Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients

Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients. The study focused on negative symptoms of schizophrenia – which include apathy, social withdrawal, and a lack of emotional expressiveness. While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism. The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry ) and has been issued online.



Rationale: This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment.

Objective: We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia.

Methods: The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model.

Results: Although we included ten RCTs with 925 patients in total (seven folic acid RCTs (n = 789), two methylfolate RCTs (n = 96), and one folinic acid RCT (n = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total (N = 7, n = 340; standardized mean difference (SMD) = - 0.20, 95% confidence interval (CI) = - 0.41, 0.02, p = 0.08, I2 = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I2 = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments (N = 4, n = 241; risk ratio = 0.32, 95% CI = 0.12-0.82, p = 0.02, I2 = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments.

Conclusions: Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.

Adjunctive L-Methylfolate Offers Benefit in Depression Treatment

Supplemental treatment with the medical food L-methylfolate may benefit patients with depression who do not respond to antidepressants, according to a review article published online in CNS Spectrums.

Rakesh Jain, MD, MPH

Rakesh Jain, MD, MPH

“L-methylfolate has been well studied in multiple clinical trials, and findings support its consideration for use as an adjunctive therapy in any depression management program, and especially in patients with characteristics suggestive of potential responsiveness,” wrote lead author and Psych Congress cochair Rakesh Jain, MD, MPH, and colleagues.

Believed to enhance the synthesis of serotonin, norepinephrine, and dopamine as well as to suppress inflammation and promote neural health, L-methylfolate is the biologically active form of folate and is available over-the-counter and in a prescription formulation. Supplemental use of L-methylfolate shows particular promise, the article explained, for improving outcomes in patients with selective serotonin reuptake inhibitor-resistant major depressive disorder and the following characteristics:

• low folate levels;

• mutations in gene-coding enzymes that are involved in the metabolism of folate;

• body mass index greater than 30 kg/m2; and

• elevated markers of inflammation, including C-reactive protein.

Conversely, L-methylfolate should be avoided in patients with hypersensitivity to the nutraceutical. Overall, however, L-methylfolate as adjunctive therapy for major depressive disorder was well tolerated in trials, with a safety profile resembling placebo.

The authors recommended use of L-methylfolate be considered in conjunction with other wellness-promoting interventions, such as diet and exercise.

“Supplementation with L-methylfolate fits well with the changing paradigm of major depressive disorder management,” they wrote, “with the ultimate goal of producing wellness instead of focusing solely on symptom reduction.”

—Jolynn Tumolo

Anyone taking methylfolate, methyl b12 etc?

For me methylfolate improves mood, instantly reduces depression mood. It helps me to think clearly. Methyl b12 on the other hand reduces drowsiness bit like a stimulant and hard to fall asleep after taking it.

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B12 deficiency causes psychosis, so if your psychosis is partially caused by a B12 deficiency, then taking methyl B12 will help you, but not everyone with psychosis has a B12 deficiency. Since I’ve been dealing with psychosis partially caused by a B12 deficiency, then taking B12 and eliminating the B12 deficiency helped reduce psychotic symptoms.

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i take fish oil and multivitamin.i think thats good enough.

I stopped taking omega 3 as it causing heart palpitations, anxiety, agitation etc.

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