching status (adjusted OR, 183;95% CI, 0.48-504 931; P = .12).DiscussionWe report that schizophrenia polygenic risk is significantly associated with insulin resistance in first-episode, antipsychotic-naive patients with schizophrenia independent from selected demographic, lifestyle,and clinical factors. This result suggests that IR is a hallmark of schizophrenia rather than a secondaryeffect of emerging symptoms and supports the hypothesis that multiple susceptibility genes might exertpleiotropic effects cooccurring between the 2 conditions. Furthermore, the results indicate a potentialassociation of IR with diminished response to antipsychotic treatment. Hence, patients with schizophreniapresenting with IR might constitute a distinct patient subgroup and require personalized treatment tailoredto this endophenotype.LimitationsLimitations of this study include incomplete metadata for subsets of clinical variables and the fact thatalthough nonresponse was the primary factor influencing medication switching, other clinical variables,such as adverse effects and treatment nonadherence, cannot be excluded in a minority of cases. Well-powered pharmacogenomic studies and more specific assays, such as the oral glucose tolerance andcortisol tests,  are required to further examine the association between IR, schizophrenia, andantipsychotic treatment response, in addition to determining the effects of other lifestyle factors such asdiet and exercise.References1. Pillinger T, Beck K, Gobjila C, Donocik JG, Jauhar S, Howes OD. Impaired glucose homeostasis infirst-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(3):261-269. doi:10.1001/jamapsychiatry.2016.3803 [PMCID: PMC6352957] [PubMed: 28097367] [CrossRef:10.1001/jamapsychiatry.2016.3803]2. Chouinard VA, Henderson DC, Dalla Man C, et al. . Impaired insulin signaling in unaffected siblingsand patients with first-episode psychosis. Mol Psychiatry. 2018. doi:10.1038/s41380-018-0045-1[PMCID: PMC6129440] [PubMed: 29523870] [CrossRef: 10.1038/s41380-018-0045-1]3. Lago SG, Tomasik J, van Rees GF, et al. . Exploring the neuropsychiatric spectrum using high-contentfunctional analysis of single-cell signaling networks. Mol Psychiatry. 2018. doi:10.1038/s41380-018-0123-4 [PubMed: 30038233] [CrossRef: 10.1038/s41380-018-0123-4]4. Ripke S, Neale BM, Corvin A, et al. ; Schizophrenia Working Group of the Psychiatric GenomicsConsortium . Biological insights from 108 schizophrenia-associated genetic loci. Nature.2014;511(7510):421-427. doi:10.1038/nature13595 [PMCID: PMC4112379] [PubMed: 25056061][CrossRef: 10.1038/nature13595]5. Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation usesthe computer program. Diabetes Care. 1998;21(12):2191-2192. doi:10.2337/diacare.21.12.2191 [PubMed:9839117] [CrossRef: 10.2337/diacare.21.12.2191]6. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. Williams Textbook of Endocrinology. 12th edPhiladelphia, PA: Elsevier Saunders; 2011.Figures and Tables6114/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 4/1014/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 5/10Table.Demographic and Clinical Data of Study Participants14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 6/10Open in a separate windowAbbreviations: %B, beta cell function (%); BMI, body mass index (calculated as weight in kilograms divided byheight in meters squared); BPRS, Brief Psychiatric Rating Scale; HOMA2, the updated Homeostasis ModelAssessment; IR, insulin resistance; NA, not applicable; PRS, schizophrenia polygenic risk score; SANS, Scale for theAssessment of Negative Symptoms; SAPS, Scale for the Assessment of Positive Symptoms; %S, insulin sensitivity(%).SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; insulin to picomoles per liter,multiply by 6.945.Data were analyzed using t test for continuous variables and Fisher exact test or χ  test for categorical variables. Pvalues were obtained by permutation testing (N = 1000 permutations).Significant (<.05) P value.Characteristic No. (%) PValueMissing, No. (%)Control (n = 58)Schizophrenia (n = 58)Control Schizophrenia       SexMale 35 (60) 36 (62)>.99 NA NAFemale 23 (40) 22 (38)Age, mean (SD), y 31.8 (7.6) 29.5 (8.5) .15 NA NABMI, mean (SD) 24.4 (3.7) 23.0 (5.0) .07 NA NARace/ethnicityWhite 58 (100) 52 (90).03 NA NAHispanic 0 (0) 5 (9)Romani 0 (0) 1 (2)SmokingNo 28 (48) 25 (43).73 NA NAYes 30 (52) 33 (57)AlcoholNo 42 (72) 28 (48).02 NA NAYes 16 (28) 30 (52)CannabisNo 44 (76) 32 (55).04 NA NAYes 14 (24) 26 (45)Family history of diabetesNo 3 (5) 26 (45).04 49 (84) 22 (38)Yes 6 (10) 10 (17)Family history of psychiatricdiseaseNo 58 (100) 45 (78)<.001 NA NAYes 0 13 (22)Previous psychiatric medicationNo 58 (100) 45 (78)<.001 NA NAYes 0 (0) 13 (22)Age at onset of psychosis, mean(SD), yNA 28.4 (8.4)NA NA 1 (2)First antipsychoticAripiprazole NA 28 (48)NA NA NAOl i NA 1 (2)abccbcbbdcbefa 2b14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 7/10Self-reported.Assessed using the Comprehensive Assessment of Symptoms and History.Antidepressant; mean (SD) duration, 7.8 (8.3) days.Antipsychotic treatment was initiated after baseline data collection and used for determining switching medicationstatus in Figure, C.Based on the fasting insulin criteria (≥25 μIU/mL).cdefg14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 8/1014/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 9/10Figure.Open in a separate windowAnalysis of the Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR) in First-Episode, Antipsychotic-Naive Patients With Schizophrenia and Healthy Control Individuals.A, Association of HOMA2-IR with clinical status. B, Association of HOMA2-IR with the 108 loci schizophreniapolygenic risk score. C, Association of antipsychotic drug switching during the initial 12 months of treatment withbaseline HOMA2-IR. Plots show adjusted mean with standard error (A) and marginal effects with 95% confidenceintervals (B and C). Statistical tests included analysis of covariance (A) and multivariable linear (B) and logistic (C)regression. Covariates were selected using bidirectional elimination and Bayesian information criterion from age, sex,body mass index, race/ethnicity, smoking, alcohol consumption, cannabis use, and previous psychiatric medication (A-C);baseline Brief Psychiatric Rating Scale, Scale for the Assessment of Positive Symptoms, and Scale for the Assessment ofNegative Symptoms scores (B; schizophrenia group); and the initial treatment drug (C). Only cases with complete datawere analyzed. P values were obtained by permutation testing (1000 permutations). P less than .05 was consideredsignificant. Numbers: A, 54 control individuals and 56 patients with schizophrenia; B, 53 control individuals and 49patients with schizophrenia; C, 20 patients with schizophrenia with no drug switch and 21 patients with schizophreniawith drug switch (13 owing to low efficacy, 5 owing to adverse effects, and 3 owing to noncompliance).P < .001.ab14/7/2020 Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatmenthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583823/?report=printable 10/10P < .05.b

Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatment

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Association of Insulin Resistance With Schizophrenia Polygenic Risk Score and Response to Antipsychotic Treatment

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