Posts Tagged ‘mood disorder’

An inconvenient truth about dreams

Larry H. Bernstein, MD, FCAP, Curator



It is natural to dream. Dreaming is a flashback recording of recent occurrences associated with cleaning out the memory of daily events.  There is much written in both literature and in neuroscience as I write this.  Dreaming is both natural and perhaps also adaptive, and dreams may be distressing or unintelligible in circumstances that we view as pathological.  This is thought to be related to a loss of plasticity of the memory circuits. This occurs with mood disorders, sleep disorders with and without leg movement disorder, and with schizophrenia.

The term given by Martin Luther King, “I had a dream” is out of place under the cirumstances I describe. I am identical twin with a nonidentical triplet sister.  Our brother died more than a decade ago, prematurely aged from living with schizophrenia.  I and my sister could talk to him and understand what he said, even though it meant nothing to others. What I did not share was the total fragmentation of mental thoughts at an early age.  Both I and my sister had guilt over the situation for years. I sought psychiatric assistance that went on for years.  But I was not schizophrenic and I had a successful career by any standard, but was burdened trying to make up in achievement what was denied to my immigrant father and to my identical twin brother. It was by no means easy in the 1960s for my parents to deal with the situation, with a societal lack of understanding, a feeling of what have I done wrong, and a serious cost burden.

I went to medical school, which I had decided as a child, when I read Paul de Kruif’s Microbe Hunters.
I had a sister two years older who was a “wunder” kind, who I tried to follow.  She had a GM scholarship and set the class curve as an undergraduate in a graduate course in numbers theory.  Fortunately, my best friend, who was as brilliant as they come and a Merit Scholar college entry, cautioned not to overburden myself with the chemistry/math major that I never declared. My brother entered the hospital as I entered medical school, and the first year that would be expected to be difficult, certainly was for me.

Only in the last 5 years did I learn from extensive testing that I had a very high intelligence to match my achievement , but that I had Asperger’s.  I also learned that I had an uncommon double mutation of the hydroxymethyl-folate reductase gene that is associated nonspecifically with neurological disorders. I take methyl folate for the genetic disorder to give access of folic acid to cross the blood brain barrier.
I’m retired for several years and had enormous difficulty in retiring, and was a workaholic.  Work had great meaning and rewards for me.

I am now 74 and had a difficult 3 years with illness and hospitalization for me and my spouse of 45 years.  We moved to be near my younger daughter, son-in-law, and grandson.  This has brought great satisfaction. All the same, my asthma, sleep apnea, and general condition declined, and the move was more difficult than any I previously experienced.  I have vivid dreams that requires clonipin for relief initially.

I have had increased frequency of dreams that can be resolved.  However, with my awareness of the suicide of Robin Williams, I was given an awareness of his situation beyond what one would expect who has not seen such patients or has not experienced this.  In my situation it was worsened by added depression.  In the recent events I thought for the first time how incredible it was for my brother to have experienced this much of his schizophrenic life, even though I am not schizophrenic by any measure.

What’s in a dream?

I have had dreams before that I thought were interesting because of the people who I knew and the situations, that might have been unusual and gave me an inclination to write down.  If I collected these, it could perhaps warrant a collection of stories.  Those that are very recent have suggested that the one when I entertained my grandson is worthwhile. It was not so noxious, but it does fit the pieces together.
I watched some of the reporting of election returns of republican and democratic candidates.  I sort of tossed around and played with the exceptional 6 year old who need not be exposed to such nonsence as we are seeing.  It was early evening and to finish his limited allowable screentime, Nanny and Grandpa, and grandchild watched a children,s movie before bedtime. It was … … a takeoff on Red Ridinghood, with good cartoon figures, some recognizable voices, and an interesting storyline.  Yes, LRRH does go through the woods to see her grandma, and she meets the wolf, who goes to her grandma’s house.  Her grandma is tied up in the closet, and the woodsman, in the role of Paul Bunyan, gives a visit at the time of rescue.  The storyline becomes a detective story to cull out the events leading up to a criminal event – who stole grandma’s recipe book, with a long family line of cooking.   The grandma was an Olympic skiing champ who beets out the characters who stole her cookbooks.  I’ll say no more than that the search comes upon grandma and LRRH escape with a parachute finish and the bad guys, led by a crafty rabbit, slide down on a ski-tram into a waiting police car.  So that evening I have a dream that is a cockamaimie replay in which I am driving on the highway and enter a tunnel (like the rail in the movie), and the lane is cluttered with a wolf, and other creatures, making passage quite impossible.


I talked to my sister who called the next day. It was terrific when she said that if I had a pad and wrote them down immediately, they would form a pattern. Again, I have a dream, and I recall there was a pattern of feeling of failure. I am on Gabapentin for the restless leg. This time I have my brother (impossible) in it, I left my coat in a conference room and can’t get it immediately, and I have to return home with an exam the next day.  In a recurring pattern, my brother is to drive.  I can’t drive because of now having a diplopia from thyroid eye disease related to Grave’s disease.  The exam has two questions about plasma from unclotted blood that is spun down and serum from clotted blood. This is very basic. The pattern is related to systemic notions of failure.  My sister had a repeated pattern of rushing to get to the classes she teaches and not getting there on time (consistent with her rush rush).

I go back to bed and get another few hours of sleep. We had watched a number of Miss Marple movies recently.  In the move I had the stressful experience of going through 40 years of save photographic equipment and photography, research literature, computer stuff, ya da, ya da, ya da.   Very thorough, and tiring.  The old lady in RRH and Miss Marple were merged into a character in a story related to the corroded pipes in Flint, and a criminal search for the cause of this problem (having watched the debate). Incredibly, this character was going through the material so rapidly, uncovering clues, and I was amazed.
I was struggling to keep up.  Then I woke up. So my spouses assurances were correct.  This is actually normal dreaming.

It is disturbing, consistent with a recent New York Times article on how the brain cleans out the garbage.  I have too much garbage.  My medication does have to be adjusted.  It is perhaps not the same as my late brother’s experience. My sister’s observations have been helpful.  My brother’s dreams were recognizable to me, but not to others, but they also had patterns, but patterns that were more distorted.  If mine have been “normal”, but more frequent, this suggests a failure in the brain’s plasticity as I am aging, perhaps from from the stress in a major move.  It is perhaps to be viewed as distressing at best compared with the worst case (my brother, or Robin Williams).

This is substantiated by my remembrance of driving on Woodward avenue or the expressway in Detroit, Michigan. I grew up on 2967 Sturtevant off of Dexter Ave. My elementary school no longer exists. We moved to the Northwest section and I graduated from Mumford High School in 1961.  I lived in Trumbull, adjacent to Bridgeport, CT for 33 years, where my children grew up.  The bizarreness of my recurring dream pattern has to do with a repeated driving and confusion between Detroit and Connecticut.  I drove from Connecticut to New York for the last five years before retirement, but I failed to record these experiences.  I had two car accidents related to narcolepsy in asbout 7 years related to my sleep apnea prior to getting it treated. In the last, I went to New Jersey to see an associate and driving back to Trumbull I veered off the highway and managed to veer into a tree in the snow. Fortunately I was able to control the car at the last minute.  Fortunately, this could be much worse.








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Serum Folate and Homocysteine, Mood Disorders, and Aging

Larry H. Bernstein, MD, FCAP, Curator



Dietary Folate and the Risk of Depression in Finnish MiddleAged Men

Tolmunen T, et al.
PSYCHOTHER AND PSYCHOSOM · OCT 2004; 73:334-339    DOI: http://dx.doi.org:/10.1159/000080385


Serum Folate, Vitamin B-12, and Homocysteine and Their Association With Depressive Symptoms Among U.S. Adults

PSYCHOSOM MED · NOV 2010;             DOI: http://dx.doi.org:/10.1097/PSY.0b013e3181f61863

Objective: To examine, in a nationally representative sample of U.S. adults, the associations of serum folate, vitamin B-12, and total homocysteine (tHcy) levels with depressive symptoms. Several nutritional and physiological factors have been linked to depression in adults, including low folate and vitamin B-12 and elevated tHcy levels.
Methods: Data on U.S. adults (age, 20–85 years; n 2524) from the National Health and Nutrition Examination Survey during the period 2005 to 2006 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of 10. Serum folate, vitamin B-12, and tHcy were mainly expressed as tertiles. Multiple ordinary least square (OLS), logistic, and zero-inflated Poisson regression models were conducted in the main analysis.
Results: Overall, mean PHQ score was significantly higher among women compared with men. Elevated depressive symptoms (PHQ score of 10) were inversely associated with folate status, particularly among women (fully adjusted odds ratio [tertiles T3 versus T1] 0.37; 95% confidence interval, 0.17–0.86), but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (50 years) and both sexes combined, tHcy was positively associated with elevated depressive symptoms (fully adjusted odds ratio [tertiles T2 versus T1] 3.01; 95% confidence interval, 1.01–9.03), although no significant dose-response relationship was found. Conclusions: Future interventions to improve mental health outcomes among U.S. adults should take into account dietary and other factors that would increase levels of serum folate.
Key words: depression, folate, vitamin B-12, homocysteine, adults.


Relationship of homocysteine, folic acid and vitamin B12 depression in a middle-aged community sample

P.S. SACHDEV, et al.   PSYCHOL MED · MAY 2005;   35, 529–538         http://dx.doi.org: /10.1017/S0033291704003721 

Background. Case control studies have supported a relationship between low folic acid and vitamin B12 and high homocysteine levels as possible predictors of depression. The results from epidemiological studies are mixed and largely from elderly populations.
Method. A random subsample of 412 persons aged 60–64 years from a larger community sample underwent psychiatric and physical assessments, and brain MRI scans. Subjects were assessed using the PRIME-MD Patient Health Questionnaire for syndromal depression and severity of depressive symptoms. Blood measures included serum folic acid, vitamin B12, homocysteine and creatinine levels, and total antioxidant capacity. MRI scans were quantified for brain atrophy, subcortical atrophy, and periventricular and deep white-matter hyperintensity on T2-weighted imaging.
Results. Being in the lowest quartile of homocysteine was associated with fewer depressive symptoms, after adjusting for sex, physical health, smoking, creatinine, folic acid and B12 levels. Being in the lowest quartile of folic acid was associated with increased depressive symptoms, after adjusting for confounding factors, but adjustment for homocysteine reduced the incidence rate ratio for folic acid to a marginal level. Vitamin B12 levels did not have a significant association with depressive symptoms. While white-matter hyperintensities had significant correlations with both homocysteine and depressive symptoms, the brain measures and total antioxidant capacity did not emerge as significant mediating variables. Conclusions. Low folic acid and high homocysteine, but not low vitamin B12 levels, are correlates of depressive symptoms in community-dwelling middle-aged individuals. The effects of folic acid and homocysteine are overlapping but distinct.


Association of folate intake with the occurrence of depressive episodes in middle-aged French men and women

P. Astorg, et al.    BRIT J  NUTR · AUG 2008; 100, 183–18       http://dx.doi.org:/10.1017/S0007114507873612

A low folate intake or a low folate status have been found to be associated with a higher frequency of depression in populations, but the existence and the direction of a causal link between folate intake or status and depression is still uncertain. The aim of this study was to seek the relation between the habitual folate intake in middle-aged men and women and the occurrence of depressive episodes. In a subsample of 1864 subjects (809 men and 1055 women) from the French SU.VI.MAX cohort, dietary habits have been measured at the beginning of the follow-up (six 24 h records) and declarations of antidepressant prescription, taken as markers of depressive episodes, have been recorded during the 8-year follow-up. No significant association was observed between folate intake and the risk of any depressive episode or of a single depressive episode during the follow-up, in both men and women. In contrast, the risk of experiencing recurrent depressive episodes (two or more) during the follow-up was strongly reduced in men with high folate intake (OR 0·25 (95% CI 0·06, 0·98) for the highest tertile v. the lowest, P for trend 0·046). This association was not observed in women. These results suggest that a low folate intake may increase the risk of recurrent depression in men.   Folate: Depression: Cohort studies


Homocysteine, vitamin B12, and folic acid levels in Alzheimer’s disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study.

Faux NG1, Ellis KA, Porter L, Fowler CJ,…, Ames D, Masters CL, Bush AI.
J Alzheimers Dis. 2011; 27(4):909-22.    http://dx.doi.org:/10.3233/JAD-2011-110752.

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.


Homocysteine and folate as risk factors for dementia and Alzheimer disease1,2,3

Giovanni RavagliaPaola FortiFabiola Maioli, …., Nicoletta BrunettiElisa Porcellini, and Federico Licastro
Am J Clin Nutr Sept 2005; 82(3): 636-643


Background: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results.

Objective: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population.

Design: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12.

Results: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy > 15 μmol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P = 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P = 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (≤11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P = 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P = 0.014), whereas the association was not significant for vitamin B-12.

Conclusions: Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.


In Western societies, the prevalence and economic costs of Alzheimer disease (AD) are soaring in step with the increased number of elders in the population (1). Therefore, it is important to identify modifiable risk factors for this disease. The sulfur amino acid homocysteine is a unique candidate for this role because of its direct neurotoxicity (24) and its association with cerebrovascular disease (5), which is currently believed to play a significant role in AD etiology (6). Moreover, elevated concentrations of plasma total homocysteine (tHcy) are an indicator of inadequate folate and vitamin B-12 status (7) and can directly affect brain function via altered methylation reactions (8).

An association between AD and elevated tHcy concentrations has been reported in case-control (9, 10) and cross-sectional (11, 12) studies. Moreover, in nondemented elderly populations, plasma tHcy is inversely associated with poor performance at simultaneously performed tests of global cognitive function (1315) and specific cognitive skills (13, 16). However, cross-sectional studies cannot determine causality. Only 2 longitudinal studies investigated the relation between hyperhomocysteinemia and risk of incident AD, but their results were inconsistent; the Framingham Study reported a strong association (17), and the Washington Heights–Inwood Columbia Ageing Project (WHICAP) reported no association (18). Clarification of this issue is important because consistent evidence of a prospective association between homocysteine and AD would more strongly support the need for intervention trials testing the effectiveness of homocysteine-lowering vitamin therapy in preventing dementia.

Therefore, we examined baseline plasma tHcy in relation to risk of incident dementia and AD in the Conselice Study of Brain Aging (CSBA), an Italian population-based study of older persons.

Study population

The CSBA is a population-based survey, already described in detail elsewhere (19,20), the principal aim of which is to provide data about epidemiology and risk factors for dementia in the elderly. Its design includes both cross-sectional and longitudinal components. The study was approved by the Institutional Review Board of the Department of Internal Medicine, Cardioangiology, and Hepatology, University of Bologna, and written informed consent was obtained from all participants.

Briefly, in 1999–2000, 1016 (75%) of the 1353 individuals aged ≥65 y residing in the Italian municipality of Conselice (province of Ravenna, Emilia Romagna region) participated in the prevalence study. Data on cognitive status at the follow-up examination in 2003–2004 were collected for 861 of the 937 participants free of dementia at baseline. A flow chart detailing the derivation of the incidence sample used in this study is reported in Figure 1.

This prospective population-based study was the first to replicate previous findings from the Framingham Study (17), indicating that hyperhomocysteinemia doubles the risk of developing dementia and AD independently of several major confounders. Our results disagree with the negative findings recently reported in the WHICAP study (18). Possible explanations for this difference are the acknowledged insufficient statistical power of the WHICAP study, the rather homogeneously high tHcy concentrations of its sample—which did not permit enough variability to detect an association—and methodologic issues related to the prolonged time between blood sample collection and processing, which could have affected tHcy measurements.

Inconsistent results were also given by the only 2 studies that examined the association between homocysteine and cognitive decline at follow-up as measured with the MMSE (30, 31). These studies, however, differed in sample size and in which confounders were taken into account. Moreover, MMSE is a reliable global screening measure of cognitive function but was not developed to estimate changes in cognitive function or to diagnose dementia (32).

The substantial evidence that tHcy is an independent vascular risk factor (5) supports the role of hyperhomocysteinemia in AD. Subjects with vascular risk factors and cerebrovascular disease have an increased risk of AD (6), and hyperhomocysteinemia has been related to cerebral macro- and microangiopathy, endothelial dysfunction, impaired nitric oxide activity, and increased oxidative stress (3335). Moreover, as shown in cell cultures, homocysteine can directly cause brain damage through several mechanisms: increased glutamate excitoxicity via activation of N-methyl-D-aspartate receptors (2), enhancement of β-amyloid peptide generation (4), impairment of DNA repair, and sensitization of neurons to amyloid toxicity (3).

On the basis of cross-sectional observations, some authors have suggested that elevated plasma tHcy concentrations are not a causative factor in dementia and AD but are only a marker for concomitant vascular disease, independently of cognitive status (36, 37). Results from other cross-sectional investigations (9, 12, 38), as well as those from the present investigation and the Framingham Study (17), argue against this interpretation, but only intervention trials can give the ultimate proof of a causal relation between hyperhomocysteinemia and AD.

In contrast with both the Framingham (17) and WHICAP (18) studies, we also found that, independent of homocysteine and other confounders (including vitamin B-12), low serum folate is associated with an increased risk of incident dementia and AD. Mandatory folate fortification of food might partially explain the negative results of the US studies, whereas in Italy, where folate fortification is not practiced, relative folate deficiency may be endemic among the elderly population. Nondemented patients with poor cognitive performance and AD patients often exhibit poor folate status (reviewed in 8), but only one study specifically examined B vitamins in relation to incident dementia. In a selected sample of nondemented Swedish elderly participants in the Kungsholmen Study, low serum folate and vitamin B-12 were predictive of AD at 3 y of follow-up (39). The sample, however, was small (370 subjects), and a clear association was detected only when both vitamins were taken into account.

Biologic explanatory mechanisms relating folate deficiency to dementia include impaired methylation reactions in the central nervous system, with a consequent insufficient supply of methyl groups, which are required for the synthesis of myelin, neurotransmitters, membrane phospholipids, and DNA (8). However, because of the study design and the relatively short follow-up time, we cannot definitely establish whether the independent association between low folate and dementia risk indicates an actual effect of folate status on cognitive function or, on the contrary, that subtle functional alterations may affect the dietary intake of folate in the early preclinical stages of dementia.


Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor

Stuart A. Lipton*Won-Ki KimYun-Beom Choi*,…, Derrick R. Arnelle§, and Jonathan S. Stamler
NAS 1997; 94(11):5923–5928    http://www.pnas.org/content/94/11/5923.abstract

Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine’s neurotoxic (agonist) attributes at 10–100 μM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.


Vitamin B12 and folate in relation to the development of Alzheimer’s disease

H-X. Wang, Å. WahlinH. Basun, …, B. Winblad, and L. Fratiglioni
Neurology May 8, 2001; 56(9):1188-1194    http:/​/​dx.​doi.​org/​10.​1212/​WNL.​56.​9.​1188

Objective: To explore the associations of low serum levels of vitamin B12 and folate with AD occurrence.

Methods: A population-based longitudinal study in Sweden, the Kungsholmen Project. A random sample of 370 nondemented persons, aged 75 years and older and not treated with B12 and folate, was followed for 3 years to detect incident AD cases. Two cut-off points were used to define low levels of vitamin B12 (≤150 and ≤250 pmol/L) and folate (≤10 and ≤12 nmol/L), and all analyses were performed using both definitions. AD and other types of dementia were diagnosed by specialists according to DSM-III-R criteria.

Results: When using B12 ≤150pmol/L and folate ≤10 nmol/L to define low levels, compared with people with normal levels of both vitamins, subjects with low levels of B12or folate had twice higher risks of developing AD (relative risk [RR] = 2.1, 95% CI = 1.2 to 3.5). These associations were even stronger in subjects with good baseline cognition (RR = 3.1, 95% CI = 1.1 to 8.4). Similar relative risks of AD were found in subjects with low levels of B12or folate and among those with both vitamins at low levels. A comparable pattern was detected when low vitamin levels were defined as B12 ≤250 pmol/L and folate ≤12 nmol/L.

Conclusions: This study suggests that vitamin B12 and folate may be involved in the development of AD. A clear association was detected only when both vitamins were taken into account, especially among the cognitively intact subjects. No interaction was found between the two vitamins. Monitoring serum B12 and folate concentration in the elderly may be relevant for prevention of AD.


Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality

Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill’s criteria for assessing “causality,” and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22 000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed.
Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism
, , , , , , ,
Biochem. J. 2014 461: 205212    http://dx.doi.org:/10.1042/BJ20131568
Hyperhomocysteinaemia can contribute to cognitive impairment and brain atrophy. MTRR (methionine synthase reductase) activates methionine synthase, which catalyses homocysteine remethylation to methionine. Severe MTRR deficiency results in homocystinuria with cognitive and motor impairments. An MTRR polymorphism may influence homocysteine levels and reproductive outcomes. The goal of the present study was to determine whether mild hyperhomocysteinaemia affects neurological function in a mouse model with Mtrr deficiency. Mtrr+/+, Mtrr+/gt and Mtrrgt/gtmice (3 months old) were assessed for short-term memory, brain volumes and hippocampal morphology. We also measured DNA methylation, apoptosis, neurogenesis, choline metabolites and expression of ChAT (choline acetyltransferase) and AChE (acetylcholinesterase) in the hippocampus. Mtrrgt/gt mice exhibited short-term memory impairment on two tasks. They had global DNA hypomethylation and decreased choline, betaine and acetylcholine levels. Expression of ChAT and AChE was increased and decreased respectively. At 3 weeks of age, they showed increased neurogenesis. In the cerebellum, mutant mice had DNA hypomethylation, decreased choline and increased expression of ChAT. Our work demonstrates that mild hyperhomocysteinaemia is associated with memory impairment. We propose a mechanism whereby a deficiency in methionine synthesis leads to hypomethylation and compensatory disturbances in choline metabolism in the hippocampus. This disturbance affects the levels of acetylcholine, a critical neurotransmitter in learning and memory.

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Burden of Depressive Disorders

Reviewer and Curator: Larry H Bernstein, MD, FCAP


This article is an important contribution to the literature on depression, substantiation the cardiovascular burden of depression on cardiovascular disease.

Burden of Depressive Disorders by Country, Sex, Age, and Year:Findings from the Global Burden of Disease Study 2010

AJ Ferrar*,FJ Charlson,RE Norman,SB Patten, G Freedman, CJL.Murray,T Vos

1Universityof Queensland, School of Population Health,Herston, Queensland, Au
2Queensland Centre for Mental Health Research, Wacol, Queensland, Au
3University of Queensland, Queensland Children’s Medical Research Institute,Herston,Queensland, Au
4Universityof Calgary, Department of Community Health Sciences,Calgary, Alberta, Ca
5University of Washington,Institute for Health Metrics and Evaluation, Seattle, Wash



Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000  studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions ,burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor fo rsuicide and ischemic heart disease.

Methods and Findings

Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of  epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data

  • quantified the severity of health loss from depressive disorders.

These weights were used to calculate

  • years lived with disability (YLDs) and
  • disability adjusted life-years (DALYs).

Separate DALYs were estimated for

  • suicide and
  • ischemic heart disease

attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010.

  • MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and
  • dysthymia for 1.4% (0.9%–2.0%).

Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause.

  • MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and
  • dysthymia for 0.5% (0.3%–0.6%).

There was more regional variation in burden for MDD than for dysthymia; with

  • higher estimates in females, and
  • adults of working age.

Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained

  • 16 million  suicide DALYs and
  • almost 4 million ischemic heart disease DALYs.

This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs.


GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden

  • allocated to suicide and ischemic heart disease.

These findings emphasize the importance of including depressive disorders as a public-health priority and

  • implementing cost-effective interventions to reduce its burden.

Please see later in the article for the Editors’ Summary.

Citation:Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G,etal.(2013) Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010. PLoS Med 10(11):e1001547. http://dx.doi.org/10.1371/journal.pmed.1001547

Abbreviations: CRA, comparative risk assessment; DALY, disability adjusted life years; DSM, Diagnostic and Statistical Manual of Mental Disorders; GBD, global burden of disease; ICD, International Classification of Diseases; MDD, major depressive disorder; MEPS, US Medical Expenditure Panel Survey; NESARC, US National Epidemiological Survey on Alcohol and Related Conditions 2000–2001 and 2004–2005; NSMHWB, Australian National Survey of Mental Health and Well being of Adults 1997; RR, relative risk; YLD, years lived with disability;YLL,years of life lost.

Figure1.YLDs by age and sex for MDD and dysthymia in 1990 and 2010.  http://dx.doi.org/10.1371/journal.pmed.1001547.g001


Figure2.YLD rates (per100,000) by region for MDD and dysthymia in 1990 and 2010. 95%UI, 95% uncertainty interval; AP-HI, Asia Pacific, high income; As-C, Asia Central; AS-E, Asia East; AS-S, Asia South;A-SE, Asia Southeast; Aus, Australasia; Caribb, Caribbean; Eur-C, Europe Central; Eur-E, Europe Eastern; Eur-W, Europe Western; LA-An, LatinAmerica, Andean; LA-C, Latin America, Central; LA-Sth, LatinAmerica, Southern; LA-Trop, Latin America, Tropical; Nafr-ME, NorthAfrica/MiddleEast; Nam-HI, North America, high income; Oc, Oceania; SSA-C, Sub-Saharan Africa, Central; SSA-E, Sub-Saharan Africa, East; SSA-S, Sub-Saharan Africa Southern; SSA-W, Sub-Saharan Africa,West.  http://dx.doi.org/10.1371/journal.pmed.1001547.g002

Figure2. YLD rates (per100,000) by region for MDD and dysthymia in 1990 and 2010

Plot 1  age dtandardized YLD rates

Editors’ Summary


Depressive disorders are common mental disorders that occur in people of all ages across all world regions. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—can make people feel that life is no longer worth living. People affected by depression lose interest in the activities they used to enjoy and can also be affected by physical symptoms such as disturbed sleep. Major depressive disorder (MDD, also known as clinical depression) is

  • an episodic disorder with a chronic (long-term) outcome and increased risk of death.

It involves at least one major depressive episode in which the affected individual experiences

  • a depressed mood almost all day, every day for at least 2 weeks.

Dysthymia is a milder, chronic form of depression that lasts for at least 2 years. People with dysthymia are often described as constantly unhappy. Both these subtypes of depression (and others such as that experienced in bipolar disorder) can be treated with antidepressant drugs and with talking therapies.

Why Was This Study Done? Depressive disorders were a  leading cause of disease burden in the 1990 and 2000 Global Burden of Disease (GBD) studies, collaborative scientific efforts that quantify the health loss attributable to

  • diseases and injuries in terms of disability adjusted life years (DALYs; one DALY represents the loss of a healthy year of life).

DALYs are calculated by adding together the years of life lived with a disability (YLD, a measure that includes a disability weight factor reflecting disease severity) and the years of life lost because of disorder-specific premature death. The GBD initiative aims

  • to provide data that can be used to improve public-health policy.

Thus, knowing that depressive disorders are a leading cause of disease burden worldwide has helped to prioritize depressive disorders in global public-health agendas. Here, the researchers analyze the burden of MDD and dysthymia in GBD 2010 by country, region, age, and sex, and

  • calculate the burden of suicide and ischemic heart disease attributable to depressive disorders (depression is a risk factor for suicide and ischemic heart disease).

GBD 2010 is broader in scope than previous GBD studies and quantifies the direct burden of 291 diseases and injuries and the  burden attributable to 67 risk factors across 187 countries.

What Did the Researchers Do and Find? The researchers collected data on

  • the prevalence, incidence, remission rates, and duration of MDD and dysthymia and on deaths caused by these disorders from published articles.

They pooled these data using a statistical method called Bayesian meta-regression and calculated YLDs for MDD  and dysthymia using disability weights collected in population surveys. MDD accounted for 8.2% of global YLDs in 2010, making it the second leading cause of YLDs. Dysthymia accounted for 1.4% of global YLDs. MDD and dysthymia were also leading causes of DALYs, accounting for 2.5% and 0.5% of global DALYs, respectively. The regional variation in the burden was greater for MDD than for dysthymia, the  burden of depressive disorders was higher in women than men, the largest proportion of YLDs from depressive  disorders occurred among adults of working age, and the  global burden of depressive disorders increased by 37.5%  between 1990 and 2010 because of population growth and ageing. Finally, MDD explained an additional 16 million  DALYs and 4 million DALYs when it was considered as a risk factor for suicide and ischemic heart disease, respectively.  This ‘‘attributable’’ burden increased the overall burden of depressive disorders to 3.8% of global DALYs.

What Do These Findings Mean? These findings update and extend the information available from GBD 1990 and  2000 on the global burden of depressive disorders. They confirm that

  • depressive disorders are a leading direct cause of the global disease burden and show that
  • MDD also contributes to the burden allocated to suicide and ischemic heart disease.

The estimates of the global burden of depressive disorders reported in GBD 2010 are likely to be more accurate than those in previous GBD studies but are  limited by factors such as the sparseness of data on depressive disorders from developing countries and, consequently,

  • the validity of the disability weights used to calculate YLDs.

Even so, these findings reinforce the importance of treating  depressive disorders as a public-health priority and

  • of implementing cost-effective interventions to reduce their  ubiquitous burden.

Additional Information. Please access these websites via  the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001547.

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