Study Discovers Constipation Has a Causal Relationship with Schizophrenia, MDD

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A study found schizophrenia and major depressive disorder (MDD) increase the risk of constipation, but the association with schizophrenia may only have limited clinical implications.¹

“Similar to previous studies, the risk of constipation was higher in participants with severe depression than in participants with mild depression,” wrote investigators, led by Jiali Liu, from the department of anorectal surgery at Affiliated Hospital of Nanjing University of Chinese Medicine, in People’s Republic of China.

Constipation, although common, is one of the most difficult diseases to diagnose and treat. According to the American Gastroenterological Association, 16% of adults face constipation. This gastrointestinal disorder has a greater prevalence in older adults, females, certain medications, and mental diseases.

Observational studies have shown the link between constipation and psychiatric disorders, namely anxiety and depression, but these studies did not examine the causal effects between the conditions.² Thus, investigators completed a Mendelian randomization analysis to assess whether constipation and psychiatric disorders—in this case, schizophrenia and MDD—had a causal relationship.¹ The study’s exposures were schizophrenia and MDD, and constipation was the outcome.

The team recruited patients with schizophrenia (30,490 cases and 312,009 controls) and MDD (170,756 cases and 329,443 controls) from Psychiatric Genomics Consortium datasets of European ancestry. Constipation genetic data (17,246 cases and 201,546 controls) was obtained from The FinnGen summary statistics.

Investigators used the inverse variance weighted (IVW) method to assess the causal relationship between schizophrenia and MDD with constipation. The LD score regression showed constipation was genetically correlated with schizophrenia and MDD (both P < .05).

The Mendelian randomization analysis further demonstrated that schizophrenia (IVW odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02 – 1.07; P < .01) and MDD (IVW OR, 1.21; 95% CI, 1.10 – 1.33; P < .01) were statistically significantly causally associated with the risk of constipation. Evidence of the causal relationship between constipation and psychiatric disorders was also shown with the MR Egger ratio (OR, 1.03; 95% CI, 0.93 – 1.16; P = .548 for schizophrenia; OR, 0.92; 95% CI, 0.48 – 1.76; P = .794 for MDD) and the weighted median odds ratio (OR, 1.05; 95% CI, 1.01 – 1.09; P < .01 for schizophrenia; OR, 1.19; 95% CI, 1.03 – 1.38; P = .02).

“Bidirectional MR analysis revealed an obviously causal effect of depression on constipation, but no causal effect of constipation on depression,” investigators wrote.

However, investigators noted that constipation could aggravate psychotic disorders, as patients with constipation were significantly more likely to experience depression, anxiety, somatization, and psychotic disorders.

The Cohran’s Q report did not show heterogeneity among these inverse variances for both schizophrenia (P = .11 > .05) and MDD (P = .09 > .05). Investigators also observed no horizontal pleiotropy in the Egger intercept test for schizophrenia (P = .81) and MDD (P = .39).

Despite schizophrenia having a statistically significant confidence interval of 1.02 – 1.07 (P < .01), it fell within the Region of Bayesian analysis and the Practical Equivalence (ROPE), which defines an odds ratio range of 0.83 – 1.19 as a lack of clinical significance.

“This suggested that the hypothesized pathophysiological links between [schizophrenia] and constipation conditions were not substantiated by our data, prompting a reevaluation of their clinical implications,” investigators wrote.

Liu and colleagues said the study was limited by only examining the Psychiatric Genomics Consortium and FinnGen populations. Moreover, they added that they only examined schizophrenia and MDD due to the unavailable data on other psychiatric disorders and future studies should include other mental conditions.

“In conclusion, we performed MR analysis concluding that there is suggestive evidence that [schizophrenia] and MDD potentially cause constipation,” investigators wrote. “However, [schizophrenia] and constipation, largely falling within the ROPE range, underscore a lack of clinical significance, and further confirmation is needed in conjunction with clinical studies.”

References

1. ^{Liu J, Huang Y, Fu X, Wei J, Wei P. Associations of Schizophrenia and Major Depressive Disorder with Constipation: A Mendelian Randomization Study. Clin Exp Gastroenterol. 2024 Nov 26;17:349-357. doi: 10.2147/CEG.S485504. PMID: 39618883; PMCID: PMC11608058.}
2. ^{Nellesen D, Chawla A, Oh DL, et al. Comorbidities in patients with irritable bowel syndrome with constipation or chronic idiopathic constipation: a review of the literature from the past decade. Postgrad Med. 2013;125:40–50. doi:10.3810/pgm.2013.03.2640}