Vitamin D

Vitamin D deficiency has been reported in patients with schizophrenia, although trials examining vitamin D supplementation have shown “variable” results.2 Some studies have demonstrated that early supplementation with vitamin D decreases the risk of developing schizophrenia by as much as 77%.14 However, to date, no randomized controlled trials have examined vitamin D supplementation specifically in patients with schizophrenia.2

Vitamins C and E

Vitamins C and E are antioxidants that “remove cellular reactive oxygen species and protect cells from oxidative stress.”2 Low levels of both vitamins have been associated with schizophrenia.  Small studies have found that vitamin C decreases serum malondialdehyde (a measure of antioxidant levels), which in turn yields improvements in BPRS scores. However, vitamin C may interact with antipsychotic medications.2 And at high doses, vitamin E may become pro-oxidant and actually increase oxidative stress.2

Other Agents

Bexarotene is a retinoid X receptor approved by the US Food and Drug Administration (FDA) for treating cutaneous T-cell lymphoma. Aberrant signaling by retinoids may play a role in neuropsychiatric illness, including schizophrenia.2 A small study of inpatients with schizophrenia (n=90) found that treatment with bexarotene yielded a significantly greater decrease in PANSS positive scores than did placebo.15 However, bexarotene should be used with caution, as it may increase total cholesterol levels and reduce total thyroxine levels.

Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated fatty acids (PUFAs), which are necessary for maintaining the structure and function of cell membranes and synthesizing other biological compounds necessary for neuronal function. Additionally, PUFAs have anti-inflammatory properties.2 Reduced levels of PUFAs have been found in patients with schizophrenia. Numerous studies have found that supplementation with omega-3 fatty acids improves schizophrenia symptoms, including extrapyramidal symptoms associated with antipsychotics.2 However, it cannot be used as monotherapy in a chronic illness population.2 It has demonstrated effectiveness in preventing relapse, even in ultra-high-risk patients.16,17


The authors conclude by noting that many therapeutic targets are potentially available for adjunctive treatment in schizophrenia and encourage larger, randomized control trials “focusing on longer treatment duration and specific antipsychotic medications.”