689533

research-article2017
APY0010.1177/1039856216689533Australasian PsychiatrySarris

Australasian
Invited Article Psychiatry
Australasian Psychiatry

Clinical use of nutraceuticals in 1­–4

© The Royal Australian and
New Zealand College of Psychiatrists 2017

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DOI: 10.1177/1039856216689533
https://doi.org/10.1177/1039856216689533

depression in mood disorders journals.sagepub.com/home/apy

Jerome Sarris  Professor of Integrative Mental Health, NICM, Western Sydney University, Campbelltown, NSW, and; Principal
Research Fellow, The University of Melbourne, Department of Psychiatry, The Melbourne Clinic, Professorial Unit, Melbourne,
VIC, Australia

Abstract
Objectives: The aim of this paper is to detail a summary of the current evidence in this area, to better inform clinical
practice. Our recent systematic reviews and meta-analyses of nutrient pharmacotherapies in the treatment unipolar
depression revealed primarily positive results for replicated studies testing S-adenosyl methionine (SAMe), methyl-
folate, omega-3 (EPA or ethyl-EPA), and Vitamin D; with supportive isolated studies found for creatine and an amino
acid combination. Mixed results were found for zinc, folic acid, Vitamin C, and tryptophan; and non-significant
study results for inositol. In bipolar depression, omega-3 and N-acetyl cysteine (NAC) were found to have supportive
evidence, with an isolated study using a chelated mineral formula also displaying efficacy. No major adverse effects
were noted in the studies (aside from occasional minor digestive disturbances with omega-3 and NAC).
Conclusions: Several clinical considerations are needed when psychiatrists are considering prescribing nutrients,
including knowledge of drug interactions, supplement safety and quality issues, individual psychological and bio-
chemical individualities, in addition to cost factors.

Keywords:  depression, major depressive disorder, bipolar disorder, mood, nutrient, supplement, nutraceutical,
omega 3, SAMe, folic acid, N-acetyl cysteine

A
s the majority of sufferers of major depressive
disorder or bipolar disorder treated with first-
line antidepressants do not achieve remission for
their depressed mood,1,2 safe and effective adjunctive
treatments that improve therapeutic response to these
pharmacotherapies are of potential benefit. Aside from
modulating neurotransmission, novel methods may
target non-neurotransmitter pathways (such as provid-
ing a reduction of inflammation).3 One potential novel
approach is via the co-prescription of nutrient-based
‘nutraceuticals’ which may augment a particular neuro-
biological activity of an antidepressant medication (e.g.
enhanced re-uptake inhibition of monoamines), or may
exert an array of additional biological effects.4
Nutrients consumed from dietary means are critical for
proper brain function, and evidence is increasingly sup-
porting both the relationship between dietary quality
and mood, and the prescriptive application of nutraceu-
tical supplements.5 A varied complex wholefood diet
that is rich in key nutrients which affect brain function,
such as zinc, folate, and omega-3, has been shown to
affect a range of neurobiological processes which may be
implicated in depression.5 Specific nutrients may target
some of these key neurobiological pathways to enhance
response to antidepressants. For example, nutraceuticals
may modulate neurobiological mechanisms underpin-
ning depression, such as monoamine impairment,
neuro-endocrinological aberrations, reduced neurogen-
esis, redox and bioenergetics abnormalities, and cytokine
alterations consistent with chronic inflammation.6,7
While the potential of enhancing the effects of antide-
pressants via nutraceuticals is compelling, only recently
have enough human clinical trials become available to
provide a clearer determination of their effectiveness.
The aim of this paper is to provide a summary of the cur-
rent major evidence in this area in order to inform clinical
practice. Consumer use of nutraceuticals for mood disor-
ders is common (in particular for women),8 and clinicians
may be unsure as to which nutraceuticals have supportive
evidence as adjunctive therapies alongside medication.
Further, clinicians may have safety concerns in respect to
co-prescription. Thus, this paper concisely summarises the
current evidence for adjunctive nutraceutical application
Corresponding author:
Jerome Sarris, Building 5, Campbelltown, NSW, Australia.
Email: J.Sarris@westernsydney.edu.au

1

(within the allowable word count), being based primarily
on our peer-reviewed systematic reviews and meta-analy-
ses. Brief clinical considerations, with an emphasis on
safety issues, are also outlined. This opinion piece is not
provided to encourage unqualified nutraceutical prescrip-
tion, more so that the readership may benefit from under-
standing the current state of evidence in the area.
Current evidence
In respect to nutraceuticals enhancing the effect of anti-
depressants in the treatment of major depressive disor-
der, our recent systematic review and meta-analysis9
revealed primarily positive results for replicated studies
testing S-adenosyl methionine (SAMe), methylfolate,
omega-3 (eicosapentaenoic acid [EPA] or ethyl-EPA), and
Vitamin D (a separate negative community-based, non-
clinical trial notwithstanding),10 creatine, and the amino
acid combination; mixed results for zinc, and Vitamin C;
while inositol revealed no significant effect over pla-
cebo. A sufficient number of double-blind randomised
controlled trials (RCTs) of adequate heterogeneity
existed for omega-3 and folic acid to be applied into a
meta-analysis. When the omega-3 data were pooled in a
meta-analysis, a highly significant effect (p=0.009) was
found with a moderate to strong clinical effect size
(g=0.61). Sensitivity analyses revealed that when meta-
analysis of the data was restricted to EPA-inclusive stud-
ies (removing the docosahexaenoic acid [DHA]-only arm
of Mozaffari-Khosravi et al. 201311), this effect size was
slightly strengthened (g=0.69; p=0.007). The pooled data
of folic acid RCTs, however, revealed a non-significant
difference between the synthetic nutrient and placebo
(p=0.23) with an effect size g of 0.49. This null effect was
maintained (p=0.29) when removing the disproportion-
ately large Bedson et al. 2014 study12 (n=475). It should
be noted that methylfolate and folinic acid (post meth-
ylenetetrahydrofolate [MTHF] reductase compounds
that are unaffected by the MTHF polymorphism) were
not included in the meta-analysis due to the heterogene-
ity between the compounds.
In respect to use of nutraceuticals in the treatment of
bipolar disorder, our systematic review13 found positive
effects for various nutrients to improve outcomes on
bipolar depression, with the most studies involving
omega-3. Other positive studies were found for N-acetyl
cysteine, and a chelated mineral and vitamin formula.
Sufficient data were available to be combined into a
meta-analysis for omega-3. The pooled data of five stud-
ies (six data sets) revealed a statistically significant effect
(p=0.029) with an effect size g of 0.34. Sensitivity analy-
ses revealed that when including only the studies using
Hamilton Depression Rating Scale outcome (Gracious et
al. 201014 and Keck et al. 200615 removed), the results
increased in significance (p=0.001; effect size g of 0.64).
It should be noted that since this meta-analysis, a
4-month RCT (n=45) studying 4 g/day of omega-3 (3 g of
EPA) alone or in combination with cytidine 2 g/day in
patients with bipolar disorder type 1, found no statistical
2
Australasian Psychiatry 
difference compared with placebo.16 The small sample
and lack of clarity in the reporting of raw data, however,
preclude any clear determination.
All of the nutraceuticals reviewed have mechanistic anti-
depressant activity underpinning their use. For example,
the one-carbon cycle nutrients (SAMe, folic acid/methyl-
folate) are critical in methylation processes of monoam-
ines.17 In particular, SAMe may improve depressed mood
via enhanced methylation of catecholamines and
increased serotonin turnover, re-uptake inhibition of nor-
epinephrine, enhanced dopaminergic activity, increased
phosphatidylcholine conversion, and decreased prolactin
secretion.18 Omega-3 (in particular EPA) exerts antidepres-
sant activity via modulation of norepinephrine, dopa-
mine and serotonin re-uptake, degradation, synthesis and
receptor binding; increase in glutathione antioxidant
capacity;19 and the enhancement of cell membrane fluid-
ity, which may benefit inter-cellular communication.20
Clinical considerations
For a brief summary of the evidence and clinical consid-
erations for co-prescribing nutraceuticals in depression,
see Table 1. Regarding specific recommendations, the
finding from the omega-3 meta-analyses, demonstrates
that this augmentation approach significantly reduces
depressive symptoms beyond placebo in both unipolar
and bipolar depression, and thus has potential clinical
and public health significance. As detailed in a recent
general meta-analysis,21 it is advised that EPA or ethyl-
EPA-dominant formulas be used, as DHA may not be
effective. In summation, EPA-rich omega-3 fish oil may
be recommended for the adjunctive treatment of depres-
sion, and is relatively inexpensive. In respect to folic
acid and methylfolate, results are less clear. As the meta-
analysis revealed, folic acid cannot be firmly recom-
mended; however, the ‘active’ form of methylfolate can
be tentatively recommended. A range of other nutrients
also have promising data supporting their adjunctive
use; however, larger replicated studies are needed before
a firmer determination can be made.
Despite the mild nature of the adverse effects reported in
the clinical trials for the nutraceuticals reviewed, they are
not without safety concerns, especially when combined
with certain medications. SAMe and creatine have been
associated with an increased risk of hypomanic/manic
episodes in depressed patients (primarily having been
reported in patients with a diagnosed bipolar disor-
der).23,24 Oral administration of SAMe is expected to be
safer than injected forms; however, caution is still
advised in patients not taking mood stabilisers.25
L-Tryptophan or 5-Hydroxytryptophan, when used in
conjunction with other serotonergic agents (such as
antidepressants, or opioid pain medications) may cause
serotonin syndrome, and thus caution is advised, espe-
cially in higher doses.26 High doses of zinc (>25 mg/day)
can lead to copper deficiency,27 and can compete for
absorption of other minerals consumed. At doses above
1000 mg/day, Vitamin C has been linked to an increase
Sarris

Table 1.  Adjunctive nutraceuticals for unipolar and bipolar depression*

Nutrient Mechanisms of action Current evidence Clinical comment

Omega-3 Re-uptake inhibition of monoamines;
Benefits neurotransmission via increasing
cell membrane fluidity; Reduces
inflammation; Enhances neurogenesis.
N-acetyl Antioxidant and anti-inflammatory
cysteine properties; Replenishes glutathione;
Enhances neurogenesis; Protects against reducing depression (larger replication Usually not available OTC in
mitochondrial toxicity; Modulates
glutamate pathway.
S-adenosyl Influences metabolism and synthesis of
methionine neurotransmitters as a necessary methyl
donor of methyl groups; Decreases
prolactin secretion and Increases
phosphatidylcholine conversion.
L-Tryptophan / Tryptophan is required for conversion
5-HTP into serotonin in the presence of B6 and
magnesium via intermediary step to the
‘active’ form 5-HTP.
Vitamin D A ‘neurosteroid’ compound that is a
ligand for receptors in the prefrontal
cortex, hypothalamus, and substantia
nigra; Involved in the expression of genes large preventative study using a very avoidant or dark-skinned people.
encoding for tyrosine hydroxylase.
Zinc Zinc is a prevalent trace element in the
amygdala, hippocampus, and neocortex;
Involved with hippocampal neurogenesis
via up-regulation of BDNF; Modifies
NMDA and glutamate activity.
Creatine Creatine plays a pivotal role in brain
energy homeostasis; Modifies the high-
energy phosphate metabolism of the brain, as an augmentation agent with
which may be impaired in depression.
MDD and Bipolar Depression: Dose: 1–2 g of EPA per day
Meta-analyses have respectively The balance of evidence suggests
revealed positive results for only modest effect as a monotherapy.
adjunctive omega-3 (mainly EPA- Can especially recommend in
dominant formulations). deficient states, or in comorbid
inflammatory conditions, or CVD.
Bipolar Depression: Dose: 1–1.5 g b.i.d.
One RCT has shown effectiveness in May take over 8 weeks for response.
study completed and results due Australia. Potentially beneficial also
shortly). Found to be not effective in in OCD, Compulsions/addictions,
MDD. Schizophrenia negative symptoms.
MDD: Dose: 200—800 mg b.i.d.
Intramuscular and oral augmentation Caution in bipolar patients due to
use of SAMe with antidepressants potential for increased switching;
has demonstrated increased response May interact with serotonergic
and remission rates in antidepressant antidepressants; Expense may be a
non-responders. A current NHMRC- caveat.
funded study is in progress to confirm
this effect.
MDD: Dose [5-HTP]:
Tryptophan augmentation with a 100—200 mg b.i.d.
range of antidepressants has been (or before sleep)
found to be effective in increasing May be of use in concert with a
effect. No difference over placebo range of antidepressants, protein
however was found in some studies deficiency, or in depression
using certain tricyclics. caused by serotonergic pathway
dysregulation. Strong caution in
higher doses; monitor for serotonin
syndrome.
MDD: Dose: 1000 IU per day
Two clinical studies showed beneficial Can be given in weekly bolus doses
effects in reducing depression. A (5000–10,000 IU); Consider in sun-
large one-off seasonal Vit D dose was Potentially better in daily or weekly
not effective. doses.
MDD: Two adjunctive clinical trials Dose: 20–30 mg per day
and epidemiological studies support Can be nauseating so preferably
having adequate consumption of taken after food; Best given with
zinc; which may be of benefit as cofactors B6 and magnesium.
an adjunctive prescription with
antidepressants.
MDD: One clinical study showed a Dose: 5 g per day
beneficial effect in using creatine Can potentially be activating so
caution needed in bipolar disorder.
escitalopram.

MDD: major depressive disorder; OCD: obsessive–compulsive disorder; CVD: cardiovascular disease; EPA: eicosapentaenoic
acid; BDNF: brain-derived neurotrophic factor; 5-HTP: 5-hydroxytryptophan; NMDA: N-methyl-D-aspartate; b.i.d.: bis in die
(twice daily administration); OTC: over-the-counter; IU: international units.
*Please consult these publications for supporting references and for further reading: Sarris et al.5; Sarris et al.9; Sarris et al.13;
Berk et al.22

3

risk in kidney stones in men due to its conversion to
oxalate and excretion in urine.28 While a very low poten-
tial concern, folic acid, especially at higher doses, has
been linked epidemiologically to increased risk of pros-
tate cancer,29 due to its effects on increasing cell prolif-
eration.30 However it should be noted that folinic acid
and methlyfolate differ from folic acid, and that ade-
quate folate consumption from vegetables and whole
grains has potential cancer protective properties.31
Caveats regarding the prescription of nutraceuticals
include the importance of only prescribing standardised,
stable, high-quality nutrient products32 (especially with
SAMe, due to it being an unstable compound, although
some current formulations have potentially a more stable
shelf-life). The prescription of correct formulations and
dosages is vital. Expense may also be an issue in the case of
SAMe and methylfolate. Clinicians may be confused as to
which products to prescribe or recommend, and in such
cases referral to specialised health professional with knowl-
edge of nutritional medicine is advised. While it is under-
standable to wait to assess if antidepressant non-response
occurs before initiating nutraceutical co-prescription,
nutraceuticals can be initiated during the initial antide-
pressant prescription. In conclusion, current evidence sup-
ports the potential application of a range of nutrient-based
nutraceuticals, and such an application may of benefit to
non-responders to antidepressant medication. Clinician
discretion is advised as to whether they utilise this
approach in their prescriptive augmentation regime.
Acknowledgements
Thanks are extended to the co-authors of some of our key papers reviewed in this opinion piece,
including A/Professor David Mischoulon, Dr Jenifer Murphy, Professor Chee Ng, and Professor
Michael Berk. JS is supported by an NHMRC Career Development Fellowship APP1125000.
Disclosures
Dr Sarris has received funding as either presentation honoraria, travel support, clinical trial
grants, book royalties from Integria Healthcare & MediHerb, Pfizer, Taki Mai, Bioceuticals
& Blackmores, Soho-Flordis, Healthworld, HealthEd, Elsevier, Chaminade University,
International Society for Affective Disorders, Complementary Medicines Australia, ANS,
Society for Medicinal Plant and Natural Product Research, Omega-3 Centre the National
Health and Medical Research Council, CR Roper Fellowship.
Funding
The author received no financial support for the research, authorship, and/or publication of
this article.
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