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B vitamins may benefit some patients with first-episode psychosis

Image of Kelly Allott
Kelly Allott

Researchers found no overall benefit of adjuvant vitamin B12, B6 and folic acid on symptoms and neurocognition in first-episode psychosis, according to study findings.

However, secondary analyses revealed that B-vitamins may benefit attention/vigilance in women and patients with elevated homocysteine and affective psychosis.

“We know that B-vitamins (particularly B6, B12 and folate) are important for brain health,” Kelly Allott, DPsych, from Orygen, The National Centre of Excellence in Youth Mental Health, and The University of Melbourne, Australia, told Healio Psychiatry. “Previous research involving people with long-term schizophrenia has shown that B-vitamin supplementation can improve symptoms of psychosis. However, no previous study had investigated whether B-vitamins could improve symptoms following a first episode of psychosis. Early effective treatments have the potential to prevent longer-term illness and functional difficulties.”

The researchers conducted a randomized, double-blind, placebo-controlled trial to evaluate whether homocysteine-lowering agents — folic acid, vitamin B12 and B6 — could lower homocysteine levels and improve symptomatology and composite neurocognition in 120 patients with first-episode psychosis.

Participants were randomized to receive once-daily adjunctive B-vitamin supplement (containing folic acid 5 mg, B12 0.4 mg, and B6 50 mg) or placebo for 12 weeks. Along with change in symptoms and neurocognition, researchers examined change in additional psychopathology measures (ie, symptoms, neurocognition, functioning, tolerability and safety).

Allott and colleagues found that B-vitamin supplementation had no significant effects on symptomology as measured by the Positive and Negative Syndrome Scale, or neurocognition. In addition, the results showed no significant group differences in secondary symptom domains.

However, over the 12 weeks, the B-vitamin group showed a greater average decrease in homocysteine levels (effect size = –0.65; P = .003). Furthermore, analysis revealed a significant group difference in the attention/vigilance domain (effect size = 0.49; P = .024) indicating that the B-vitamin group remained stable while the placebo group declined in performance.

Overall, 14% of the sample had high homocysteine levels at baseline, which was tied to greater improvements in attention/vigilance after taking B vitamins, according to the results.

“B-vitamin (B6, B12, folate) supplementation can aid concentration skills in young people with first-episode psychosis,” Allott told Healio Psychiatry. “People with psychosis who have elevated homocysteine levels (>15 mcmol/L) have a stronger response to B-vitamin supplementation than those who have normal homocysteine levels. This indicates that B-vitamin supplementation personalized to those with elevated homocysteine may be particularly beneficial.”

In addition, being female and having affective psychosis was linked to better neurocognition in select domains in patients taking B vitamins, according to the study.

“Given the high tolerability and low side-effect profiles of nutritional supplements, future research could explore using targeted multi-nutrient interventions for synergistic action in [first-episode psychosis],” Allott and colleagues wrote in Biological Psychiatry. “Individuals who have abnormal homocysteine or blood vitamin levels may be the most responsive to adjuvant vitamin treatment, strongly supporting a precision medicine or biomarker-guided treatment approach.” – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.

Editor’s note: This article was updated 1/30 with comments from the author.

Image of Kelly Allott
Kelly Allott

Researchers found no overall benefit of adjuvant vitamin B12, B6 and folic acid on symptoms and neurocognition in first-episode psychosis, according to study findings.

However, secondary analyses revealed that B-vitamins may benefit attention/vigilance in women and patients with elevated homocysteine and affective psychosis.

“We know that B-vitamins (particularly B6, B12 and folate) are important for brain health,” Kelly Allott, DPsych, from Orygen, The National Centre of Excellence in Youth Mental Health, and The University of Melbourne, Australia, told Healio Psychiatry. “Previous research involving people with long-term schizophrenia has shown that B-vitamin supplementation can improve symptoms of psychosis. However, no previous study had investigated whether B-vitamins could improve symptoms following a first episode of psychosis. Early effective treatments have the potential to prevent longer-term illness and functional difficulties.”

The researchers conducted a randomized, double-blind, placebo-controlled trial to evaluate whether homocysteine-lowering agents — folic acid, vitamin B12 and B6 — could lower homocysteine levels and improve symptomatology and composite neurocognition in 120 patients with first-episode psychosis.

Participants were randomized to receive once-daily adjunctive B-vitamin supplement (containing folic acid 5 mg, B12 0.4 mg, and B6 50 mg) or placebo for 12 weeks. Along with change in symptoms and neurocognition, researchers examined change in additional psychopathology measures (ie, symptoms, neurocognition, functioning, tolerability and safety).

Allott and colleagues found that B-vitamin supplementation had no significant effects on symptomology as measured by the Positive and Negative Syndrome Scale, or neurocognition. In addition, the results showed no significant group differences in secondary symptom domains.

However, over the 12 weeks, the B-vitamin group showed a greater average decrease in homocysteine levels (effect size = –0.65; P = .003). Furthermore, analysis revealed a significant group difference in the attention/vigilance domain (effect size = 0.49; P = .024) indicating that the B-vitamin group remained stable while the placebo group declined in performance.

Overall, 14% of the sample had high homocysteine levels at baseline, which was tied to greater improvements in attention/vigilance after taking B vitamins, according to the results.

“B-vitamin (B6, B12, folate) supplementation can aid concentration skills in young people with first-episode psychosis,” Allott told Healio Psychiatry. “People with psychosis who have elevated homocysteine levels (>15 mcmol/L) have a stronger response to B-vitamin supplementation than those who have normal homocysteine levels. This indicates that B-vitamin supplementation personalized to those with elevated homocysteine may be particularly beneficial.”

In addition, being female and having affective psychosis was linked to better neurocognition in select domains in patients taking B vitamins, according to the study.

“Given the high tolerability and low side-effect profiles of nutritional supplements, future research could explore using targeted multi-nutrient interventions for synergistic action in [first-episode psychosis],” Allott and colleagues wrote in Biological Psychiatry. “Individuals who have abnormal homocysteine or blood vitamin levels may be the most responsive to adjuvant vitamin treatment, strongly supporting a precision medicine or biomarker-guided treatment approach.” – by Savannah Demko

Disclosure: The authors report no relevant financial disclosures.

Editor’s note: This article was updated 1/30 with comments from the author.

    Perspective
    Joshua L. Roffman

    Joshua L. Roffman

    Recent randomized clinical trials in chronic schizophrenia patients suggest a small but consistent benefit for supplemental folic acid, particularly for negative symptoms. The new study by Allott and colleagues, in press in Biological Psychiatry, is the first to evaluate a multivitamin cocktail including folic acid (5 mg) and other B-vitamins in younger, first episode psychosis patients. Improved clinical outcomes in early stages of psychosis predict better outcomes later on, as early interventions potentially harness a period of increased cortical plasticity. That folic acid and other B-vitamins are safe, inexpensive and readily available — and possibly demonstrate some efficacy against negative symptoms, which are generally treatment-resistant and strongly associated with impaired function — provides a very solid rationale for this study in first episode patients.

    At first blush, the results of the study are disappointing, in that the vitamin intervention did not associate with significant improvement in either composite measures of illness severity or cognition, nor specifically with negative symptom change. However, interpretation of these findings requires a close comparison of the present study with earlier trials, and some additional biological context around folate transport to the brain. Notably, blood folate levels were markedly higher at baseline — nearly twice as high, for example, as those reported in studies conducted by our group — and baseline symptom severity was much lower, as the authors acknowledge. Given previous cross-sectional associations between low blood folate levels and increased symptom severity, one wonders whether any beneficial effects of folic acid were already maximized at baseline within this sample. Indeed, previous work demonstrates that CSF folate levels plateau at moderate blood folate levels, reflecting saturation of specialized folate transporters in the blood-brain barrier. In this light, the authors’ negative findings are not surprising — and nor is the emergence of a hint of treatment-related cognitive benefit among patients with especially high homocysteine (and, presumably, low folate) measures at baseline. 

    In short, additional work is needed to determine whether folic acid supplements might improve symptoms in first episode psychosis patients, especially those with low blood folate (or high blood homocysteine). Indeed, the previous work of Levine and colleagues demonstrated a clear benefit of a multivitamin intervention (including 2 mg folic acid) for both clinical and cognitive measures among a group of schizophrenia patients with baseline homocysteine elevation. 

    In the meantime, clinicians and patients at all stages of psychotic illness should continue to consider folic acid or methylfolate supplementation. While benefits may be more pronounced in patients with low blood folate or high homocysteine, given the low cost and low risk of folic acid-based interventions, empiric supplementation trials (even without laboratory testing, and certainly without genetic testing) remain a reasonable option.

    References:

    Goff DC, et al. Am J Psychiatry. 2004;doi:10.1176/appi.ajp.161.9.1705.

    Levine J, et al. Biol Psychiatry. 2006;doi:10.1016/j.biopsych.2005.10.009.

    Obeid R, et al. Clin Che. 2007;doi:10.1373/clinchem.2006.085241.

    Roffman JL, et al. JAMA Psychiatry. 2013;doi:10.1001/jamapsychiatry.2013.900.

    Roffman JL, et al. Mol Psychiatry. 2018;doi:10.1038/mp.2017.41.

    • Joshua L. Roffman, MD, MMSc
    • Department of psychiatry
      Massachusetts General Hospital
      Harvard Medical School
      Healio Psychiatry Peer Perspective Board Member

    Disclosures: Roffman reports research support from Pamlab.

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