Nutritional Supplements in Psychiatric Disorders – The Evidence
Time to read: 8 minutes
Diet and nutrition are considered key modifiable factors in the development of mental health disorders. [Lai et al 2014]; [O’Neil et al 2014]
High fat and high sugar diets are unbalanced and nutrient-poor and these deficits can be a risk factor for not only cardiometabolic diseases and cancer but also mental health disorders.
Nutritional neuroscience is an emerging research field that investigates how nutrient supplementation can not only complement an inadequate diet but also provide added physiological benefits and act as adjuncts to pharmacotherapy. [Jacka 2017]; [Marx et al 2017]
Commonly cited nutrient supplements in the literature include the following [Firth et al 2019]:
Vitamins:
- Vitamin B9 (folate) deficiency is linked to a number of psychiatric disorders including depression, dementia, and schizophrenia. In addition, vitamin D deficiency is linked not only to bone metabolism issues but also with cognitive impairment, dementia, psychosis, depression, and autism. [Maddock et al 2017]
Dietary minerals:
- Deficiencies in trace minerals such as zinc and magnesium are associated with the underlying pathophysiology of depression and anxiety. [Młyniec K et al 2014; Młyniec K et al 2015]
Pre/probiotics:
- The growing interest in the gut microbiome and its role in the development of mental health disorders has resulted in the development of specific strains of gut bacteria that may be advantageous as well as investigations into probiotic nutrients that promote health-related microbiota.
Polyunsaturated fatty acids (PUFAs):
- PUFAs are essential fatty acids required for forming all membranes in the body and are especially necessary for the development, maintenance, and function of the brain. An imbalance in the types of fatty acids consumed is linked to mood disorders, psychosis, ADHD, and cognitive deficits. [Simopoulos et al 2008]
Amino acids
- N-acetylcysteine (NAC) is an acetylated derivative of the amino acid cysteine and a precursor to glutathione that has been clinically investigated as a potential disease modifier in mood disorders, schizophrenia, OCD, and addiction and substance use disorders. [Ooi et al 2018]
- Glycine is an important amino acid neurotransmitter that on the NMDA receptor and therefore may have a therapeutic effect in NMDA receptor hypofunction states associated with schizophrenia. [Javitt et al 2001]
Although there is very little evidence that wide-scale usage of multivitamin and mineral tablets reduces the incidence of disease, specific nutrients for specific populations (i.e. folic acid during pregnancy or omega-3 for patients with myocardial infarction) do have substantial supporting evidence.
A recent meta-review of RCTs analysed the literature to determine the possible causal relationship between nutrient supplements and the outcome on mental health illnesses for which a standardised mean difference (SMD) was used to measure effect size versus placebo. [Firth et al 2019]
FOLATE
Dietary folate comes in a variety of different forms, including folic acid, folinic acid, and methylfolate.
Methylfolate is readily absorbed, overcoming any genetic predispositions towards folic acid malabsorption, and successfully crossing the blood‐brain barrier.
The use of methylfolate in the management of mood disorders may be beneficial, especially when patients have polymorphisms of the methylene tetrahydrofolate reductase gene (MTHFR), which result in less efficient conversion of folate to methylfolate (its active metabolite) in the single carbon cycle. [Zheng et al., 2020]
MTHFR polymorphisms can now be determined by genetic analysis and may help target patients where methylfolate containing supplements may have clinical utility. [Dartois et al., 2019]
Depression:
- Small benefit when methylfolate is used at 7.5 to 15 mg/day (SMD=0.37; p=0.04) although a more moderate-sized effect was also observed with high dose (15 mg/day) as adjunctive treatment in treatment-resistant depression (SMD=0.73; p=0.002).
- The systematic review by Zheng et al. showed that adjunctive folate is effective and safe.
Schizophrenia:
- Moderate benefit observed on negative symptoms but only with methylfolate at 15 mg/day (SMD=0.30; p=0.05) as an adjunctive treatment.
- A placebo‐controlled trial of methylfolate in schizophrenia reported significant increases in white matter within just 12 weeks, with a reduction in negative symptoms [Roffman J et al., 2018]
- A systematic review showed folate was not effective in schizophrenia. [Zheng et al., 2020]
PUFAs
PUFAs
Omega-3 fatty acids such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) as well as omega‐6 fatty acids, such as linoleic acid have been assessed for their effect on mental health disorders.
Depression:
- Small-to-moderate effect size when formula contained >50% EPA and providing a dose of 2,200 mg/day EPA (SMD=0.42; p<0.001) both individually and as an adjunct.
- Omega‐3 may be most beneficial for patients presenting with raised inflammatory markers.
- DHA showed no benefits
- No effect with PUFAs when depression was a comorbid disorder to chronic physical conditions
Bipolar disorder:
- Small effect size was observed in patients with bipolar disorder but only on depressive symptoms (SMD=0.34; p=0.029).
ADHD:
- Small positive effects for total ADHD symptoms, along with hyperactivity‐impulsivity and inattention subdomains with high EPA formulas providing up to 2,513 mg EPA/day.
- No effects on comorbid emotional/behavioural problems
- Although significant benefits on composite ADHD symptom scores have been reported, when adjusting for publication bias, this resulted in a non-significant result.
- However, a trend for a positive effect on parent‐rated oppositional behaviour was observed (SMD=0.23; p=0.05).
Schizophrenia:
- No effect observed on symptoms of schizophrenia, including depressive symptoms.
- Positive but mixed results in first-episode psychosis attributed to neuroprotective properties.
AMINO ACIDS
Amino Acids
N-Acetylcysteine (NAC):
- NAC is found in abundance in high protein foods and has been shown to have substantial antioxidant activity.
- NAC is a precursor to glutathione (primary endogenous antioxidant). Oral glutathione and L‐cysteine are broken down by the first‐pass metabolism and do not increase brain glutathione levels, while oral N‐acetylcysteine, is more easily absorbed, and can increase brain glutathione and dopamine.
- NAC reduces oxidative stress a glutamatergic dysfunction but also has wider preclinical effects on mitochondria, apoptosis and neurogenesis.
- Glutathione, NAC and Oxidative Stress.
- NAC in Schizophrenia and Bipolar Disorder
- NAC in Addiction and other Psychiatric disorders
Glycine:
Glycine is abundantly found in meat, dairy, and legumes and has been suggested to be an NMDA receptor modulator.
Depression:
- NAC at 2-3 g/day provided a small-to-moderate benefit on depressive symptoms (SMD=0.37 p=0.001); however, more studies are necessary as data quality is low.
Bipolar disorder :
- NAC at 2-3 g/day had a small effect size on functional impairment in patients with bipolar disorder (SMD=0.31; p=0.002); however, more studies are necessary as data quality is low.
Schizophrenia:
- Adjunctive treatment with NAC had a moderate effect on total symptom scores (SMD=0.74; p=0.03) although there were indications of a high risk of publication bias.
- Glycine (2.8‐60 g/day) and sarcosine (2 g/day) showed a moderate effect on total symptoms, (but not positive symptoms) as an adjunctive treatment (SMD=0.66; p=0.04). However, significant benefits for negative symptoms were observed in individuals treated with non‐clozapine antipsychotics.
OCD:
- Small effect size was observed on obsessive-compulsive symptoms when administered as an adjunctive treatment although this result wasn’t significant (SMD=0.29; p=0.064).
OTHER NUTRITIONAL SUPPLEMENTS
Vitamin D
- Moderate effect size was observed in patients with depression when 50,000 IU/week was administered (SMD=0.58; p<0.01); however, results are variable. Sunlight exposure is a major contributing factor to this heterogeneity.
Zinc
- Moderate effect size on depressive symptoms when administered as an adjunct at 25 mg/day (SMD=0.66; p<0.01).
Magnesium
- No data on adjunctive treatment in patients with MDD however, supplementation at 225-4,000 mg/day showed there was no effect on depressive symptoms.
Pre- and probiotics
- Patients with mild-to-moderate depression had reduced depressive symptoms when treated with various probiotics (SMD=0.68; p=0.029).
Vitamin E
- Although no effect was observed on patients with schizophrenia, vitamin E did prevent antipsychotic-induced tardive dyskinesia from worsening over one year. [Bergman et al. 2017]
Inositol
- Supplementation with inositol (median 12 mg/day) had no effect on depressive symptoms in bipolar disorder or MDD. There was also no effect on total symptom scores in schizophrenia with 6-12 mg/day inositol.
SUMMARY
Several nutritional interventions are efficacious for a range of specific mental disorders.
EPA as an adjunct to antidepressants in depression, high dose methylfolate in patients with schizophrenia or depression shows the most robust evidence.
Although the data on NAC is still limited, it does appear to be effective at reducing depressive symptoms and providing benefits as an adjunctive treatment in schizophrenia at doses above 2000mg/day.
Nutrient supplementation should not be considered as a substitute for a good diet. Dietary interventions can reduce all-cause mortality, cardiovascular and cancer mortality and depressive symptoms. [Reedy J et al., 2014], [Firth J et al., 2019]
Clinical trials on nutrient supplementation need to use a targeted approach that is biomarker-guided to enable clinicians to be able to determine what nutritional deficiencies or key nutrient levels require optimisation in patients with mental health disorders.
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