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Osvaldo P. Almeida, MD, PhD, FRANZCP; Kieran McCaul, PhD; Graeme J. Hankey, MD, FRACP; Paul Norman, PhD, FRACS; Konrad Jamrozik, MBBS, DPhil; Leon Flicker, MBBS, FRACP, PhD

Arch Gen Psychiatry. 2008;65(11):1286-1294.

Context  The prevalence of depression in later life increases with plasma total homocysteine concentration (tHcy). High tHcy accounts for about 15% of prevalent cases, but observational studies are prone to confounding and bias. Genetic association studies are not prone to the same sources of error and offer an opportunity to explore the consistency and external validity of this association.

Objective  To determine if tHcy is causally related to depression in later life.

Design  Cross-sectional study (Health in Men Study), systematic review, and meta-analysis.

Patients  Community sample of 3752 men aged 70 years or older (Health in Men Study).

Main Outcome Measures  Fifteen-Item Geriatric Depression Scale and self-reported past or current treatment for depression (Health in Men Study).

Results  In the Health in Men Study, the odds ratio (OR) of prevalent depression increased 4% (OR, 1.04; 95% confidence interval [CI], 1.02-1.05) with every unit increase of tHcy (micromoles per liter). The tHcy was 0.19 mg/L higher among participants with the MTHFR C677T TT genotype compared with the CC genotype. The meta-analysis showed that older adults with high tHcy had increased risk of depression (OR, 1.70; 95% CI, 1.38-2.08) and TT carriers were 22% more likely than CC carriers to have current depression or a history of depression (OR, 1.22; 95% CI, 1.01-1.47).

Conclusions  The triangular association between the MTHFR genotype, tHcy, and depression implies that higher concentrations of tHcy increase the risk of depression and that lowering tHcy by 0.19 mg/L could reduce the odds of depression by about 20%. Confirmatory data from sufficiently powered randomized trials of homocysteine-lowering therapy are now required to test if the relationship between tHcy and depression is truly causal.

Author Affiliations: Western Australian Centre for Health and Ageing, Western Australian Institute for Medical Research, Perth (Drs Almeida, McCaul, and Flicker); Department of Psychiatry (Dr Almeida), Stroke Unit, Department of Neurology (Dr Hankey), and Department of Geriatric Medicine (Dr Flicker), Royal Perth Hospital, Perth, Australia; Schools of Psychiatry and Clinical Neurosciences (Dr Almeida), Medicine and Pharmacology (Drs Hankey and Flicker), and Surgery (Dr Norman), University of Western Australia, Perth; Department of Surgery, Fremantle Hospital, Fremantle, Australia (Dr Norman); and School of Population Health and Clinical Practice, University of Adelaide, Adelaide, Australia (Dr Jamrozik).

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