by Natasha Kate, MBBS; Sandeep Grover, MD; and Munish Agarwal, MD

Ms. Kate is Junior Resident, Dr. Grover is Assistant Professor, and Dr. Agarwal is Senior Resident— All from the Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Psychiatry (Edgemont) 2010;7(11):42–44

Funding: There was no funding for the development and writing of this article.

Financial Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Key Words: Depression, Vitamin B12 deficiency, treatment resistance

Abstract: We present two cases of treatment-resistant depression that improved with recognition and correction of the underlying medical etiology of vitamin B12 deficiency. Supplementations of vitamin B12 to the same antidepressant regimen that the patient had not responded earlier led to response. Two male subjects who were vegetarians presented with long-standing histories of depression and had not responded to three adequate trials of antidepressants. Upon investigation, the authors found that the subjects had low vitamin B12 levels. Both cases improved with supplementation of vitamin B12. Subjects with depression who do not respond to conventional antidepressants should be evaluated for nutritional factors.


At times, medical disorders may be mistaken for a primary psychiatric disturbance because of prominent and commonly associated psychiatric or behavioral manifestations. The lack of recognition of the underlying medical condition precludes optimal treatment even though the psychiatric treatment might be appropriate for the symptoms, often manifesting as inadequate response or psychotropic treatment resistance.[1] Increasing severity of the underlying medical illness can also increase the risk of relapse in psychiatric disorders despite adequate psychotropic medication.[2]

In this case series, we present two cases of men with major depression with cognitive dysfunction who did not respond to adequate antidepressants trials. On investigation, both men were found to have an underlying medical etiology in the form of low serum vitamin B12 levels. Both cases improved with vitamin B12 supplementation and continuation of same antidepressant.

Case 1

Mr. D, a 43-year-old man, presented with chief complaints of insomnia since age 18. He was premorbidly well adjusted with no family history of mental illness. He had a history of tobacco dependence syndrome and was using the substance at the time he presented for treatment. History revealed that he was a vegetarian. He had difficulty in falling asleep, which progressed over the years to difficulty in maintaining sleep followed by complete insomnia. To overcome his sleep problem, he started taking alcohol, which helped him initially but over the years his insomnia persisted. About 4 to 5 years after the onset of insomnia, he started having cognitive symptoms in the form of slowness in thinking, difficulty in calculations, and forgetfulness for names of objects and people. These symptoms were followed by a major depressive episode. He was treated by many physicians and psychiatrists with antidepressants in various combinations in adequate doses for adequate duration (imipramine 150mg/day for 2 years; fluoxetine 20mg/day for 3 years; clomipramine 75mg/day for 3 months; mirtazapine 30mg/day for 5 months; escitalopram 20mg/day for 5 months; and milnacipran 100mg/day for 3 months) with no improvement. About one year prior to presentation, he stopped taking alcohol as it did not help his symptomatology and led to problems at work place. When he presented to the authors’ office initially, the possibility of primary insomnia with major depression was considered. On further investigation, no abnormality was detected in his hemogram, including peripheral blood smear, liver function test, renal function test, ultrasound abdomen, thyroid function test, electrocardiogram, electroencephalogram, and computerized tomography of brain. Mr. D was started on trazadone up to 150mg/day, but he did not show improvement in any of the symptoms over the period of four weeks. Psychometric evaluation revealed significant impairment in memory (retention and recall for immediate, recent, and remote memory), attention and concentration, and perceptuo-motor tasks. Later, further investigation revealed low serum B12 levels of 127pg/mL (normal range= 180–914pg/mL); however, the test for antiparietal cell antibodies was negative. After tests detected vitamin B12 deficiency, Mr. D was treated with Vitamin B12 1000mg/day intramuscular (IM) for seven days along with folic acid followed by 1000mg IM every alternate day for the next two weeks. No further change was made in the antidepressant medication. Within three weeks, his sleep improved and depressive symptoms reduced significantly (Hamilton Depression Rating Scale [HDRS] score reduced from 20 to 6), and later he continued on trazodone 150mg/day and oral vitamin B12 supplementation of 200mg/day. Over the follow-up period of 1.5 years, Mr. D maintained this treatment regimen and continued to see improvement in his cognitive symptoms.

Case 2

Mr. S, a 29-year-old man who had anxious-avoidant personality traits, presented with a history of major depressive disorder of five years leading to marked dysfunction. Over this time period, his symptoms were treated with escitalopram 20mg/day for three months and venlafaxine 225mg/day for two months along with supportive psychotherapy without any improvement. Following this, he started on imipramine, which was gradually increased up to 150 mg/day with which he also did not show any improvement over the period of two months. He was then re-evaluated, and history revealed that he was a vegetarian and, besides depressive symptoms (HDRS-28), he also had cognitive symptoms in the form of forgetfulness. His psychometry revealed significant impairment, especially for attention-concentration, new learning, and immediate and visual recall. He was investigated, and serum B12 levels were found to be low at 148pg/mL (normal range=180–914pg/mL). Following this, he was started on vitamin B12 1000mg/day IM for seven days along with folic acid, followed by 500mg IM every alternate day for the next two weeks. No further change was made in the antidepressant medication. Within four weeks, depressive symptoms improved (HDRS-4), and he was continued on oral vitamin B12 supplementation of 200mg/day along with imipramine 150mg/day. Over the follow-up period of four months, he had a minor relapse of depressive symptoms following a life stressor, which improved with continuation of the previously mentioned regimen and supportive psychotherapy. After two months of starting B12 supplementation, his repeat psychometry showed improvement in all cognitive domains.


Literature suggests that depression is the most common psychiatric disorder seen in subjects with vitamin B12 deficiency, and the symptoms are similar to a functional disorder, thereby making underlying medical illness difficult to suspect. Subjects with vitamin B12 deficiency and depression may present with history of past episodes with spontaneous remission or response to treatment with antidepressants and later recognition or development of vitamin B12 deficiency.[3–5]

In this case series, the symptoms of depression and cognitive dysfunction improved with vitamin B12 supplementation without the change in antidepressants that were given for the adequate period prior to supplementation with B12. These two cases highlight the fact that an underlying medical etiology should be considered as a possibility in subjects presenting with treatment-resistant symptoms.

1.    O’Brien RF, Kifuji K, Summergrad P. Medical conditions with psychiatric manifestations. Adolesc Med. 2006;17:49–77.
2.    Iosifescu DV, Nierenberg AA, Alpert JE, et al. Comorbid medical illness and relapse of major depressive disorder in the continuation phase of treatment. Psychosomatics. 2004;45:419–425.
3.    Smith ADM. Megaloblastic madness. Br Med J. 1960;2:1840–1845.
4.    Fraser TN. Cerebral manifestations of Addisonian pernicious anaemia. Lancet. 1960;2:458–459.
5.    Strachan RW, Henderson JG. Psychiatric syndromes due to avitaminosis B12 with normal blood and marrow. Quart J Med 1965; 34:303–317.