Olfactory Impairment and Depression: A Systematic Review and Meta-Analysis

Depression and olfactory impairment are both highly prevalent in older adults and associated with poor quality of life, cognitive decline, and increased mortality. Clarifying their association could identify olfactory dysfunction as a potential marker of late-life depression.

To quantify the association of objective olfactory impairment (OOI) and subjective olfactory impairment (SOI) with subjectively and/or objectively determined depression in population-based studies, and to examine potential moderators.

PubMed, Embase, EBSCOhost, and Web of Science were searched from inception to July 11, 2024, without language restrictions. Reference lists of relevant publications were screened manually.

Eligible studies included population-based cross-sectional or longitudinal investigations of the association between OOI or SOI and depression in adults in the general population. Two reviewers independently applied inclusion criteria and resolved disagreements by consensus.

Data were extracted independently by 2 reviewers in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Risk of bias was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analyses were performed separately for OOI and SOI. Heterogeneity and publication bias were evaluated.

Odds ratios (ORs) and 95% CIs for the association between OOI or SOI and depression.

A total of 23 studies representing 17 independent cohorts (N = 187 056 individuals; mean [SD] age, 63.6 [16.4] years; 63% female) were included. After excluding nonindependent cohorts, 7 and 11 independent studies remained for the primary analyses of SOI and OOI, respectively. SOI was associated with depression across the 7 studies (OR, 1.56 [95% CI, 1.19-2.05]; I2 = 79%). The association remained robust in low risk of bias studies (OR, 1.71 [95% CI, 1.18-2.46]), across age groups, and for subjective and objective depression. OOI showed an association with objective depression across the 11 studies (OR, 1.26 [95% CI, 1.02-1.56]; I2 = 53%) that attenuated after publication bias adjustment (OR, 1.12 [95% CI, 0.87-1.44]) but remained robust in older adults (≥65 years) and individuals with anosmia.

In this systematic review and meta-analysis, SOI showed a consistent, moderate association with depression, likely reflecting negative self-perception and/or the evaluation of one's own olfactory decline rather than comparison with population norms. OOI is less consistently associated with objective depression but appears to be relevant in specific subgroups, particularly older and anosmic individuals, suggesting partially overlapping mechanisms in late life. Longitudinal and mechanistic studies are needed to clarify causal pathways. Clinicians should be aware of the observed associations, although their clinical implications remain to be further established.