Low Folate, Vitamin D Implicated in First-Episode Psychosis

Batya Swift Yasgur, MA, LSW

December 22, 2017

Nutritional deficiencies, especially deficiencies in folate and vitamin D, are associated with first-episode psychosis (FEP), new research suggests.

Australian researchers found significantly lower levels of folate and vitamin D in patients with FEP, compared to healthy control persons. Limited evidence also suggested that serum levels of vitamin C were reduced in people with FEP.

"The extent of nutritional deficiencies was present right from illness onset," said lead author Joseph Firth, PhD, NICM, School of Science and Health, University of Western Sydney, Australia.

"Seeing it in young people, even prior to antipsychotic treatment, is surprising," he told Medscape Medical News.

The study was published online November 30 in Schizophrenia Bulletin.

Critical Period

"Nutritional deficiencies resulting from insufficient intake or absorption of nutrients critical to human health are now a recognized risk factor for psychiatric disorders," the authors write.

Previous research has demonstrated deficiencies in blood levels of an array of nutrients in long-term schizophrenia patients, including deficiencies in the B vitamins (folate and B-12), antioxidant vitamins (C and E), and vitamin D.

However, which specific nutritional deficiencies are present at the time of FEP, independently of antipsychotic treatment, has "yet to be determined," the investigators note.

"We were motivated by the fact that many studies have examined individual nutrient levels in schizophrenia and early psychosis, but the literature has not yet examined these more broadly across multiple nutrients at once," said Dr Firth.

The authors call the issue "particularly pertinent" because dietary quality appears to be reduced from psychosis onset, and inflammation and oxidative stress ― both of which may be linked to poor nutrition ― are "highest at this point of illness."

Moreover, the FEP phase may be regarded as a "critical period," because it is the stage in which neuroprogression is active.

The current study used meta-analytic techniques "to investigate the presence and severity of nutritional deficits in FEP across every class of vitamin or dietary mineral examined in this population to date."

Beyond determining which deficits might be present, the investigators sought to systematically review the clinical correlates of nutritional status to identify which particular vitamins and minerals were related to physical and mental health outcomes in FEP.

Early Effect

In July 2017, the investigators searched several databases of studies in the English language. They included only studies in which >75% of individuals were specified as representing cases of FEP, or were currently receiving treatment from "early intervention in psychosis" services, or were within the first 3 years of having received antipsychotic treatment for a psychotic disorder.

Eligible studies compared blood levels (including levels of whole blood, plasma, serum, erythrocytes, leukocytes, and other blood components) of any vitamin or dietary mineral in FEP to a non-FEP control sample or reported on clinical correlates of vitamin/mineral levels in FEP samples.

A total of 28 articles (2612 participants, of whom 1221 had FEP and 1391 were healthy control persons) were selected. The studies assessed differences in blood levels of vitamins A, B-12, C, D, E, and folate and 10 minerals ― zinc, magnesium, sodium, potassium, calcium, copper, chromium, iron, manganese, and selenium.

The researchers identified nine studies, which had independent samples, that reported on vitamin B levels (872 participants: 425 with FEP and 447 control persons). In eight of those studies, patients with FEP were medication-naive. The studies assessed folate and vitamin B-12 levels.

Random effects meta-analyses found significantly lower blood levels of folate in patients with FEP, compared with healthy control persons. The researchers called the effect size "moderately large" (N = 6, n = 827, g = −0.624, 95% confidence interval [CI] = −1.176 to −0.072, P = .027).

There was significant heterogeneity across all studies (Q = 66.0, P < .01, I 2 = 92.4%). A range of blood measures showed significant differences between FEP and control persons in plasma, serum, and red blood cell levels.

The four studies (620 participants) that examined blood levels of vitamin B-12 found no significant difference between FEP patients and healthy control persons (g = −0.059, 95% CI = −0.22 to 0.10, P = .468, Q = 2.96, I 2 = 0%).

Of the five studies that examined relationships between folate levels and psychiatric symptoms, as measured by the Positive and Negative Syndrome Scale (PANSS), only one found a significant correlation with PANSS total scores.

However, three studies found significant correlations between serum folate and PANSS subscales, with lower folate levels predicting more severe negative or general symptoms (but not positive or cognitive symptoms). Two of the three studies that examined clinical correlates of vitamin B-12 found an inverse correlation between B-12 and negative symptoms.

Meta-analyses of the seven studies that examined blood levels of vitamin D using plasma and serum measures (906 participants, 429 with FEP, 477 control persons) found that in patients with FEP, vitamin D levels were reduced. There was a large, significant difference between the two groups (g = −1.055, 95% CI = −1.99 to −0.119, P = 0.027).

The three studies that examined correlations between vitamin D and psychiatric symptoms all found some link between low vitamin D levels and worse mental health.

Of the five studies that assessed blood levels of antioxidant vitamins (vitamins A, C, and E) in FEP patients, two studies found significant differences in vitamin C levels between FEP patients and control persons, with the FEP patients having large deficits. However, the authors note, the sample was small, there was substantial heterogeneity, and the studies did not report the specifics of FEP classification.

One study found that in newly diagnosed patients with schizophrenia who were receiving vitamin C supplementation, higher levels of vitamin C were associated with greater symptomatic improvement over 8 weeks.

No significant differences were found in meta-analyses between FEP patients and healthy control persons in levels of any dietary minerals.

The authors state that their study is the first to examine serum nutrient status in FEP and the first to demonstrate that reduced nutritional status exists independently and, in some cases, prior to antipsychotic treatment.

"Previous research has found that nutritional deficiencies exist in long-term illness, but this was often attributed to medication. Seeing it in young people in early stages of illness is surprising," said Dr Firth.

Supplementation Helpful

Commenting on the study for Medscape Medical News, Barbara L. Gracious, MD, of Orange Park Medical Center, Florida, and adjunct associate professor of psychiatry and nutrition, Ohio State University, Columbus, said the study "provides the relative strength of a meta-analysis to find that low folate and vitamin D levels are associated with worse symptomatology and with first-episode illness, not just chronic psychosis."

One of the study's strengths was "comparing serum values in those with FEP to values in control groups," observed Dr Gracious, who was not involved with the study.

A limitation was that the study did not contain a "full nutrient analysis" and investigated six vitamins and ten minerals, "so there is the possibility of selection bias," she said.

The relationship between psychosis and deficiencies in vitamin D and folate may be attributable to their role in ensuring healthy neurons, normal neurodevelopment, and appropriate neurotransmitter production and function and to their anti-inflammatory and antioxidant effects, she suggested.

"Checking folate and 25-OH vitamin D levels is easy to do, and supplementation may be helpful on an individual basis for brain as well as metabolic health," she said.

Dr Firth emphasized that levels of vitamin C, D, and folate "should be assessed in young people being treated for psychosis, and if deficient, clinicians should recommend dietary improvement or perhaps even supplementation if diet alone cannot resolve the deficits."

Dr Firth is supported by a Blackmores Institute fellowship. Other researchers are supported by National Health and Medical Research Council fellowships and the National Institute for Health Research.

Schizophr Bull. Published online November 30, 2017. Full text


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