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Clinical and Research Reports   |    
Vitamin B12 Levels and Psychiatric Symptomatology: A Case Series
Naveen Jayaram, M.B.B.S., M.D.; Mukund G. Rao, M.B.B.S., M.D.; Aniruddh Narasimha, M.B.B.S; Dhanya Raveendranathan, M.B.B.S., M.D.; Shivarama Varambally, M.B.B.S., M.D.; Ganesan Venkatasubramanian, M.B.B.S., M.D.; B. N. Gangadhar, M.B.B.S., M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2013;25:150-152. doi:10.1176/appi.neuropsych.12060144
View Author and Article Information

Conflict of interest: None declared.

From the Dept. of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.

Send correspondence to Dr. Shivarama Varambally, Dept. of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India; e-mail: drvarambally@gmail.com

Copyright © 2013 American Psychiatric Association

Received June 08, 2012; Accepted October 16, 2012.

Cobalamin (Vitamin B12) has been implicated in the pathogenesis of various neuropsychiatric disorders. A review of 19 patients (14 vegetarians) with demonstrable vitamin B12 deficiency showed varied psychiatric symptomatology, with the majority not having significant hematological or neurological manifestations.

Abstract Teaser
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Cobalamin (Vitamin B12), a water-soluble essential vitamin, has a vital role in DNA synthesis during cell division.1 It is also linked with synthesis of neurotransmitters such as dopamine and serotonin, and thus has been implicated in the pathogenesis of various neuropsychiatric disorders.2 In earlier times, a one-carbon hypothesis of schizophrenia was hypothesized, citing impaired transmethylation leading to an accumulation of toxic metabolites.3

Although varied psychiatric manifestations caused by vitamin B12 deficiency have been described, the possibility of psychiatric disorders being caused by B12 deficiency is often overlooked. Psychiatric manifestations of vitamin B12 deficiency can include depression, apathy, irritability, dementia, catatonia, delirium, and hallucinations.4,5 Higher vitamin B12 levels are thought to be associated with a more favorable outcome in depression.6 A study in general psychiatric inpatients reported the incidence of vitamin B12 deficiency to be 4%–6%.7 Neuropsychiatric abnormalities are reported to be present in up to 28% of patients in the absence of any change in the hematocrit values or increase in red cell mean corpuscular volume (MCV); these indices are usually the most commonly investigated for B12 deficiency. Hence, a vitamin B12 level estimation is warranted in such conditions.

Poor intake or absorption causes vitamin B12 deficiency. It is synthesized by bacteria and is found only in animal-derived products such as meat, egg, and dairy products, but not in plant-derived products. With improved nutrition, vitamin B12 deficiency is relatively rare in developed countries, but is still prevalent in the developing world. In particular, it is prevalent in the Indian population, as a pure vegetarian diet is followed by various sections of society.8 In this case series, we report on 19 patients where vitamin B12 deficiency and psychiatric symptomatology were coexistent.

A large number of our cases were diagnosed with psychosis. The systemic examinations were within normal limits for all, except in the case of three patients, one of whom had sensory deficits in both lower limbs; the other two had pallor. Table 1 shows the clinical characteristics of patients who had serum B12 levels in the lower range of normal.

 
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TABLE 1.Summary of Clinical Case Characteristics

Of the patients who had psychosis, the majority of them had prominent Schneiderian first-rank symptoms, most commonly, thought alienation phenomena, commenting and 3rd-person auditory hallucinations, delusions of persecution and reference, and passivity phenomena. Those with depression had characteristic features of depression—prominently depressive cognitions, anhedonia, easy fatigability, and somatic symptoms. The patient with episodic psychosis had prominent psychotic symptoms, but no classic first-rank symptoms. The patient with bipolar disorder had classic manic symptoms.

This report highlights the importance of assessment of Vitamin B12 in patients with psychiatric illness. All patients presented with psychiatric symptoms alone, and were diagnosed to have coexistent vitamin B12 deficiency only on subsequent evaluation. B12 deficiency was suspected in these patients in view of their vegetarian diet; of 19 patients, 14 had followed a strict vegetarian diet. A functional B12 deficiency is known to be common in vegetarians, as Vitamin B12 is not present in plant products.1 However, because of the cross-sectional design of our study, cause–effect relationship cannot be inferred, and the association could be primary or secondary to the psychiatric disorder, or incidental. However, there has been a report of psychotic symptoms deemed to be resistant to psychotropic treatments that dramatically improved after administration of Vitamin B12.4,9,10

Although reports of dementia-like syndrome have also been documented in the existing literature, this is less likely in our cohort because these patients were predominantly middle-aged. Most of the elderly population in our hospital would be attending a separate clinic dealing with Geriatric Psychiatry.

The majority of the patients did not have significant hematological and neurological manifestations, and Vitamin B12 deficiency was diagnosed on laboratory assessments. Pallor was also absent on physical examination in all but two of the cases. Also, in a few of the patients, B12 levels were in the lower limit of the normal range, lending credence to earlier reports suggesting that psychiatric manifestations often predate the neurological symptoms, at times by as much as a few years.11 Also, psychiatric manifestations can occur before the levels of vitamin B12 are below 175 pg/L, and it has been proposed that the threshold needs to be increased to 660 pg/L.11 Studies also mention a “window period” within which treatment may reverse changes, after which axonal demyelination and other pathological changes may be irreversible.10

Recently, obtaining vitamin B12 levels in all psychiatric patients has also been recommended, as mild vitamin B12 deficiency could have been present and undetected for long periods of time.8 In particular, screening patients with psychiatric illness in high-risk groups, such as elderly persons, those on a vegetarian diet, and having gastrointestinal disorders was recommended.10 Serum B12 estimation is a simple and sensitive laboratory investigation, and a level above 600 pg/ml is advisable.12 Also, the possibility of testing B12 levels in those patients not on a vegetarian diet but not responding to conventional treatments might be indicated.

A major limitation of our study was a lack of corresponding folic acid level measurement, which was not possible in our set-up for logistic reasons; however, there were sufficient clinical grounds to consider a primary B12 deficiency in isolation.

Most of the patients in our series had no major physical comorbidity that is known to be associated with cobalamin deficiency, and they were predominantly vegetarians. Hence, a high index of suspicion must be exercised in psychiatric patients who are vegetarians and who present with symptoms that are refractory to conventional psychotropics or antidepressants. Also, based on our observations, a syndromal psychotic illness in patients who are vegetarians may merit Vitamin B12 assessment.

In summary, this report emphasizes the importance of investigation for vitamin B12 deficiency in psychiatrically ill patients, especially those in high-risk groups. The downstream changes due to impaired DNA synthesis leading to the development of psychopathology are, as yet, unknown. Future studies are needed to further evaluate the role of vitamin B12 in the pathogenesis of psychiatric disorders.

Herrmann  W;  Lorenzl  S;  Obeid  R:  [Review of the role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric disorders: current evidence and preliminary recommendations].  Fortschr Neurol Psychiatr 2007; 75:515–527
[CrossRef] | [PubMed]
 
Catalano  G;  Catalano  MC;  O’Dell  KJ  et al:  The utility of laboratory screening in medically ill patients with psychiatric symptoms.  Ann Clin Psychiatry 2001; 13:135–140
[CrossRef] | [PubMed]
 
Regland  B:  Schizophrenia and single-carbon metabolism.  Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:1124–1132
[CrossRef] | [PubMed]
 
Catalano  G;  Catalano  MC;  Rosenberg  EI  et al:  Catatonia: another neuropsychiatric presentation of vitamin B12 deficiency? Psychosomatics 1998; 39:456–460
[CrossRef] | [PubMed]
 
Holmes  JM:  Cerebral manifestations of vitamin B12 deficiency.  BMJ 1956; 2:1394–1398
[CrossRef] | [PubMed]
 
Hintikka  J;  Tolmunen  T;  Tanskanen  A  et al:  High vitamin B12 level and good treatment outcome may be associated in major depressive disorder.  BMC Psychiatry 2003; 3:17
[CrossRef] | [PubMed]
 
Brett  AS;  Roberts  MS:  Screening for vitamin B12 deficiency in psychiatric patients.  J Gen Intern Med 1994; 9:522–524
[CrossRef] | [PubMed]
 
Marks  PW;  Zukerberg  LR:  Case records of the Massachusetts General Hospital. Weekly Clinicopathological Exercises: Case 30-2004: a 37-year-old woman with paresthesias of the arms and legs.  N Engl J Med 2004; 351:1333–1341
[CrossRef] | [PubMed]
 
Masalha  R;  Chudakov  B;  Muhamad  M  et al:  Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency.  Isr Med Assoc J 2001; 3:701–703
[PubMed]
 
Raveendranathan  D;  Shiva  L;  Venkatasubramanian  G  et al:  Vitamin B12 deficiency masquerading as clozapine-resistant psychotic symptoms in schizophrenia.  J Neuropsychiatry Clin Neurosci 2013; 25:e34–e35
[CrossRef] | [PubMed]
 
Berry  N;  Sagar  R;  Tripathi  BM:  Catatonia and other psychiatric symptoms with vitamin B12 deficiency.  Acta Psychiatr Scand 2003; 108:156–159
[CrossRef] | [PubMed]
 
Dommisse  J:  Subtle vitamin B12 deficiency and psychiatry: a largely unnoticed but devastating relationship? Med Hypotheses 1991; 34:131–140
[CrossRef] | [PubMed]
 
References Container
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TABLE 1.Summary of Clinical Case Characteristics
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References

Herrmann  W;  Lorenzl  S;  Obeid  R:  [Review of the role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric disorders: current evidence and preliminary recommendations].  Fortschr Neurol Psychiatr 2007; 75:515–527
[CrossRef] | [PubMed]
 
Catalano  G;  Catalano  MC;  O’Dell  KJ  et al:  The utility of laboratory screening in medically ill patients with psychiatric symptoms.  Ann Clin Psychiatry 2001; 13:135–140
[CrossRef] | [PubMed]
 
Regland  B:  Schizophrenia and single-carbon metabolism.  Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:1124–1132
[CrossRef] | [PubMed]
 
Catalano  G;  Catalano  MC;  Rosenberg  EI  et al:  Catatonia: another neuropsychiatric presentation of vitamin B12 deficiency? Psychosomatics 1998; 39:456–460
[CrossRef] | [PubMed]
 
Holmes  JM:  Cerebral manifestations of vitamin B12 deficiency.  BMJ 1956; 2:1394–1398
[CrossRef] | [PubMed]
 
Hintikka  J;  Tolmunen  T;  Tanskanen  A  et al:  High vitamin B12 level and good treatment outcome may be associated in major depressive disorder.  BMC Psychiatry 2003; 3:17
[CrossRef] | [PubMed]
 
Brett  AS;  Roberts  MS:  Screening for vitamin B12 deficiency in psychiatric patients.  J Gen Intern Med 1994; 9:522–524
[CrossRef] | [PubMed]
 
Marks  PW;  Zukerberg  LR:  Case records of the Massachusetts General Hospital. Weekly Clinicopathological Exercises: Case 30-2004: a 37-year-old woman with paresthesias of the arms and legs.  N Engl J Med 2004; 351:1333–1341
[CrossRef] | [PubMed]
 
Masalha  R;  Chudakov  B;  Muhamad  M  et al:  Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency.  Isr Med Assoc J 2001; 3:701–703
[PubMed]
 
Raveendranathan  D;  Shiva  L;  Venkatasubramanian  G  et al:  Vitamin B12 deficiency masquerading as clozapine-resistant psychotic symptoms in schizophrenia.  J Neuropsychiatry Clin Neurosci 2013; 25:e34–e35
[CrossRef] | [PubMed]
 
Berry  N;  Sagar  R;  Tripathi  BM:  Catatonia and other psychiatric symptoms with vitamin B12 deficiency.  Acta Psychiatr Scand 2003; 108:156–159
[CrossRef] | [PubMed]
 
Dommisse  J:  Subtle vitamin B12 deficiency and psychiatry: a largely unnoticed but devastating relationship? Med Hypotheses 1991; 34:131–140
[CrossRef] | [PubMed]
 
References Container
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