Homocysteine, Depression and Cognitive Function in Older Adults

http://www.practiceupdate.com/journalscan/5809

J Affect Disord 2013 Aug 05;[EPub Ahead of Print], AH Ford, L Flicker, U Singh, V Hirani, OP Almeida
http://www.sciencedirect.com/science/article/pii/S016503271300565X

TAKE-HOME MESSAGE

1. Is there an association between depression and high levels of homocysteine with cognitive deficits in elderly people?
2. Over 300 elderly individuals, two-thirds of whom met DSM criteria for major depression, underwent cognitive performance and memory tests.
3. High levels of homocysteine were associated with poorer performance on cognitive function and memory tests, independently of depression status.

Commentary By

David Rakel, MD, FAAFP

The literature for homocysteine as a predictor of disease has been up and down more times than a Coney Island roller coaster. But the data on its association with cognitive function appear to be climbing to a plateau. The authors of this study of 358 elderly patients with depression wanted to see if there was a correlation between depression and homocysteine levels. They did not see a connection to depression, but individuals with elevated homocysteine levels (> 13 µmol/L) were almost twice as likely to show decline in memory and on global cognitive testing.

The body requires folate, vitamins B12 and B6, and S-adenosyl-L-methionine (SAMe) for normal production of serotonin, norepinephrine, and dopamine. If this methylation cycle is not working optimally, the homocysteine level will rise. This can happen with poor nutrition (eg, alcoholism), deficient cofactors (folate, B6, B12, SAMe), or genetic predisposition (MTHFR [methylenetetrahydrofolate reductase] gene defect). In patients with excellent nutrition but elevated homocysteine, consider checking for the MTHFR polymorphism.

So what can we recommend to keep the homocysteine level low?

• Eat foods rich in folate, such as dark, leafy greens. And eat foods rich in B-vitamins, including nuts, beans, whole grains, lean meat, and fish.
• If able, avoid prolonged acid suppression, as acid is needed for B-vitamin absorption.
• If the homocysteine level does not go down with good nutrition, supplement with vitamin B12 500–1000 µg, B6 50 mg, and folic acid 1 mg.
• Some people require higher doses of folic acid to lower homocysteine. The active form of folate is methylfolate (MTHF) and it is the methylfolate that crosses the blood–brain barrier. In someone with poor cognition, consider using MTHF, 5–15 mg daily. You also want to use this form at a high dose (15 mg) if you are using folic acid to augment the effects of antidepressants.1

1. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.

SUMMARY

PracticeUpdate Editorial Team

Background: Depression and high total plasma homocysteine (tHcy) are independently associated with cognitive impairment in older adults. We designed this study to determine if high tHcy is a mediator of cognitive performance in older adults with major depression.

Methods: We recruited 358 community-dwelling older adults experiencing depressive symptoms, 236 (65.9%) of who met DSM-IV-TR criteria for major depression. Assessment included the Montgomery Asberg Depression Rating Scale (MADRS), fasting tHcy and the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery.

Results: Individuals with major depression and high tHcy had significantly worse immediate verbal and delayed visual recall. Non-depressed participants with high tHcy had lower MMSE, immediate and delayed recall scores than those with normal tHcy. The odds of cognitive inefficiency for those with high tHcy was nearly doubled for the MMSE (OR 1.9, 95%CI 1.1-3.3), immediate (OR 1.9, 95%CI 1.1-3.5) and delayed (OR 1.9, 95%CI 1.1-3.4) word recall after adjusting for age, gender, IHD and MADRS score.

Limitations: The presence of sub-syndromal depressive symptoms in our non-depressed group and exclusion of participants with established cognitive impairment may limit the generalizability of this study.

Conclusions: Elevated tHcy was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal tHcy independent of the presence of major depression or the severity of depressive symptoms. Homocysteine lowering B-vitamin supplementation may offer a potential therapeutic target to try and mitigate the often-disabling impact of cognitive deficits found in this population.