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Antihypertensive Drug That Targets Genes May Increase Schizophrenia Risk

March 30, 2021

mark munger, pharmdPsychiatric disease affects approximately 51 million U.S. citizens (20.6% of U.S. Adults) per year.1 Schizophrenia is a chronic severe neurological brain disorder estimated to affect 1.1 percent of the population or approximately 2.6 million adults in the United States aged 18 or older. An estimated 40% of individuals with the schizophrenia are untreated.2 Cardiovascular morbidity and mortality are elevated in schizophrenic patients, primarily due to higher incidence of risk factors and less effective treatment management processes.3 Importantly, a shared pathophysiology may contribute to this association.  A recent genome-wide association study (GWAS) in bipolar disease has identified the CACNA1C gene, which encodes a protein that is the target of calcium channel blockers.4 In addition, a study has reported associations between antihypertensive medications and psychiatric disorders-but with different directionality based on drug class.5 Because directionality is different, perhaps drug class is more important to this association than actual blood pressure reduction drug effects.  

To this question, a Mendelian randomization study has assessed the association between single-nucleotide variant (SNV) and drug target gene expression from expression quantitative trait) loci data (eQTLs) and SNV-disease association from published GWAS studies.6 The study had 40,675 patients with schizophrenia (64, 643 controls), 20,352 patients with bipolar disorder (31,358 controls), and 135, 458 patients with major depressive disorder (344,901 controls). Blood eQTLs were measured in 31,684 persons from 37 cohorts between 10/4/2019 and 06/01/2020.  A 1-SD lower expression of the angiotensin-converting enzyme (ACE) gene in blood was associated with lower SBP (mmHg) (-4.0; 95% CI: 2.7-5.3).  An increased risk of schizophrenia odds ratio (OD) of 1.75 (95% CI: 1.28-2.38). 

These findings suggest an adverse reaction of ACE messenger RNA and protein levels which increase schizophrenia risk.  Careful observation of patients being treated with ACEi based on salt classification may be warranted in patients with active symptoms or with a family history of schizophrenia.

Mark A. Munger, PharmD, FCCP, FACC, is a professor of pharmacotherapy and adjunct professor of internal medicine, at the University of Utah, where he also serves as the associate dean of Academic Affairs for the College of Pharmacy.

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  1. Mental Illness.  Accessed 03/2021
  2. Schizophrenia Fact Sheet.   Accessed 03/2021
  3. Ayerbe L, Forgnone I, Addo J, Siguero A, Gelati S, Ayis S.  Hypertension risk and clinical care in patients with biopolar disorder or schizophrenia: a systematic review and meta-analysis.  J Affect Disord 2018;225:665-70. 
  4. Ferreira MAR, O’Conovan MC, Meng YA, et al. Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008;40(9):1056-8.
  5. Boal AH, Smith DJ, McCallum L, et al. Monotherapy with major antihypertensive drug classes and risk of hospital admissions for mood disorders. Hypertension 2016;68(5):1132-8.
  6. Chauquet S, Zhu Z, O’Donovan MC, Walters JTR, Wray NR, Shah S. Association of antihypertensive drug target genes with pscyhiatric disorders. JAMA Pscyhiatry 2021; published March 10, 2021. doi:10.1001/jamapschiatry.2021.0005

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