Author Affiliations: Dr. Sabeen is Assistant Professor and Dr. Holroyd is Professor, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville.
Abstract: Vitamin B12 deficiency is a common occurrence in the elderly and is associated with delirium, dementia, depression, and psychosis. Psychiatric symptoms may occur in the absence of characteristic hematologic or neurologic symptoms suggestive of B12 deficiency. Because psychiatric symptoms can occur in low-to-moderate “normal” vitamin B12 levels, homocysteine or methylmalonic acid levels should also be checked in those with psychiatric symptoms. Importantly, dementia or cognitive decline become irreversible if not treated promptly. Psychosis appears to respond to vitamin B12 replacement, even after prolonged periods of a B12-deficient state, again pointing out the need to check for B12 deficiency in the elderly with psychosis. Future research and follow-up studies are needed. (Annals of Long-Term Care: Clinical Care and Aging 2009;17:32-36)
Cobalamin, commonly known as vitamin B12, is a member of the vitamin B complex family. Vitamin B12 plays an essential role in maintaining homeostasis in the nervous and the hematologic systems. Psychiatric symptoms are associated with deficiencies in vitamin B12 and can be difficult to diagnose, as the psychiatric manifestations can present without the hematologic or neurologic ones. This article reviews the association of psychiatric illness and vitamin B12 deficiency.
To briefly review the biochemistry, two forms of vitamin B12, methylcobalamin and 5-deoxyadenosyl cobalamin, are active in the human body.1 Methylcobalamin is required for the synthesis of the enzyme methionine synthase via a methylation reaction. Methionine synthase is an enzyme required for the production of the amino acid methionine from homocysteine. Thus, in vitamin B12 deficiency, the level of homocysteine increases secondary to decreased utilization.2 The other form of cobalamin, 5-deoxyadenosyl cobalamin, is involved in the transformation of L-methylmalonyl-CoA to succinyl-CoA.3 This is essential for the synthesis of hemoglobin in the production of red blood cells and for the production of energy from fats and protein, as well as fatty acid production. This latter process plays an integral part in the formation and maintenance of the myelin sheath. Methylmalonic acid (MMA) is a metabolite of aforementioned enzymatic process that, in the situation of B12 deficiency, will be increased. It is noted then that increased levels of both homocysteine and MMA can be markers of functional vitamin B12 deficiency,4 which can occur even in the presence of “normal” vitamin B12 serum levels.
The literature review was conducted on PubMed, National Library of Medicine, and The Cochrane Library using the following terms: B12 deficiency, psychiatric illness and B12 deficiency, dementia and B12 deficiency, methylmalonic acid, homocysteine, reversible dementia, mood disorder, and B12 deficiency.
Causes of Vitamin B12 Deficiency
Vitamin B12 has a very specific mechanism in order to be absorbed by the body. The acidic environment of the stomach frees the vitamin from food, where it binds with R protein and travels to the small intestine. In the small intestine, the R protein is degraded by pancreatic enzymes facilitated by the alkaline environment. Intrinsic factor (IF) secreted by specialized stomach cells binds with vitamin B12 in the terminal ileum, and the vitamin B12-IF complex is then absorbed. The absorption takes place via a receptor mechanism in the presence of calcium supplied by the pancreas and about 1% by passive diffusion.5 The most common causes of vitamin B12 deficiency are usually due to problems with malabsorption, given the complicated route of absorption, rather than dietary deficiency.
In pernicious anemia, an autoimmune process results in the destruction of the cells of the stomach leading to a twofold problem with B12 absorption: decreased acidity interfering with separation of vitamin B12 from food and antibodies to IF. This causes a reduction in IF, and thus the formation of vitamin B12-IF complex necessary for absorption. In the elderly population, B12 malabsorption can also occur due to reduced gastric acid production or pancreatic enzyme deficiency.6 Other causes are surgical removal of stomach and portions of small intestine, celiac disease and tropical sprue, pancreatic insufficiency, alcoholism, prolonged use of gastric acid–reducing medications, and AIDS. Less commonly, a strict vegetarian diet low in vitamin B12 causes deficiency.
Supplements of vitamin B12 come in injectable, oral, and nasally-inhaled forms. Given that the etiology of deficiency is usually due to absorption, injectable forms are usually used rather than oral. The injectable form is usually dosed as 1000 mcg per month, although many prefer to give it weekly for the first month to ensure rapid replacement, followed by monthly maintenance therapy. Those patients who refuse injection may try the nasally-inhaled form, but rather than given monthly, it is typically given weekly at a dose of 500 mcg. Whatever the replacement method, follow-up vitamin B12 levels should be checked to ensure adequate replacement. In addition, IF can be replaced if that is deficient and causing B12 deficiency.
Recently, studies revealed that high-dose oral vitamin B12 is equally as effective as the injectable form, and may be superior.7-9 It is clearly cost-effective, noninvasive, and requires fewer office visits.7,8 High-dose oral B12 is widely used, mostly in Sweden since the 1970s, but also in Canada.7,10 The recommended oral dose for B12 replacement is 2000 mcg per day. Kuzminski et al9 reported that 1000 mcg per day initially, then weekly, followed by monthly were effective in reversing the hematological and neurological picture.
The prevalence of vitamin B12 deficiency is estimated to be 10-15% in a population that is age 60 years or older.11 However, it is estimated that only 5-10% of those have obvious clinical symptoms suggestive of a deficiency state.12 Common clinical nonpsychiatric manifestations of B12 deficiency include a macrocytic anemia and spinal cord disturbances with decreases in vibration and position sense. As well, there may be gastrointestinal symptoms of vitamin B12 deficiency, including constipation, decrease in appetite, glossitis, and glossodynia.13
Various psychiatric symptoms have been found to be associated with vitamin B12 deficiency. The exact mechanism by which B12 deficiency leads to psychiatric symptoms is not known.6 Depression, psychosis, and cognitive disturbances including dementia or delirium are the major psychiatric symptoms associated with this deficiency.
Studies by multiple authors have revealed that psychiatric manifestations of B12 deficiency may occur in the absence of hematological or spinal cord symptoms.14-18 Research has also revealed that psychiatric symptoms can occur with B12 levels slightly lower than normal values but considerably higher than the values associated with macrocytic anemia.14-18 This has led to considerable controversy about the lowest “normal” value of serum vitamin B12.6 Some have suggested that the “normal” range of vitamin B12, usually considered to be 190 pg/mL to 900 pg/mL may be correct for hematologic symptoms, but not for neurologic or psychiatric symptoms.19 A study by Catalano et al20 involving patients in a general medical hospital suffering from affective and cognitive illness found that 31.3% and 20.6% of consecutive patients, respectively, had a B12 level of 400 pg/mL, suggesting that levels in the low-normal range may be functionally low.
The Bronx Longitudinal Aging Study21 looking at the incidence of dementia in previously asymptomatic (without any cognitive problems) elderly revealed that those with moderate levels of vitamin B12 (mean, 558 pg/mL) had the same incidence as those with low vitamin B12 levels of 200 pg/mL or less. This suggests that low-normal or even moderate-normal values of vitamin B12 can predispose to cognitive decline in the elderly. Thus, current vitamin B12 levels may not identify the patients predisposed to the cognitive effects of vitamin B12 deficiency.22,23 Therefore, although laboratory diagnosis of vitamin B12 deficiency usually includes a serum vitamin B12 assay, serum homocysteine or MMA can be used to diagnose a deficient state despite a “normal” serum vitamin B12, as both will be elevated in both serum and urine in functional vitamin B12 deficiency.
Specific psychiatric syndromes associated with B12 deficiency follow:
Vitamin B12 deficiency is associated with cognitive decline. The cognitive deterioration in B12 deficiency is generally attributed to demyelination of the cerebrum; however, the exact mechanism is unclear.24 Vitamin B12 has been attributed to improved cognitive functioning, specifically in the function of frontal lobe and language.25 Interestingly, cognitive changes have also been found in adolescents with vitamin B12 deficiency.25,26
The cognitive decline can be either delirium (presumably if caught early) or dementia. Unfortunately, the reversibility of the dementia process with replacement of vitamin B12 is not promising if caught too long after cognitive symptoms are present. Some researchers emphasize the need to replace B12 “in a precise clinical window, before the onset of the first symptoms.”25 Others have underscored the urgency to correct B12 deficiency within 6-12 months to obtain maximum response to treatment, as longer periods of deficiency lead to irreversible damage to cognitive function.27 Still others note that only a small number of patients with a cognitive/psychiatric presentation respond to treatment with replacement of B12, although most patients respond hematologically, and about half of neurologic symptoms respond.12
An elevated serum homocysteine level has been found to be associated with a higher risk of dementia and Alzheimer’s disease (AD) in some studies.28,29 One study showed a low level of vitamin B12 in the cerebrospinal fluid but not in the serum, in those patients diagnosed with AD.30 Another study found that a serum B12 level of 203.252 pg/mL or less and a low folate level (≤ 4.413 ng/mL) were associated with a twofold increase in the risk of developing AD in 370 study participants followed over a 3-year period.31 Controversy remains surrounding the best correlate of B12 deficiency and cognitive impairment. It is unclear whether the serum B12 level, a B12 carrier protein assay, or an increased level of MMA is linked more specifically to cognitive impairment or can assess the effectiveness of B12 replacement treatment in terms of cognitive functioning.32
An interesting case report illustrates a case of cognitive decline in vitamin B12 deficiency. A patient in the sixth decade of life had features of decline in executive function, long- and short-term memory impairment, disorientation, and confusion. Neurological examination was notable for posterior column involvement and a low-normal B12 level (307 pg/mL). Further evaluation determined deficiency of IF affecting B12 absorption. After B12 replacement along with IF, detailed neuropsychological testing showed an improved performance, including better cognitive speed when repeated.33
Depression is one of the common psychiatric symptoms of vitamin B12 deficiency. Vitamin B12 and folate are involved in the synthesis of S-adenosylmethionine (SAMe), a methyl group donor essential for the synthesis of neurotransmitters that have been implicated in mood disorders. A study by Bottiglieri et al30 found a decreased level of SAMe in the cerebrospinal fluid in patients with severe depression. A meta-analysis of clinical studies looking at 3884 elderly, both men and women, showed a 70% more likelihood of experiencing depression in a vitamin B12–deficient group.34 Another study of community-dwelling women age 65 years and older found that those suffering from severe depression were two times as likely to have B12 deficiency as women with a normal or nondeficient state.35 In psychiatric inpatients, 30% of patients hospitalized for depression were found to be vitamin B12–deficient.36
An interesting case report of a 52-year-old woman reported catatonia with depressive symptoms and decreased cognition without any hematological or neurological changes, with a B12 level of 150 pg/mL (range, 190 pg/mL-1190 pg/mL). This patient had remission of her psychiatric symptoms and returned to premorbid baseline with correction of the deficiency without any psychotropic medication.37 Catatonia as a symptom of vitamin B12 deficiency has also been reported.38
There is a paucity of studies looking longitudinally at the association of vitamin B12 deficiency and development of depression. Although controlled studies are lacking as to the response to vitamin B12 replacement in depression, it is recommended that all patients with indicators of vitamin B12 deficiency be treated as a part of the depression treatment.
Psychosis has been reported in B12 deficiency, including both hallucinations and delusions.14,39 Multiple case reports of both acute-onset and chronic psychosis in the setting of vitamin B12 deficiency have been reported. Evans et al14 reported two patients with psychosis in the absence of hematological or neurological symptoms. Along with resolution of psychosis, electroencephalography findings suggestive of cerebral dysfunction in these two patients were reversed with B12 replacement.
Acute onset of persecutory delusions in a patient with symptoms of lower-extremity paralysis without megaloblastic anemia revealed a B12 level of less than 9 pg/mL (normal, 200 pg/mL-950 pg/mL).40 Authors in this case report suggested that folate supplement masked the hematological presentation. With vitamin B12 supplementation, psychosis improved in 2 months, and there was also partial improvement of neurological symptoms.
Another case report presented a patient with delusions and command hallucinations in the setting of nitrous oxide abuse, whose B12 level was in the lower-normal range (202 pg/mL), with significantly increased MMA (127.2 mg/L) and homocysteine (6.543 mg/L).41 The psychosis resolved with vitamin B12 supplementation.
Two case reports discuss persecutory delusions and auditory hallucinations in patients with cervical vertebral disease (stenosis, spondylosis) that apparently misled the treating physicians in not initially exploring the possibility of vitamin B12 deficiency until the development of the psychosis.42,43 In both cases, there was resolution of psychotic symptoms with vitamin B12 replacement.
A case report of a patient with a 2-year history of auditory hallucinations and persecutory delusions with signs of posterior column involvement without anemia showed complete resolution of symptoms following vitamin B12 replacement.44
Although there can be resolution of symptoms with vitamin B12 supplementation, the exact mechanism of B12 deficiency leading to psychosis remains unknown. It is encouraging to note that in the cases of psychosis associated with vitamin B12 deficiency, there appear to be good outcomes even after prolonged periods of times (at least up to 2 yr) of psychosis, with replacement of vitamin B12. This suggests that vitamin B12 deficiency should be considered in the case of any psychosis, and especially in the elderly. Homocysteine or MMA levels should be checked, as well for vitamin B12 levels in the low-to-moderate normal range, to ensure correct diagnosis.
Considering the above discussion, it is our recommendation that patients with any psychiatric or neurologic symptoms should have homocysteine or MMA levels checked for vitamin B12 levels of lower than 500 pg/mL to ensure that one does not miss functional vitamin B12 deficiency.
Data specifically focused on B12 deficiency prevalence, clinical presentation, or practice of replacement are extremely limited in the long-term care (LTC) setting. However, the necessity and importance of checking for B12 deficiency in LTC residents cannot be emphasized enough.
Vitamin B12 deficiency is a common occurrence in the elderly population. Psychiatric symptoms may become evident without the hematological changes or obvious neurological symptoms suggestive of B12 deficiency. Psychiatric symptoms occur in ranges of low to moderate normal vitamin B12 levels; thus, homocysteine or MMA levels should also be checked in those with psychiatric symptoms. Importantly, since psychiatric illnesses—in particular, dementia or cognitive decline—become irreversible if not treated promptly, it is imperative that vitamin B12 levels be checked routinely in the elderly population for presentation of any cognitive or psychiatric symptoms. Future research is needed to determine a more accurate “normal” level of vitamin B12 in those with psychiatric symptoms, and to study whether checking homocysteine or MMA levels may be a better first step in diagnosing this condition. Follow-up studies in those with psychiatric symptoms treated with vitamin B12 are also needed.
The authors report no relevant financial relationships.