Depression the Homocysteine Hypothesis of Depression

8/6/2019 Depression the Homocysteine Hypothesis of Depression

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Am J Psychiatry 164:6, June 2007 861

Reviews and Overviews

ajp.psychiatryonline.org

The Homocysteine Hypothesis of Depression

Marshal Folstein, M.D.

Timothy Liu, M.D.

Inga Peter, Ph.D.

Jennifer Buel, B.S.

Lisa Arsenault, B.S.

Tammy Scott, Ph.D.

Wendy W. Qiu, M.D., Ph.D.

High levels of homocysteine are associ-

ated with cerebrovascular disease,

monoamine neurotransmitters, and de-

pression of mood. A plausible hypothesis

for these associations is that high ho-

mocysteine levels cause cerebral vascu-

lar disease and neurotransmitter defi-

ciency, which cause depression of mood.

The homocysteine depression hypothe-

sis, if true, would mandate inclusions of

imaging studies for cerebrovascular dis-

ease and measures of homocysteine,

folate, and B12 and B6 vitamins in the

clinical evaluation of older depressed pa-

tients. Longitudinal studies and c linical

trials should be designed to challenge

the hypothesis.

(Am J Psychiatry 2007; 164:861867)

If depression of mood is in some cases a symptom ofdisease, knowledge of etiology would lead to prevention

and knowledge of pathogenesis would lead to a cure. Al-

though there probably are multiple genetic and environ-

mental causes of depression, we review the evidence here

to support one hypothesis or model of depression as a dis-

ease. The hypothesis is that genetic and environmental

factors elevate homocysteine levels, which cause vascular

disease of the brain, and/or transmitter alterations, which

cause depression.

Background

We provide background information, recently reviewed

by Coppen and Bolander-Gouaille (1), and then review

studies supporting the hypothesis. Homocysteine is a sul-

furated amino acid derived from ingested methionine

found in cheeses, eggs, fish, meat, and poultry. It is directly

toxic to neurons and blood vessels and can induce DNA

strand breakage, oxidative stress, and apoptosis (2, 3). The

methionine-homocysteine metabolic pathway intermedi-

aries are S-adenosylmethionine and S-adenosylhomocys-

teine. The pathway produces methyl groups required for

the synthesis of catecholamines and DNA. This is accom-plished by remethylating homocysteineusing B12 and

folate as cofactorsback to methionine. Homocysteine is

cleared by transulfuration to cysteine and glutathione, an

important antioxidant. Transulfuration requires vitamins

B6 and B12.

The components of the homocysteine-methionine cy-

cle, as well as cysteine and glutathione and the enzymes of

the pathway, are affected by genetic variation, diet, kidney

and gastrointestinal diseases, and prescribed and over-

the-counter drugs. Since homocysteine is a sensitive indi-

cator of B vitamin deficiency, an elevated homocysteine

level is a marker for a pathogenic process as well as a cause

of pathology.

Evidence Supporting the Hypothesis

Prevalence ofHyperhomocysteinemia in the

Population and in Disease

Homocysteine levels are higher in the elderly and in men

(4). In 1,160 adults from the original Framingham HeartStudy cohort who had survived to 67 to 96 years of age, a

high homocysteine level (>14 mol/liter) was present in

29.3%. Homocysteine levels were correlated with age and

correlated inversely with folate and vitamins B6 and B12 (5).

In another study, of women ages 15 to 44, 13% of the sam-

ple had elevated total plasma homocysteine levels, defined

as a concentration 10.0 mol/liter (6).

Samples of geriatric patients have higher levels of ho-

mocysteine than do samples of community-dwelling eld-

erly. For example, among patients ages 65 and over who

were admitted into an acute care geriatric ward in North-

ern Italy, 74.2% of men and 68.9% of women had elevated

homocysteine levels. Elevated total plasma homosysteine

concentrations were associated with older age, male gen-

der, increasing serum creatinine, lower Mini-Mental State

Examination score, and disability (4).

Some studies find elevated levels of homocysteine in

Alzheimers disease (7, 8) and cognitive impairment (9),

but others do not (10, 11). Hyperhomocysteinemia was

also present in 20% of stroke patients but only 2.2% of

comparison subjects (odds ratio=5.75; 95% confidence in-

terval [CI]=1.2453.4, p


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862 Am J Psychiatry 164:6, June 2007

HOMOCYSTEINE AND DEPRESSION


Causes of Hyperhomocysteinemia

Serum levels of homocysteine increase after methionine

loading; in dietary deficiency of B12, folate, and B6 (13); and

because of renal disease (14, 15) and genetic variation of

the enzymes (such as methyl-tetrahydro-folate reductase

[MTHFR] and cystathionine beta-synthatase [CBS]) essen-

tial for the metabolism of homocysteine. Other causes of

hyperhomocysteinemia include gastric atrophy (16), in-flammatory bowel disease (17), and laxative use (18), all of

which interfere with absorption of nutrients. Anticonvul-

sants and diuretics elevate homocysteine levels (19).

Homocysteine and Vascular Disease

The association between homocysteine and vascular

disease has been documented in studies of genetic varia-

tion and from population-based studies of prevalence and

incidence. McCully (20) first described the similarity of the

homocystinuric vascular lesions to atherosclerosis in two

autopsied cases of children with homocystinuria. Further-

more, he showed that the lesions of atherosclerosis could

be induced in rabbits by administering either dietary or

parenteral methionine or homocysteic acid parenterally.

The rabbits died from pulmonary embolism and pulmo-

nary infarct (21).

Genetic Mutations Elevate Homocysteine Levels

Mutations ofMTHFR and CBSgenes cause a rare reces-

sive genetic disease: homocystinuria. It was first described

in 1962 when Carson and Neil, screening urine for amino

acid abnormalities in mentally retarded subjects, found

four cases of elevated homocysteine levels of 2,000

screened. It was clear from later studies that vascular dis-

ease was a regular feature of the phenotype (22). In pa-tients with homocystinuria, the probability of having a

clinically detected thromboembolic event by age 15 was

27%, and the probability of not surviving to age 30 was

23% (23). Many mutations have been discovered to cause

homocystinuria. Another feature of homocystinuria is the

high prevalence of psychiatric disorders. In a study of 63

homocystinuric patients who had been treated with B6,

the overall rate of clinically significant psychiatric disor-

ders was 51%, including episodic depression (10%),

chronic disorders of behavior (17%), chronic obsessive-

compulsive disorder (5%), and personality disorders

(19%). The average IQ was 80 (SD=27) (24). In summary,

mutations of genes regulating homocysteine metabolismcause mental retardation, vascular brain disease, and psy-

chiatric symptoms.

In addition to the mutations that cause homocystinuria,

there are several known allelic variants of the MTHFR

gene. Approximately 10% of the population carries the

c67TTMTHFR allele, which is associated with elevated ho-

mocysteine levels (25). These normal variants increase the

risk for myocardial infarction and ischemic stroke, partic-

ularly among younger patients and women (2632). How-

ever, two studies showed no association between the

c67TT allele and stroke (25, 33).

Interaction of genes and environment were found in a

study from Hungary that demonstrated that MTHFR

c67TT alleles, when combined with environmental effects,

such as drinking or smoking, increased the risk of vascular

disease more than the alleles or environmental factors by

themselves (34). Many other genes in the methioninepathway are known, but their allelic variants have not yet

been explored for clinical associations.

Elevated Homocysteine Levels and Risk

Maternal deficiency of folate and elevated homocys-

teine levels during pregnancy increase the risk of neural

tube defects and possibly schizophrenia (3537). By 1989,

elevated homocysteine was established as an indepen-

dent risk for vascular disease. Ueland and Refsum (38),

distinguished investigators in this area, noted, Impaired

homocysteine metabolism seems to exist in 1530% of pa-

tients with premature cardiovascular disease. Moderate

hyperhomocysteinemia is a risk factor for cardiovasculardisease, independent of conventional risk factors.

Results of a recent meta-analysis of prospective studies

suggest that lowering the serum homocysteine level by

25% (about 3 mol/liter) decreases the risk for ischemic

heart disease. Reduction of levels reduces the risk of heart

disease by 11% and stroke by 19% (16). Another meta-

analysis of 72 studies concluded that lowering homocys-

teine concentrations by 3 micromol/liter from current lev-

els (achievable by increasing folic acid intake) would re-

duce the risk of ischemic heart disease by 16%, deep vein

thrombosis by 25%, and stroke by 24% (39).

A dose-response relationship was found in a prospectivestudy in Rotterdam. The risk of stroke and myocardial in-

farction increased directly with total homocysteine level

(6% to 7% for every 1 mol/liter increase in total homocys-

teine level) (40, 41). Studies in other countries report the

same dose-response relationship between homocysteine

and vascular disease (42, 43). Such cross-national studies

are important because of regional variations in diet and

gene frequencies. In addition to clinically diagnosed stroke,

silent brain infarcts, diagnosed by magnetic resonance im-

aging (MRI), and ischemic white matter disease are also as-

sociated with elevated levels of homocysteine (4446).

Further support for the idea that homocysteine is a

cause of vascular disease comes from studies indicatingthat increasing intake of dietary folate, which effectively

lowers homocysteine levels, lowers the risk of ischemic

stroke in men (47, 48).

In summary, elevated levels of homocysteine, and in

some populations, alleles of the MTHFR genotype, in-

crease the risk for vascular disease of the brain. The pro-

portion of all strokes due to this mechanism is not known

but likely varies by age, geographic location, and preva-

lence of known causes of elevated homocysteine levels.


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FOLSTEIN, LIU, PETER, ET AL.


Intervention Studies

Results of recent intervention studies designed to lower

homocysteine levels are mixed. Although homocysteine

levels can be reduced, vascular disease is not prevented

(4953). Explanations for this failure include lack of ade-

quate power and selection criteria, which include cases in

which documented vascular disease has already occurred.

Nevertheless, cognitive improvement has been foundafter homocysteine levels were lowered (54, 55). Depres-

sion has been relieved by lowering homocysteine levels

with B vitamin supplementation (56).

Stroke As a Cause of Depression

If homocysteine causes vascular disease, is vascular dis-

ease then the intermediate cause of hyperhomocysteine-

mia-related depression? Depression as a specific feature of

stroke was first described in a small case-control study us-

ing a detailed structured clinical psychiatric interview of

patients in a rehabilitation program following stroke and

orthopedic conditions. Depression was more often found

in stroke patients than in orthopedic patients matched forlevels of disability (57). Because the groups were matched

for disability, the increased rate of depression in stroke pa-

tients could not be attributed only to a psychological reac-

tion to loss of function, i.e., disability. Since then, Robin-

son (58) and many others have extensively studied

poststroke depression. In a review, Robinson noted that

Pooled data from studies conducted throughout the

world have found prevalence rates for major depression of

19.3% among hospitalized stroke patients and 23.3%

among outpatient samples. There is evidence that anti-

depressants improve mood after stroke but no evidence

that depression can be prevented (58, 59).

Further evidence of the specificity of depression caused

by stroke comes from studies indicating that left hemi-

sphere stroke commonly causes depression. Narushima et

al. (60) showed in a meta-analysis that there was a signifi-

cant inverse correlation between severity of depression

and distance of the lesion from the frontal pole among 163

patients with left hemisphere stroke but not among 106

patients with right hemisphere stroke.

Cardiovascular Disease and Depression

Stroke is often associated with heart disease, and de-

pression is a symptom and a risk for heart disease (61).

The pathogenesis of depression in heart disease is not

known. Possible mechanisms include cerebral infarcts

and drugs used to treat depression and heart disease, in-

cluding diuretics and anticonvulsants (62).

Vascular Disease in Depressed Populations

Several studies indicate that a large proportion of eld-

erly persons with depression also have had either a stroke

or other evidence of vascular disease. Many studies find

high rates of cerebrovascular disease and white matter le-

sions on MRI in depressed elderly patients. For example,

in a Japanese study in which patients were matched for

age, the frequency of silent cerebral infarction varied with

both age and the age of depression onset. Among patients

over the age of 65 diagnosed with major depression, silent

cerebral infarction was observed in 65.9% of those with

depression onset before the age of 65 and in 93.7% of those

with onset of depression after age 65 (63). In other studies,

deep white matter lesions were most common in patients

who first presented with depression late in life (6467).

Coffey et al. (68) identified changes in subcortical white

matter lesions in 44 of 67 depressed inpatients (66%) re-

ferred for ECT. Two autopsy studies demonstrated that the

white matter intensities seen in the MRIs of patients with

depression were ischemic lesions (69, 70).

Alexopoulos et al. (71) observed a characteristic cognitive

pattern in depressed patients with vascular disease. In 1997,

he named these cases vascular depression. Vascular dis-

ease was found in 75 of 139 depressed patients (54%). The

vascular group was older and had more hypertension and

less family history of depression (72). Furthermore, a severe

reduction in mental speed remained after recovery from thedepressive episode, which suggested underlying brain dis-

ease, such as infarcts (73). Recently, the concept of vascular

depression has been challenged (7476).

Although elderly depressive patients are often the sub-

jects of studies of vascular disease and depression, one

study found scan abnormalities associated in children

with psychiatric disorders. White matter hyperintensities

of 153 child and adolescent psychiatry inpatients were

rated on T2-weighted MRI scans. Within the unipolar de-

pression group (N=48), white matter hyperintensities

were significantly associated with a higher prevalence of

past suicide attempts (p=0.03, Fishers exact test) (77).However, in another study, increased rates of white matter

hyperintensities were not found in young patients with

mood disorders (78).

Several studies have shown that premorbid depression

can significantly increase the risk of stroke over the subse-

quent 1015 years. Depression has been reported to be a

risk for vascular disease in several large population-based

prospective studies (e.g., reference 79). However, these

studies did not include baseline MRI scans to document

the absence of preexisting cerebrovascular disease. In

summary, depression occurs frequently after stroke, and

high proportions of imaging studies of older depressed

patients show infarcts or white matter lesions that indi-

cate the presence of ischemic vascular disease.

Homocysteine and Neurotransmitter Alterations

Homocysteine and stroke might cause depression by al-

teration of neurotransmitters (80, 81). Evidence for the as-

sociation between homocysteine and neurotransmitters is

found in studies that directly measure neurotransmitter

metabolites and in studies demonstrating the antidepres-

sant effects of folate and S-adenosylmethionine, a cofac-


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tor and an intermediate metabolite of the methionine-ho-

mocysteine pathway.

The most direct evidence for the association between

homocysteine and neurotransmitters is from a study

showing that depressed patients with increased total

plasma homocysteine levels had significantly lower levels

of serum, red cells, and CSF folate, as well as lower levels of

CSFS

-adenosylmethionine (SAMe). The depressed pa-tients with high total plasma homocysteine levels were

also found to have significantly lower mean CSF concen-

trations of 5-hydroxyindoleacetic acid, homovanillic acid,

and 3-methoxy-4-hydroxyphenylglycol (MHPG) (82).

The relationship between homocysteine and neu-

rotransmitters is indirectly suggested by studies showing

that mood can be modified by alteration of the homocys-

teine pathway. S-adenosylmethionine, an intermediary in

the homocysteine pathway, has been found to function as

an antidepressant. Its effects have been shown to be supe-

rior to placebo and comparable to standard tricyclic anti-

depressants (83, 84). In addition, three randomized trials

have suggested supplemental folate as a treatment for de-pression (85, 86). In a study of depressed patients who had

failed to benefit from paroxetine treatment but were cur-

rently receiving other treatments, low serum folate levels

were found to be associated with poorer response to those

treatments (87). Relapse of depression has also been

found to be related to folate (88, 89). The improvement in

mood followingS-adenosylmethionine or supplemental

folate administration suggests the involvement of the ho-

mocysteine pathway in depression (90).

Direct evidence of the association between homocys-

teine and neurotransmitter levels comes from studies of

Parkinsons disease. Parkinsons patients receivingL-dopa,which requires the donation of a methyl group from S-ad-

enosylmethionine to be metabolized, had higher levels of

homocysteine than patients not takingL-dopa (91). Use of

L-dopa could create a methyl sink, thus preventing the

remethylation of homocysteine to methionine with the re-

sult of high homocysteine levels. Another potential mech-

anism for the homocysteine effect on transmitters is by

inhibition of the enzyme necessary to catalyze the methy-

lation reactions between the catecholamines and S-ade-

nosylmethionine (SAMe) (9294).

Association of Homocysteine and

Depressive Disorders

The relationship of the homocysteine-methyl donor

pathway to depression was noted first by Reynolds and col-

leagues (9598) in the 1970s. Subsequent clinical and pop-

ulation-based studies have noted elevated homocysteine

levels in depression (82, 99). Associations between ho-

mocysteine, folate, B12, and depression vary in particular

populations. The Hordaland study of older men and

women in Norway found that elevated homocysteine cou-

pled with the T/T allele ofMTHFR gene was associated

with depression but that folate and B 12 without the T/T al-

lele were not associated (100, 101). The Rotterdam study of

older men and women found that hyperhomocysteinemia,

vitamin B12 deficiency, andto a lesser extentfolate defi-

ciency were related to depressive disorders (102).

Two studies of special populations did not find that ho-

mocysteine was related to depression. The first included

women only and found vitamin B12 deficiency to be

present in 14.9% of the 478 nondepressed subjects, 17.0%

of the 100 mildly depressed subjects, and 27.0% of the 122

severely depressed subjects. No association was found be-

tween homocysteine and depression or folate and depres-

sion (103). The second was an ethnically diverse U.S. pop-

ulation sample ages 1539 years. Subjects with any

lifetime diagnosis of major depression had serum and red

blood cell folate concentrations that were lower than

those of subjects who had no history of depression. In this

young population, serum homocysteine was not found to

be associated with lifetime depression diagnoses (104).

Homocysteine, B12, folate, or some combination is relatedto depression, but age, sex, race, and renal function must

be specified. Because there are many types of depression

in populations of different ages, as well as many causes for

elevated homocysteine, including genetic predisposition

and brain disease, samples of randomly selected subjects

will be heterogeneous. Therefore, adequate power to dem-

onstrate a specific relationship necessitates large samples.

Conclusions

There is strong published evidence for the association

between homocysteine level and depression, vascular dis-

ease, and neurotransmitters. More large population-based prospective studies are needed to challenge the idea

that elevated homocysteine levels cause vascular disease,

which causes depression. Intervention trials are needed to

determine whether depression treatment will be en-

hanced by homocysteine reduction. Since there are many

causes of elevated homocysteine levels and probably

many causes of depression, prospective and intervention

studies must include a large enough sample to ensure ad-

equate power to demonstrate outcome. Subjects included

in prevention studies should not have depression, vascu-

lar disease, or elevated homocysteine levels at baseline.

If the hypothesis is not rejected by further study, then

evaluation of elderly depressed patients should includeimaging for vascular disease and measurement of ho-

mocysteine, folate, B6, and B12 levels.

Received Feb. 19, 2005; revision received April 21, 2005; accepted

June 20, 2005. From the Friedman School of Nutrition Science and

Policy, Tufts University, Boston. Address correspondence and reprint

requests to Dr. Folstein, 111 Hamlet Hill Rd., Unit 406, Baltimore, MD

21210; [email protected] (e-mail).

All authors report no competing interests.

Supported by a grant from the National Institute on Aging, AG-

21790 (to Dr. Folstein), and AG-022476 (to Dr. Qiu) and by a General


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Clinical Research Center grant funded by the National Center for Re-

search Resources of the NIH under grant number MO1-RR-00054.

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Depression the Homocysteine Hypothesis of Depression