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[Preprint]. 2024 Apr 4:2024.01.30.24301418.
doi: 10.1101/2024.01.30.24301418.

A vagal influence on schizophrenia? A nationwide retrospective cohort of vagotomized individuals

Cornelia F Richter  1 , Karolina P Skibicka  2   3 , Urs Meyer  1   4 , Sabine Rohrmann  5 , Jean-Philippe Krieger  1   2
Affiliations

A vagal influence on schizophrenia? A nationwide retrospective cohort of vagotomized individuals

Cornelia F Richter et al. medRxiv. .

Abstract

Background and objectives: Emerging preclinical evidence suggests that vagal signals contribute to the development of schizophrenia-related abnormalities in brain and behavior. Whether vagal communication in general, and its impairment in particular, is a risk factor for schizophrenia in humans remains, however, unclear. Vagotomy, the surgical lesion of the vagus nerve, was routinely performed as a treatment for peptic ulcer before modern treatment options were available. Hence, the primary aim of this study was to investigate whether vagotomy modulates the subsequent risk of developing schizophrenia. Moreover, given the existence of diverse vagotomy techniques (i.e., "truncal" or "selective"), our secondary goal was to test whether the extent of denervation modulates the risk of schizophrenia.

Methods: Using a nationwide retrospective matched cohort design, we identified 8,315 vagotomized individuals from the Swedish National Patient Register during the period 1970-2020 and 40,855 non-vagotomized individuals matching for age, sex and type of peptic ulcer. The risk of being diagnosed with schizophrenia and associated psychoses (ICD10 codes F20-29) was analyzed using Cox proportional hazards regression models, including death as competing risk.

Results: When considering all types of vagotomy together, vagotomy was not significantly associated with schizophrenia (HR: 0.91 [0.72; 1.16]). However, truncal vagotomy (which denervates all subdiaphragmatic organs) significantly increased the risk of developing schizophrenia by 69% (HR: 1.69 [1.08; 2.64]), whereas selective vagotomy (which only denervates the stomach) showed no significant association (HR: 0.80 [0.61; 1.04]).

Discussion: Our results provide epidemiological support for the hypothesis that impairments in vagal functions could increase the risk of schizophrenia. Notably, the finding that truncal but not selective vagotomy is associated with an increased risk of schizophrenia raises the possibility that the activity of subdiaphragmatic non-gastric vagal branches may be of particular relevance for the development of schizophrenia.

Keywords: cohort study; gut-brain axis; schizophrenia; ulcer; vagus nerve.

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Conflict of interest statement

5Conflicts of interests The authors have no conflicts to declare.

Figures

Figure 1.
Figure 1.. Flowchart.
NPR = National Patient Registry
Figure 2.
Figure 2.. Cumulative incidence function of schizophrenia among patients with overall vagotomy and matched controls.
Figure 3.
Figure 3.. Cumulative incidence function of schizophrenia among patients with truncal or selective vagotomy and matched controls.
Figure 4.
Figure 4.. Regression Results of Cox proportional hazards model for overall vagotomy and subsequent diagnosis of schizophrenia.
Crude model controlled for age, sex, and controls per case. Adjusted model controlled for age, sex, weighted Charlson Comorbidity Index, ICD-period, controls per case. HR = Hazard Ratio, 95% CI = 95% Confidence Interval. Vertical line: reference value.of 1
Figure 5.
Figure 5.. Regression results of Cox proportional hazards model for selective or truncal vagotomy and subsequent diagnosis of schizophrenia.
Crude model controlled for age, sex, and controls per case. Adjusted model controlled for age, sex, weighted Charlson Comorbidity Index, ICD-period, controls per case. HR = Hazard Ratio, 95% CI = 95% Confidence Interval. Vertical line: reference value of 1
Figure 6:
Figure 6:. Regression results of Cox proportional hazards model for selective or truncal vagotomy and schizophrenia, with follow-up restriction.
Crude model controlled for age, sex, and controls per case. Adjusted model controlled for age, sex, weighted Charlson Comorbidity Index, ICD-period, controls per case. HR = Hazard Ratio, 95% CI = 95% Confidence Interval. Vertical line: reference value of 1
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