Associations Between Polygenic Risk Score Loading, Psychosis Liability, and Clozapine Use Among Individuals With Schizophrenia

Abstract

ImportancePredictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices.ObjectiveTo examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics.Design, Setting, and ParticipantsThis genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022.ExposuresPolygenic risk scores for SCZ.Main Outcomes and MeasuresMultinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics.ResultsPolygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RRs were significantly different from 1; RRs were highest for individuals with SSD taking clozapine (RR, 3.24; 95% CI, 2.76-3.81; P = 2.47 × 10−46), followed by individuals with SSD taking other antipsychotics (RR, 2.30; 95% CI, 1.95-2.72; P = 3.77 × 10−22), parents (RR, 1.44; 95% CI, 1.25-1.68; P = 1.76 × 10−6), and siblings (RR, 1.40; 95% CI, 1.21-1.63; P = 8.22 × 10−6). Polygenic risk scores for SCZ were positively associated with clozapine vs other antipsychotic use (OR, 1.41; 95% CI, 1.22-1.63; P = 2.98 × 10−6), suggesting a higher likelihood of clozapine prescriptions among individuals with higher PRS-SCZ.Conclusions and RelevanceIn this study, PRS-SCZ loading differed between groups of individuals with SSD, their relatives, and unrelated healthy controls, with patients taking clozapine at the far end of PRS-SCZ loading. Additionally, PRS-SCZ was associated with a higher likelihood of clozapine prescribing. Our findings may inform early intervention and prognostic studies of the value of using PRS-SCZ to personalize antipsychotic treatment.

Pharmacogenomic scores in psychiatry: Systematic review of existing evidence

“…It is important to highlight that in most of the reviewed studies, high PGSSCZ was associated with poor treatment response 32–34, 37, 38, 40, 41, 43, 45–47 , more treatment resistance 31, 35, 36, 42, 44 , more antipsychotics-induced side effects 48–50 or more psychiatric hospitalizations 39 . A notable exception was a positive association with lower symptom burden in SCZ patient treated with clozapine 38 .…”

“…Table 1 provides a summary of the findings extracted from each of the articles included in this systematic review (Table 1). Several studies (20 studies) revealed that individuals with higher genetic loading for SCZ had a poorer treatment outcome to psychiatric medications [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50] , while the remaining studies didn't find significant associations. For example, in patients with SCZ, a negative correlation (r = -0.05[95%CI: -0.09 --0.01]) was found between PGSSCZ and response to second generation antipsychotics (olanzapine, aripiprazole, risperidone, quetiapine, haloperidol, ziprasidone, perphenazine) following six weeks treatment 34 dosing (>600 mg/day) suggesting that individuals with a higher PGSSCZ may require increased doses of clozapine to achieve effective treatment response 33 .…”

The ever-growing case for clozapine in the treatment of schizophrenia: an obligation for psychiatrists and psychiatry

“…Currently, personalized medicine approaches aim to optimize clozapine treatment further. These include developing predictive markers for treatment resistance [29 ▪▪ ,79,80 ▪▪ ], clozapine response [4 ▪ ,81,82], and adverse effects – especially agranulocytosis and myocarditis [83 ▪ ,84 ▪ ] – as well as individualizing dosing and switching regimes [85 ▪ ,86 ▪ ]. Moreover, studies designed to conclusively determine, whether clozapine might have disease-modifying properties and slow illness progression, when used very early [4 ▪ ], are urgently needed.…”

An international research agenda for clozapine-resistant schizophrenia

“…Initial research into the potential diagnostic value shows that patients on clozapine have higher schizophrenia-PRSs than patients on other antipsychotic drugs during follow-up. 48 If this finding is confirmed in additional cohorts, PRSs could help identify individuals who might benefit from clozapine and thus ensure that clozapine treatment is started at the appropriate time. Given evidence of the increased likelihood of remission following ECT and clozapine treatments in patients with high schizophrenia PRSs, 49,50 future studies of clozapine-resistant schizo phrenia might uncover associations between PRSs and specific symptom domain improvements following augmentation strategies.…”