Vitamin B₁₂ Deficiency Masquerading as Clozapine-Resistant Psychotic Symptoms in Schizophrenia

“Ms. V,” a 27-year-old single woman, with a vegetarian diet, presented with more than 10 years of illness characterized by irritability and assaultive behavior, auditory hallucinations, delusions of reference, persecution, and misinterpretation, with significant acting-out behavior. She was diagnosed with paranoid schizophrenia as per ICD-10 criteria. She was treated with risperidone up to 8 mg, lithium 600 mg, and 13 sessions of electroconvulsive therapy. She did not improve significantly, and a decision to start her on clozapine was made. Investigations, including a complete hemogram, peripheral smear, fasting blood sugar, lipid profile, renal function test, liver function test, serum electrolytes, thyroid function test, electrocardiogram, and electroencephalogram, did not reveal any abnormality. She was started on clozapine, which was gradually increased up to 225 mg. She had side effects like hypersalivation, constipation, tremors, tachycardia; hence, clozapine was decreased to 200 mg. She had two episodes of generalized tonic–clonic seizures. Clozapine was subsequently decreased to 175 mg, and valproate up to a dose of 1,000 mg was initiated. She was maintaining well for 5 months, after which she had a relapse due to drug default. Subsequently, she was restarted on clozapine, which was increased up to 200 mg, along with valproate 1,000 mg and eight sessions of electroconvulsive therapy. She showed significant improvement and hence was discharged. She was maintaining well for 9 months.

However, she had a relapse of psychotic symptoms again while on regular medication. The Scale for the Assessment of Positive Symptoms (SAPS)⁷ rating at the time of admission was 33. Physical examination revealed pallor. Blood investigation results were as follows: hemoglobin: 9.7 (normal: 13–17) g/dl, MCV: 108.3 (normal: 80–101 fl), PCV: 31 (normal: 40–50 L/L), MCH: 33.7 (normal: 27–32 pg), MCHC: 31.2 (normal: 315–345 g/L. Serum vitamin B₁₂ value at that time was 236 (normal: 174–878 pg/ml). Peripheral smear revealed a macrocytic normochromic picture with mild anisocytosis and hypersegmented neutrophils. The patient had no dermatological, neurological, or other physical findings suggestive of vitamin B₁₂ deficiency, no coexisting medical history, and was not on any other medication. It was decided to administer her intramuscular vitamin B₁₂ in view of the low serum value. She was given cyanocobalamin 1,000 μg/day daily for 1 month. She was maintained on an unchanged dose of clozapine 200 mg and valproate 750 mg. Within 1 to 2 days of vitamin administration, the patient was seen to have significant change in her ward behavior in the form of reduction of anger, fearfulness, and suspiciousness. Over the next week, she showed significant improvement in psychiatric symptoms, with prominent reduction of the delusions of persecution, reference, and auditory hallucinations. By the end of 1 month of daily parenteral supplements, the SAPS score came down to 10. She continues to be on the same medication combination and daily oral vitamin B₁₂ preparation while also receiving monthly parenteral vitamin supplementation. She continues to be asymptomatic for more than 8 months since then, with a current SAPS score of 2. There is a significant improvement in her socio-occupational functioning, and she has gained complete insight into her illness, with regular medication adherence. Her current serum B₁₂ level is 1,192 pg/ml, and MCV is 94.3 fl.

This patient had a normal smear picture during the early part of her illness; hence this is unlikely to be organic psychosis caused by vitamin B₁₂ deficiency. However, during the course of her illness, probably due to inadequate nutrition, she developed vitamin B₁₂ deficiency. This is likely to have been a factor in her being a nonresponder to various antipsychotics, including clozapine, especially after an initial period of response to clozapine.

Vitamin B₁₂ plays a very vital role in the central nervous system. It is vital for homocysteine methylation to methionine, which is necessary for the synthesis of s-adenosyl methionine, which is essential for neurotransmitter metabolism. Any abnormality in the methylation process has been hypothesized to be a possible biochemical basis for neuropsychiatric manifestations of vitamin B₁₂ deficiency. The levels of an excitatory neurotoxin called methytetrahydrofolate are markedly elevated in vitamin B₁₂ deficiency and may be responsible for neuronal destruction.⁸

The patient described in this report had a relapse of psychotic symptoms while on regular medication with clozapine and improved with parenteral B₁₂ supplementation while other medications were unchanged. Psychiatric manifestations in the absence⁵ of any overt clinical examination findings indicative of vitamin B₁₂ deficiency (including neurological symptoms) are worth noting. 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 550 pg/L.⁹

This case clearly highlights the role of vitamin B₁₂ in treatment of schizophrenia nonresponsive to antipsychotics including clozapine and ECT. Earlier surveys have shown that a large number of psychiatric patients have low serum B₁₂ levels, ranging from 6% to 15%.¹⁰ This case highlights the need for vitamin B₁₂ measurement in the initial part of the disease process itself to assess whether it is a causative factor or whether the deficiency contributes to a poorer outcome. Co-existing B₁₂ deficiency in a patient with psychosis maybe more frequent than B₁₂ deficiency causing organic psychosis, but early initiation of parenteral B₁₂ supplementation may be beneficial in both situations.