{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:02:49Z","timestamp":1785225769838,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The adenosine hypothesis of schizophrenia provides an integrative framework in which reduced adenosinergic signalling contributes to dopaminergic hyperactivity and glutamatergic hypofunction. Enzymes regulating purine metabolism, including inosine triphosphatase (ITPA), adenosine monophosphate deaminase 1 (AMPD1), and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase\/IMP cyclohydrolase (ATIC), may influence adenosine availability and thereby modulate disease susceptibility and treatment response. As part of a pilot pharmacogenetic investigation, we investigated whether functional polymorphisms in these genes are associated with schizophrenia risk, treatment resistance, and symptom severity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A total of 249 patients with schizophrenia (including 47 with treatment-resistant schizophrenia - TRS) and 93 healthy controls were genotyped for\n                      <jats:italic>ITPA<\/jats:italic>\n                      rs1127354,\n                      <jats:italic>AMPD1<\/jats:italic>\n                      rs17602729, and\n                      <jats:italic>ATIC<\/jats:italic>\n                      rs2372536 in this exploratory, hypothesis-generating study. Case-control and TRS analyses were conducted using \u03c7\n                      <jats:sup>2<\/jats:sup>\n                      tests and logistic regression with Bonferroni correction. Symptom severity (BPRS), global functioning (GAF), and positive and negative symptom subscales were examined using two-way ANOVA with false discovery rate (FDR) adjustment for multiple exploratory comparisons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ITPA<\/jats:italic>\n                      rs1127354 showed a nominally significant recessive association with schizophrenia risk based on a very small genotype count (OR = 0.09, p = 0.033), driven by rare AA homozygosity, but did not remain significant after Bonferroni correction. No significant case-control associations were observed for AMPD1 or ATIC. In contrast,\n                      <jats:italic>ATIC<\/jats:italic>\n                      rs2372536 was significantly associated with TRS (\u03c7\n                      <jats:sup>2<\/jats:sup>\n                      = 10.86, p = 0.004; CG vs. CC OR = 2.68, 95% CI 1.20\u20136.55), remaining significant after Bonferroni correction. In exploratory dimensional analyses, uncorrected genotype-related effects were observed for global functioning and overall symptom severity; after FDR adjustment, only the association between\n                      <jats:italic>ATIC<\/jats:italic>\n                      rs2372536 and negative symptoms remained statistically supported at q &amp;lt; 0.10.\n                      <jats:italic>AMPD1<\/jats:italic>\n                      rs17602729 showed associations with overall symptom burden at the unadjusted level.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings provide preliminary evidence that genetic variation in purine metabolism may contribute to clinical heterogeneity in schizophrenia. In particular,\n                      <jats:italic>ATIC<\/jats:italic>\n                      rs2372536 was associated with treatment resistance and negative symptom severity, supporting a potential role of adenosinergic mechanisms in antipsychotic response. Associations with schizophrenia risk and other dimensions were exploratory and require replication in larger, independent cohorts. Integration of genetic data with biochemical measures of purine and adenosine metabolism will be important to establish clinical relevance and support precision-oriented therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1876365","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:46:24Z","timestamp":1785224784000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic variants in purine metabolism and treatment resistance in schizophrenia: evidence supporting the adenosine hypothesis \u2013 a pilot study"],"prefix":"10.3389","volume":"17","author":[{"given":"Milica","family":"Pjevac","sequence":"first","affiliation":[{"name":"Centre for Clinical Psychiatry, University Psychiatric Clinic","place":["Ljubljana, Slovenia"]},{"name":"Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Blagus","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ale\u0161","family":"Oblak","sequence":"additional","affiliation":[{"name":"Centre for Clinical Psychiatry, University Psychiatric Clinic","place":["Ljubljana, Slovenia"]},{"name":"Department of Psychiatry, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Vogrinc","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea","family":"Terzi\u0107","sequence":"additional","affiliation":[{"name":"Centre for Clinical Psychiatry, University Psychiatric Clinic","place":["Ljubljana, Slovenia"]},{"name":"Department of Psychiatry, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurij","family":"Bon","sequence":"additional","affiliation":[{"name":"Centre for Clinical Psychiatry, University Psychiatric Clinic","place":["Ljubljana, Slovenia"]},{"name":"Department of Psychiatry, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vita","family":"Dol\u017ean","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana","place":["Ljubljana, Slovenia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1111\/j.1365-2710.2005.00679.x","article-title":"Allopurinol as an adjunct to haloperidol in chronic schizophrenia: a double-blind, randomized, placebo-controlled trial","volume":"30","author":"Akhondzadeh","year":"2005","journal-title":"J. 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