The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials

Abstract

The role of nutrition in mental health is becoming increasingly acknowledged. Along with dietary intake, nutrition can also be obtained from "nutrient supplements", such as polyunsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, amino acids and pre/probiotic supplements. Recently, a large number of meta-analyses have emerged examining nutrient supplements in the treatment of mental disorders. To produce a meta-review of this top-tier evidence, we identified, synthesized and appraised all meta-analyses of randomized controlled trials (RCTs) reporting on the efficacy and safety of nutrient supplements in common and severe mental disorders. Our systematic search identified 33 meta-analyses of placebo-controlled RCTs, with primary analyses including outcome data from 10,951 individuals. The strongest evidence was found for PUFAs (particularly as eicosapentaenoic acid) as an adjunctive treatment for depression. More nascent evidence suggested that PUFAs may also be beneficial for attention-deficit/hyperactivity disorder, whereas there was no evidence for schizophrenia. Folate-based supplements were widely researched as adjunctive treatments for depression and schizophrenia, with positive effects from RCTs of high-dose methylfolate in major depressive disorder. There was emergent evidence for N-acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia. All nutrient supplements had good safety profiles, with no evidence of serious adverse effects or contraindications with psychiatric medications. In conclusion, clinicians should be informed of the nutrient supplements with established efficacy for certain conditions (such as eicosapentaenoic acid in depression), but also made aware of those currently lacking evidentiary support. Future research should aim to determine which individuals may benefit most from evidence-based supplements, to further elucidate the underlying mechanisms.

Keywords: N-acetylcysteine; Nutrient supplements; adjunctive treatment; attention-deficit/hyperactivity disorder; depression; eicosapentaenoic acid; methylfolate; omega-3; polyunsaturated fatty acids; schizophrenia; vitamin D.

Figure 1

PRISMA flow chart

Figure 2

Effects of nutrient supplements in depressive disorders, shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo; diamonds represent p≤0.05 compared to placebo; * represents trim‐and‐fill estimate adjusted for publication bias. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to, MDD – major depressive disorder, EPA – eicosapentaeonoic acid, DHA – docosahexaenoic acid, SSRIs – selective serotonin reuptake inhibitors, NA – not available.

Figure 3

Effects of nutrient supplements in anxiety, shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to.

Figure 4

Effects of nutrient supplements in schizophrenia, shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo; diamonds represent p≤0.05 compared to placebo. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to, HQ – high quality.

Figure 5

Effects of nutrient supplements in states at risk for psychosis, shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to, EPA – eicosapentaeonoic acid, DHA – docosahexaenoic acid.

Figure 6

Effects of nutrient supplements in bipolar disorder, shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo; diamonds represent p≤0.05 compared to placebo. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to, BPD – bipolar disorder, MDD – major depressive disorder, CGI‐S – Clinical Global Impression ‐ Severity, CGI‐I – Clinical Global Impression ‐ Improvement.

Figure 7

Effects of nutrient supplements in attention‐deficit/hyperactivity disorder (ADHD), shown as standardized mean difference with 95% CI. Circles represent no significant difference from placebo; diamonds represent p≤0.05 compared to placebo; * represents trim‐and‐fill estimate adjusted for publication bias. A2 – AMSTAR‐2 total score, A2‐CA – AMSTAR 2 “critical domains” adhered to, PUFAs – polyunsaturated fatty acids, NA – not available, RCTs – randomized controlled trials.