CNS Drugs

DOI 10.1007/s40263-017-0446-8

REVIEW ARTICLE

Ascorbic Acid to Manage Psychiatric Disorders

Morgana Moretti1 • Daiane Bittencourt Fraga1 • Ana Lúcia S. Rodrigues1

Ó Springer International Publishing Switzerland 2017

Abstract Ascorbate has critical roles in the central ner-

vous system (CNS); it is a neuromodulator of glutamater-
gic, cholinergic, dopaminergic, and c-aminobutyric acid
(GABA)-ergic neurotransmission, provides support and
structure to neurons, and participates in processes such as
differentiation, maturation, and survival of neurons. Over
the past decade, antioxidant properties of ascorbate have
been extensively characterized and now it is known that
this compound is highly concentrated in the brain and
neuroendocrine tissues. All this information raised the
hypothesis that ascorbate may be involved in neurological
disorders. Indeed, the biological mechanisms of ascorbate
in health and disease and its involvement in homeostasis of
the CNS have been the subject of extensive research. In
particular, evidence for an association of this vitamin with
schizophrenia, major depressive disorder, and bipolar dis-
order has been provided. Considering that conventional
pharmacotherapy for the treatment of these neuropatholo-
gies has important limitations, this review aims to explore
basic and human studies that implicate ascorbic acid as a
potential therapeutic strategy. Possible mechanisms
involved in the beneficial effects of ascorbic acid for the
management of psychiatric disorders are also discussed.
& Morgana Moretti
morganamoretti@hotmail.com
1
Department of Biochemistry, Center of Biological Sciences,
Universidade Federal de Santa Catarina, Campus
Universitário, Trindade, Florianópolis, SC 88040-900, Brazil
Key Points
Ascorbate can act as a neuromodulator in the central
nervous system.
Ascorbate depletion has been documented in several
psychiatric disorders.
Clinical and non-clinical studies suggest that
ascorbic acid administration alleviates behavioral
and biochemical alterations in psychiatric disorders.
1 Introduction
Ascorbic acid, also known as vitamin C, is a water-soluble
vitamin that is implicated in multiple vital functions. The
chemical structure of ascorbic acid includes an enolic
hydroxyl group, tautomer of a-hydroxyketone, which
provides the reducing capability and the acid behavior of
this compound. Ascorbic acid is stable in its dry form;
however, it rapidly oxidizes in solution and when exposed
to the air or heat. In mammals, at physiological pH,
deprotonation occurs at the C3 hydroxyl group, forming the
ascorbate anion, the endogenous form of this molecule [1].
The name ‘ascorbic acid’ also reflects a biological property
of this substance. Specifically, the word ‘ascorbic’ denotes
the antiscorbutic property of this vitamin [2].
The majority of mammals synthesize ascorbate from
glucose through a series of enzymatic reactions. However,
humans do not synthesize it due to the presence of the non-
functional gene for L-gulono-c-lactone oxidase, a manda-
tory enzyme for the final stage of ascorbate biosynthesis.
Considering the high availability of this compound in foods

and dietary supplements, the mutation should not cause
problems for organisms unable to synthesize it. Besides
being widely available, ascorbate is easily absorbed by a
family of intestinal sodium-dependent transporters named
type 1 sodium-dependent vitamin C transporters (SVCT1)
[3]. Once absorbed, ascorbate is distributed throughout the
tissues, with higher concentrations found in adrenal glands,
brain, and spinal cord [1, 3].
The proposed route by which ascorbate enters the cen-
tral nervous system (CNS) involves slow transport from
plasma to the cerebrospinal fluid (CSF) across the choroid
plexus epithelium, via type 2 sodium-dependent vitamin C
transporters (SVCT2). If blood dehydroascorbate (oxidized
form of ascorbate) is present in substantial quantities, it can
quickly enter the CNS via glucose transporters (GLUT1)
present in the blood–brain barrier endothelium. Once in the
CSF, ascorbate or dehydroascorbate enter the neurons
through SVCT2 or GLUT1, respectively; dehydroascorbate
is then reduced to ascorbate and stored. Glial cells obtain
ascorbate by reduction of dehydroascorbate, uptaked by
GLUT1 [4].
Ascorbate is required for several physiological pro-
cesses in the human body. For example, dopamine b-hy-
droxylase, the enzyme that catalyzes the conversion of
dopamine to norepinephrine, uses ascorbate as a cofactor
[5]. Besides acting as an enzymatic cofactor, ascorbate is a
reducing agent and scavenger of free radicals [6, 7]. This
compound can interact with and stabilize free radicals
produced during cellular metabolism [8], preventing the
oxidation of biomolecules and different kinds of biological
damage, including cell death [9]. It is important to mention
that deregulation of cellular redox balance is associated
with degenerative processes and neurotoxic effects pro-
duced by excessive glutamate release [10], which is
implicated in a number of neuropathological conditions,
including Huntington’s disease, Alzheimer’s disease,
Parkinson’s disease, epilepsy, schizophrenia, and major
depressive disorder [11–15].
Ascorbate is present in millimolar concentrations in
neuron-rich areas and exerts important neuromodulatory
functions; thus, it has been hypothesized that this com-
pound could be more than a simple ‘micronutrient’ in the
CNS. In addition to its essential role for catecholamine
synthesis, it is recognized that ascorbate is involved in the
formation of the myelin sheath by Schwann cells [16, 17],
and regulates the sodium–potassium ATPase enzyme
[18, 19]. It was also reported that ascorbate modulates
acetylcholine release in synaptic vesicles from rat brain
synaptosomes [20] and cultured adrenal chromaffin cells
[21]. Ascorbate has also a functional role in both
dopaminergic and glutamatergic neurotransmission
[1, 3, 22]. This compound exerts inhibitory effect on the
function of N-methyl-D-aspartate (NMDA) receptors [23].
M. Moretti et al.
Fig. 1 a The antidepressant-like effect of ascorbic acid is associated c
with activation of dopaminergic (D2 receptors), serotonergic (5-HT1A,
5-HT2A/2C, and 5-HT3) and noradrenergic (a1-, a2-, and b-adreno-
ceptors) systems. Other mechanisms associated with the antidepres-
sant-like effect of ascorbic acid in mice include inhibition of NMDA
receptors and potassium channels, activation of GABAA receptors,
and a possible inhibition of GABAB receptors. The anti-immobility
effect of this compound in the tail suspension test is also dependent on
activation of PI3K/Akt pathway, inhibition of GSK-3b enzyme, and
stimulation of mTOR and its target proteins. b Major depressive
disorder, schizophrenia, bipolar disorder, and neurodegenerative
diseases seem to be associated with increased brain oxidative stress
and inflammation. The beneficial effect of ascorbic in these
neuropathologies, especially in major depressive disorder, is possible
associated with its antioxidant and anti-inflammatory capacity. 4EBP
eukaryotic translation initiation factor 4E-binding proteins, 5-HT
5-hydroxytryptamine, Akt protein kinase B, AMPA a-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid, D2 dopamine receptor,
eF2K elongation factor 2 kinase, ERK extracellular signal-regulated
kinases, GABA c-aminobutyric acid, GSK-3b glycogen synthase
kinase-3b, MEK mitogen-activated protein kinase, mTOR mammalian
target of rapamycin, mTORC1 mammalian target of rapamycin
complex 1, NMDA N-methyl-D-aspartate, p70S6K p70 ribosomal S6
kinase, PI3K phosphoinositide 3-kinase, P phosphorylation, PSD95
postsynaptic density protein 95
Moreover, it dose-dependently modulates the dopaminer-
gic system (low doses enhance dopamine-mediated
behavioral effects [24] and high doses seem to antagonize
dopamine-mediated behavioral effects [1]), and is released
in the brain of rats after the administration of dopamine
receptor agonists [25, 26].
Considering the involvement of ascorbate in CNS
homeostasis, we present pre-clinical and clinical evidence
for associations of this compound with some psychiatric
disorders. We focus on the biochemistry and neuronal
metabolism interface, animal models that are suitable for
this area of research, and the clinical studies that have
investigated the potential therapeutic use of ascorbic acid
administration. The main mechanisms associated with
beneficial effects of ascorbic acid in these pathologies are
presented in Fig. 1; all of them are discussed throughout
the text.
2 Role of Ascorbic Acid in Neuropsychiatric
Disorders
2.1 Schizophrenia
Schizophrenia is a chronic and severe mental illness
defined by three categories of symptoms. Positive symp-
toms are psychotic behaviors not commonly seen in heal-
thy people, including delusions, hallucinations, and
paranoia. Negative symptoms are associated with disrup-
tions to regular behaviors and emotions and include social
withdrawal, anhedonia, and apathy. The third category of
Ascorbic Acid in Psychiatric Disorders

symptoms, called cognitive symptoms, comprises deficits
in attention, memory, and poor executive functioning,
symptoms that might be subtle for some patients and more
severe for others. Historically, the dopamine hypothesis of
schizophrenia or the dopamine hypothesis of psychosis has
prevailed. It emerged from the discovery that dopamine
receptor agonists induce psychotic symptoms, whereas
dopamine receptor antagonists decrease these symptoms.
Therefore, this hypothesis attributes symptoms of
schizophrenia, particularly psychosis, to a disturbed and
hyperactive dopaminergic signal transduction [27, 28]. The
second neurochemical hypothesis of schizophrenia is the
glutamate hypothesis. The glutamatergic theory of
schizophrenia is based on findings indicating a hypofunc-
tion of glutamatergic signaling and the ability of NMDA
receptor antagonists, such as ketamine and phencyclidine,
to induce schizophrenia-like symptoms in animals [29, 30],
as well as studies supporting disturbances on NMDA
receptor-related gene expression in this disorder [31].
Schizophrenia-related psychosis involves hyper-
dopaminergic activity in the mesolimbic pathway. At the
preclinical level, amphetamine (AMPH) administration,
which sensitizes the mesolimbic dopaminergic pathway,
induces schizophrenia-related symptoms [32, 33]. White
and colleagues [34] verified that bilateral infusions of
ascorbic acid into the neostriatum (but not into the over-
lying cerebral cortex) potentiates the capacity of
haloperidol to antagonize AMPH-induced rearing, sniffing,
and head bobbing. These results suggest that the neostria-
tum is implicated in the ability of ascorbic acid to increase
the anti-AMPH effects of haloperidol, a dopamine receptor
antagonist. Likewise, the effect of haloperidol was also
enhanced by treatment with ascorbic acid in the psychosis
produced by phencyclidine in humans [35]. Pretreatment
with ascorbic acid also blocked AMPH-induced stereotype
[36] and hyperlocomotion [37] in mice. Moreover, it
decreased ipsilateral turning behavior elicited by AMPH in
rats with unilateral lesions of the nigrostriatal dopaminer-
gic system [38].
Presently, these effects are not completely understood,
but all of them indicate that the antagonism of dopamin-
ergic function by ascorbate may account, at least in part,
for its possible antipsychotic effects. It has been described
that ascorbate regulates the binding of haloperidol and
other dopamine receptor antagonists [39, 40], suggesting
that, like haloperidol, ascorbate may act on dopamine
receptors [41–44]. It was also reported that ascorbate
decreases the ability of some drugs to release dopamine in
the striatum and nucleus accumbens. For example,
administration of ascorbic acid reduces the depletion of
dopamine after methamphetamine and 1-methyl-4-phenyl
pyridinium (Mpp1) administration [45, 46]. Additionally,
ascorbate may indirectly influence dopamine transmission
M. Moretti et al.
by acting on the glutamatergic neurotransmitter system. It
has been suggested that L-glutamate presynaptically mod-
ulates the striatal dopaminergic function by acting on
NMDA-receptors located on dopaminergic terminals. Like
dopamine, ascorbate is a neuromodulator closely associ-
ated with glutamatergic transmission [47]; however, there
is limited preclinical evidence of the involvement of the
glutamatergic system in the mechanism underlying the
beneficial effects of ascorbic acid in animal models of
schizophrenia.
As previously mentioned, ascorbate can react with a
range of reactive oxygen species (ROS) to neutralize or
decrease their reactivity. A growing body of evidence
demonstrates a disturbed equilibrium between pro-oxidant/
antioxidant homeostasis as well as the occurrence of
oxidative stress in schizophrenia [48]. Preclinical evidence
revealed that glutathione (GSH) deficit during brain
development induces schizophrenia-like behavior in adult
rats [49]. It was reported that rats with transitory GSH
deficit presented poor water maze performance, impaired
place discrimination in the homing board with distributed
visual or olfactory cues, and more working memory errors
in the radial maze when several olfactory cues were pre-
sent. These data suggest that antioxidant system deficiency
and oxidative stress are enough to elicit olfactory dis-
crimination and cognitive impairment (schizophrenia-like
behavior) in rodents. Interestingly, the same study descri-
bed that the synthesis of ascorbate is increased to com-
pensate for the GSH deficit.
Patients with schizophrenia have been reported to have
decreased levels of ascorbate in serum (0.75 ± 0.21 mg/
dL) and leucocytes [24.05 ± 4.69 g/108 white blood cells
(WBC)] as compared to healthy controls (serum:
1.26 ± 0.43 mg/dL; leucocytes: 28.32 ± 4.20 g/108
WBC) [50]. In another study, patients with schizophrenia
had lower fasting ascorbate levels and lower urinary
ascorbate excretion after 1 g of oral ascorbic acid load
[51]. The same study investigated plasma ascorbate levels
in a separate group of schizophrenic patients versus con-
trols after supplementation with ascorbic acid in addition to
antipsychotic treatment. The authors found that plasma
ascorbate levels were similar in both groups, but urinary
excretion was lower among the patient sample, suggesting
an impaired ascorbic acid metabolism in schizophrenia.
Plasma ascorbate level was also found to be decreased
among 14 Indian inpatients with schizophrenia
(0.2904 ± 0.196 mg/L) when compared to control subjects
(0.8078 ± 0.51965 mg/L) [52].
In a double-blind, placebo-controlled 8-week study with
40 schizophrenic patients, the administration of placebo
plus antipsychotics significantly decreased serum malon-
dialdehyde (indicative of oxidative stress) and increased
plasma ascorbate levels (20.41 ± 2.84 at baseline vs.
Ascorbic Acid in Psychiatric Disorders
22.79 ± 2.27 after 8 weeks of treatment). In the same
study, coadministration of ascorbic acid (500 mg/day) and
atypical antipsychotics elicited similar results, but plasma
ascorbate reached more elevated levels (21.51 ± 2.84 lM/
L at baseline vs. 33.54 ± 2.84 lM/L after 8 weeks of
treatment). This combination therapy also improved psy-
chiatric scores indicative of suspiciousness, hostility,
excitement, and somatic concern compared to placebo plus
atypical antipsychotics [53]. Remarkably, Heiser et al. [54]
demonstrated that antipsychotic drugs (olanzapine,
haloperidol, and clozapine) led to a significantly higher
formation of ROS in the whole blood of rats, an effect
counteracted by the administration of ascorbic acid. Con-
sistent with this finding, a case report showed substantial
benefit from the addition of ascorbic acid to conventional
treatment with neuroleptic for a 37-year-old chronic schi-
zophrenic patient [55]. Moreover, Beauclair et al. [56]
performed an 8-week open-label trial of progressively
increasing doses of ascorbic acid among patients with
residual symptoms of schizophrenia regardless of antipsy-
chotic treatment. Ten of 13 patients exhibited improvement
on clinical global impression scores, mainly in the positive
symptom domain. Moreover, plasma ascorbate levels
improved from a mean baseline level of 0.47 mg/100 mL
to a mean of 1.08 mg/100 mL after 4 weeks and 1.10 mg/
100 mL after 8 weeks of treatment.
Despite some controversial results [57], most existing
data suggest a possible association between ascorbic acid
levels and schizophrenic symptoms and a potential use-
fulness of this vitamin as a therapeutic adjuvant in the
treatment of schizophrenia, as shown in Table 1. The
molecular mechanisms underlying the beneficial effects of
ascorbic acid in schizophrenia are not established, but lit-
erature data suggest that this compound not only modulates
glutamatergic and dopaminergic systems but also decreases
oxidative stress in animal models of schizophrenia and in
schizophrenic patients. Current drugs treating schizophre-
nia essentially target dopamine receptors; however, there
are substantial adverse effects associated with available
antipsychotics and no mechanistically novel treatment has
emerged to substitute for them. In view of preclinical and
clinical evidence presented herein and considering the
attractive risk–benefit profile of ascorbic acid, it could be
an interesting approach to manage schizophrenic symp-
toms, particularly as add-on treatment along with standard
antipsychotics.
2.2 Major Depressive Disorder
Major depressive disorder, the most common mood dis-
order, is a serious and often debilitating psychiatric illness
that represents a substantial cause of morbidity and
mortality worldwide. The monoamine hypothesis of major
depressive disorder, which postulates that this disorder
occurs as a consequence of a deficiency on monoamine
neurotransmitters, has been the prevalent theory of the
neurochemical basis of this disorder for almost 50 years.
Although there are several monoamine-based treatment
options used in the management of depressive symptoms,
the remission rates are low (often less than 60%) [58] and
new classes of drugs are required. Many preclinical
studies have established the antidepressant properties of
ascorbic acid. It elicits an antidepressant-like behavior in
the tail suspension test (a predictive test for depression)
[59–62] and reverses depressive-like behavior induced by
acute restraint stress [63] and chronic unpredictable stress
[64] with efficacy comparable to the conventional
antidepressant fluoxetine.
The antidepressant-like effect of ascorbic acid may be
associated with its participation in neurotransmitter syn-
thesis. Ascorbate serves as a specific electron-donating
cofactor for conversion of dopamine into norepinephrine
by dopamine b-hydroxylase. Furthermore, this compound
is required to recycle tetrahydrobiopterin, which is neces-
sary for the activation of the rate-limiting enzyme for
catecholamine synthesis, tyrosine hydroxylase, as well as
tryptophan hydroxylase in the synthesis of serotonin.
Ascorbate has also been shown to contribute to differen-
tiation of monoaminergic cells during the development
period. Meredith and May [65] used knockout
(SVCT2?/-) and transgenic (expressing extra copies of
the SVCT2) mouse models with varying intracellular
ascorbate levels and showed that this compound could
regulate embryonic brain cortex monoamine synthesis. The
authors found that very low levels of ascorbate decreased
cortex levels of norepinephrine and dopamine. The
reduction of ascorbate levels also led to decreased tyrosine
hydroxylase content, but not tryptophan hydroxylase
levels. These results suggest that an adequate ascorbate
availability during development could account for pre-
vention of depressive symptoms in adult age. A more direct
involvement of the monoaminergic system in the antide-
pressant effect of ascorbic acid was observed in recent
preclinical studies. It was revealed that pre-treatment of
mice with haloperidol or sulpiride prevented the antide-
pressant-like effect evoked by ascorbic acid, suggesting
that the dopaminergic system is involved in the antide-
pressant-like action of this compound in the mouse tail
suspension test through an activation of dopamine D2
receptors [59]. The same study showed that the antide-
pressant-like effect of ascorbic acid involves activation of
5-HT1A, 5-HT2A/2C, and 5-HT3 serotonin receptors, as
well as a1-, a2-, and b-adrenoceptors. Moreover, ascorbic
acid caused a synergistic antidepressant-like effect with
conventional antidepressants (fluoxetine, imipramine, and
bupropion) in the tail suspension test [59, 60].
 M. Moretti et al.

Table 1 Ascorbic acid studies in schizophrenic patients

Study Study design Sample Measurement/intervention Main findings

Dadheech Case–control 68 subjects newly diagnosed Blood samples were analyzed for : malondialdehyde level, ; serum
et al. [50] with schizophrenia and 40 malondialdehyde, total ascorbate, levels of total ascorbate, and
healthy controls dehydroascorbate, reduced reduced glutathione, as well as ;
ascorbate, leucocyte ascorbate, and leucocyte ascorbate in
reduced glutathione schizophrenics compared with
controls
D’Souza and Case–control 14 inpatients with Plasma ascorbate levels Ascorbate levels were significantly
D’Souza schizophrenia, 18 controls lower in patients than in controls
[52]
Suboticanec Case–control Study 1: 20 individuals with Study 1: evaluation of serum and Patients had ; serum and urinary
et al. [51] schizophrenia, 15 controls. urinary ascorbate levels. Study 2: excretion of ascorbate after oral
Study 2: 15 individuals ascorbic acid (70 mg/day for ascorbic acid load. After ascorbic
with schizophrenia, 15 4 weeks) in a new group of acid supplementation, no difference
controls cases/controls in ascorbate serum levels between
groups, but urinary excretion ; in
schizophrenic patients, suggesting
impaired ascorbic acid metabolism
in schizophrenia
Dakhale Prospective, 40 schizophrenic patients Ascorbic acid (500 mg/day) or : serum malondialdehyde and ;
et al. [53] double-blind, placebo along with atypical plasma ascorbate levels in
placebo- antipsychotics for 8 weeks schizophrenic patients, effects
controlled, reversed by ascorbic acid along
non-crossover with atypical antipsychotics
trial compared with placebo with
atypical antipsychotics
Beauclair Open-label trial 13 patients with Evaluation of plasma ascorbate 10 patients showed clinical
et al. [56] schizophrenia with residual levels in patients given improvement after
symptoms antipsychotic plus increasing doses supplementation, plasma ascorbate
of ascorbic acid (1–8 g daily) over levels improved
8 weeks
: increased, ; decreased

In recent years, a growing body of evidence has impli-
cated the glutamatergic system in the neurobiology and
treatment of major depressive disorder. Several gluta-
matergic modulators, including positive modulators of a-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptors, antagonists of NMDA receptors, and
metabotropic glutamate receptors agonist-antagonists, are
under investigation in animal models of depression and
clinical trials. In line with the newest discoveries in this
field, the involvement of glutamatergic system in the
antidepressant-like effect of ascorbic acid has also been
explored. Moretti et al. [62] was the first to demonstrate
that the antidepressant-like effect of ascorbic acid in the
tail suspension test is dependent on NMDA receptor inhi-
bition. Later, it was observed that the anti-immobility
effect of this compound in an animal model of depression
induced by central administration of tumor necrosis factor-
a involves, at least partially, a decreased p38 mitogen-
activated protein kinase phosphorylation, activation of the
monoaminergic system, as well as inhibition of NMDA
receptors and nitric oxide synthesis [60].
The modulation of NMDA receptors has been suggested
as a strategy to counteract depressive symptoms in animal
and clinical studies. The rapid antidepressant effect of
NMDA receptor antagonists depends on extracellular sig-
nal-regulated kinases (ERK)1/2 and protein kinase B (Akt)-
mediated activation of mammalian target of rapamycin
(mTOR) signaling in the brain. Ketamine, the most studied
NMDA receptor antagonist for the management of treat-
ment-refractory major depressive disorder, modulates this
signaling pathway and stimulates several mTOR target
proteins associated with cellular survival and synaptogen-
esis, including eukaryotic translation initiation factor 4E
binding protein (4E-BP) and p70 ribosomal S6 kinase
(p70S6K) [66]. Supporting the involvement of the gluta-
matergic system in the antidepressant effect of ascorbic
acid, it was demonstrated that the anti-immobility effect of
this compound in the tail suspension test is dependent on
stimulation of mTOR [67]. The same study showed that
ascorbic acid activates the phosphoinositide 3-kinase
(PI3K)/Akt pathway and inhibits the glycogen synthase
kinase-3b (GSK-3b) enzyme, effects that are associated
Ascorbic Acid in Psychiatric Disorders
with increased plasticity and cellular survival. The authors
also demonstrated that the antidepressant-like effect of
ascorbic acid depends on induction of heme oxygenase-1,
which plays a key role in cell protection against inflam-
matory insult and oxidative/nitrosative stress. These data
reinforce the notion that these are important targets for
antidepressant activity and contribute to elucidating the
antidepressant mechanisms of ascorbic acid. Other mech-
anisms involved in the antidepressant effect of ascorbic
acid in mice include an inhibition of potassium channels
[61], activation of c-aminobutyric acid (GABA)A receptors
and a possible inhibition of GABAB receptors, effects also
found with the administration of ketamine [68]. The main
mechanisms involved in the antidepressant-like effect of
ascorbic acid are shown in Fig. 1a.
Although preclinical studies substantially indicate an
antidepressant-like effect of ascorbic acid, inconsistent
results are reported in humans. It has been demonstrated
that ascorbate deficiency (below 11 lM/L) is associated
with increased depressive symptoms [69], indicating that
ascorbate may play a role in mood regulation. This
assumption is supported by studies showing the occurrence
of depressive symptoms in individuals with scurvy [70] and
by the development of scurvy in a depressive patient [71].
Khanzode et al. [72] also reported decreased levels of
plasma ascorbate in depressed (0.37 ± 0.14 mg %) versus
control subjects (0.65 ± 0.06 mg %). In this study, levels
of plasma ascorbate in the depressed group increased sig-
nificantly after 4 weeks (0.471 ± 0.137 mg %) and
12 weeks (0.491 ± 0.110 mg %) of antidepressant treat-
ment as compared to baseline levels. There are also some
clinical studies that report a positive effect of ascorbic acid
administration on the mood of healthy individuals. A ran-
domized, double-blind, placebo-controlled, 14-day trial
with sustained-release ascorbic acid (3000 mg/day)
administered to 42 healthy young adults showed that this
compound increased the intercourse frequency and
improved mood [73]. Additionally, in a cross-sectional
study of 133 men and 146 women aged 65–75 years, a
negative association between the intake of ascorbic acid
and depressive symptoms was reported; the observed odds
ratios of depressive symptoms were significantly lower in
the highest tertile of vitamin C intake than in the lowest
tertile. [74]. Accordingly, ascorbic acid intake was signif-
icantly lower among individuals with major depressive
disorder (109.2 ± 52.5 mg/day [75]; 94.9 ± 16.7 mg/day
[76]) than in control participants (148.4 ± 65.6 mg/day
[75]; 106.9 ± 15.3 mg/day [76]), and a negative correla-
tion between severity of the disease and dietary ascorbic
acid was found [76].
Regarding the possible beneficial effect of ascorbic acid
in depressive patients, a clinical report revealed that it
reduced depressive symptoms in a 5-year-old girl treated
with adrenocorticotropic hormone for chronic hepatitis
[77]. More recently, a double-blind, placebo-controlled
pilot trial investigated the effectiveness of ascorbic acid
administered in combination with fluoxetine for depressive
pediatric individuals. Patients treated with ascorbic acid
(1 g/day) plus fluoxetine for 6 months had a significant
reduction in depressive symptoms compared with those that
received fluoxetine plus placebo [78]. In agreement with
these outcomes, an 8-week double-blind clinical trial
showed that the administration of ascorbic acid (500 mg)
with antidepressants decreased depression scores in a sam-
ple of 22 patients [79]. Conversely, some clinical studies did
not find any beneficial effect of ascorbic acid in treating
adult patients with major depressive disorder. In a ran-
domized, single-blind study with 45 diabetic patients, a
6-week administration of ascorbic acid (1 g/day) decreased
anxiety levels as assessed by the DASS-21 (Depres-
sion Anxiety Stress Scales 21-item) questionnaire, without
affecting stress and depression scores [80]. More recently,
an 8-week randomized placebo-controlled clinical trial of
43 adult patients with major depressive disorder and suicidal
behavior reported no valuable effect of ascorbic acid
(1 g/day) in association with citalopram (up to 60 mg/day)
as compared with citalopram plus placebo [81]. Table 2
summarizes key findings from studies investigating ascor-
bic acid and major depressive disorder association.
2.3 Bipolar Disorder
Bipolar disorder is a mood disorder characterized by dramatic
changes in mood, energy, and behavior. Bipolar I disorder is
marked by episodes of mania (an extreme elevation of mood)
and depression. Bipolar II disorder is characterized by pre-
dominantly depressive episodes accompanied by occasional
hypomanic episodes (a less severe form of mood elevation). In
the early phase, bipolar disorder is associated with an exces-
sive dopaminergic/glutamatergic transmission and decreased
cholinergic muscarinic signaling. In the chronic phase of the
disorder, commonly associated with inadequate treatment,
patients may have a greater rate of medical and psychiatric co-
morbidities and manifest cognitive impairments and func-
tional decline [82]. Standard mood stabilizer treatments,
including lithium, valproic acid, and carbamazepine, regulate
glutamatergic neurotransmission through K? buffering,
modulation of calcium-dependent phospholipase A2, block-
ade of sodium channels, or modulation of Ca2?-mediated
signaling pathways. Although current pharmacotherapy can
have profound beneficial effects for some patients, there is an
urgent need for more effective treatments, mainly for
depressive phases, that are closely associated with substance
abuse and suicide [83].
Ascorbate modulates intracellular sodium levels, has
antioxidant and anti-inflammatory properties, and increases
Table 2 Clinical studies investigating ascorbic acid and major depressive disorder association
Study Study design Sample Measurement/intervention Main findings

Gariballa [69]
DeSantis [70]
Khanzode et al. [72]
Oishi et al. [74]
Payne et al. [75]
Prohan et al. [76]
Brody [73]
Cocchi et al. [77]
Amr et al. [78]
Aburawi et al. [79]
Mazloom et al. [80]
Sahraian et al. [81]
: increased, ; decreased
Cross-sectional
Case report
Prospective, open-label,
randomized trial
Cross-sectional
Case–control
Case–control
Randomized double-blind,
placebo-controlled trial
Case report
Double-blind, placebo-
controlled trial
Double-blind, placebo-
controlled trial
Randomized, single-blind,
placebo-controlled trial
Randomized, double-blind,
placebo-controlled trial
322 patients aged C65 years
55-year-old man with scurvy
62 patients with major
depressive disorder and 40
age- and sex-matched healthy
volunteers
133 men and 146 women aged
65–75 years
144 patients with major
depressive disorder and 134
controls aged C60 years
30 male students with major
depressive disorder and 30
healthy controls
42 healthy young adults
1 child with chronic hepatitis
and under
adrenocorticotropic hormone
therapy
12 depressed children and 12
controls
22 depressed patients
45 diabetic patients with major
depressive disorder
43 adult patients with major
depressive disorder
Nutritional status assessed from
anthropometric, hematological, and
biochemical data at baseline and after
6 weeks and 6 months
Mental health assessment
Evaluation of lipid peroxidation,
superoxide dismutase activity, and
ascorbate concentrations
Ascorbic acid content analysis of the diet
Ascorbic acid content analysis of the diet
Ascorbic acid content analysis of the diet
3 g/day of sustained-release ascorbic acid
for 14 days
3 g/day of ascorbic acid
Ascorbic acid (1 g/day) or placebo plus
fluoxetine for 6 months
Ascorbic acid (500 mg/day) or placebo
plus antidepressant for 8 weeks
Ascorbic acid (1 g/day) or placebo for
6 weeks
Ascorbic acid (1 g/day) or placebo in
addition to citalopram for 8 weeks
Patients with ascorbate depletion had
significantly : symptoms of depression
compared with those with higher
concentrations at baseline and at 6 weeks
Patient was depressed and irritable, had
difficulty sleeping, and showed little
interest in his surroundings
: serum superoxide dismutase, : serum
malondialdehyde, and ; plasma ascorbate
levels in depressed patients compared with
control subjects. Fluoxetine and citalopram
reversed these alterations
; prevalence of depressive symptoms in men
under higher dietary intake of ascorbic acid
; ascorbic acid dietary intake among older
adults with major depressive disorder
compared with healthy controls
; ascorbic acid intake in students with major
depressive disorder compared with healthy
subjects. Significant negative correlation
between severity of depression and dietary
ascorbic acid
; scores on Beck Depression Inventory
Reduced depression severity
Fluoxetine plus ascorbic acid produced a
better antidepressant effect than fluoxetine
alone
Ascorbic acid with antidepressants decreased
significantly the total Hamilton Depression
Rating Scale scores
A significant decrease in anxiety level in
ascorbic acid group, but no significant
differences in stress and depression scores
Ascorbic acid plus citalopram was no more
effective than placebo plus citalopram for
treating adult patients with suicidal
behavior
M. Moretti et al.
Ascorbic Acid in Psychiatric Disorders

neurotransmitter synthesis, properties that are useful for the
treatment of bipolar disorder [84]. Ouabain, an inhibitor of
the Na?/K?-ATPase enzyme, induces hyperactivity in rats
and increases intracellular levels of calcium. Intracere-
broventricular administration of ouabain is now considered
a relevant animal model of mania and induces brain bio-
chemical alterations that are also seen in bipolar disorder
patients, including lipid and protein oxidation in the pre-
frontal cortex and hippocampus [85]. Ascorbate modifies
the activity of the Na?/K?-ATPase enzyme [19] and acts
as an antioxidant that effectively scavenges free radicals
and protects the brain against oxidative stress [6, 7],
mechanisms underlying a possible therapeutic action of
ascorbic acid in bipolar disorder.
It is well-known that the GSK-3b-mediated signaling
pathway is a central modulator in mood regulation; the
inhibition of this pathway produces both antimanic and
antidepressant effects. Many drugs with mood-stabilizing
properties, such as lithium, valproate, and atypical antipsy-
chotics, directly and indirectly modulate the PI3K, GSK-3b,
and Wnt-mediated signaling pathways, all implicated in the
pathogenesis of bipolar disorder [86, 87]. Regarding the
effect of ascorbic acid on GSK-3b, Huang and colleagues
[88] showed that this neuromodulator prevented inactivation
of the Akt–GSK-3b pathway mainly by altering ROS levels.
In contrast, another study revealed that ascorbic adminis-
tration did not alter GSK-3b phosphorylation in an animal
model of depression, although it reduced the oxidative
damage [63]. Limited findings on this topic, inconsistent data
on the influence of ascorbic acid on GSK-3b pathway
modulation, and lack of preclinical evidence dealing with
other mechanisms underlying the putative mood-stabilizing
effect of ascorbic acid encourage more preclinical studies to
better elucidate the possible beneficial effects of this com-
pound in bipolar disorder.
Clinical studies have been conducted to investigate how
ascorbic acid may be helpful for bipolar disorder patients.
While some studies have showed little or no beneficial
effect of ascorbic acid, others have indicated that symptom
dimensions improved. In a controlled trial involving 40
male psychiatric patients with a clinical state of subscurvy,
ascorbic acid saturation reduced depressive, manic, and
paranoid symptoms together with an improvement in
general personality functioning [89]. The effect of ascorbic
acid intake in bipolar disorder patients was also assessed by
a double-blind, placebo-controlled trial. Naylor and Smith
[90] reported that the severity of both manic and depressive
symptoms of 23 bipolar patients were lower following a
single 3 g dose of ascorbic acid than after placebo, an
effect observed 3–6 h after its administration, with better
effects in depression scores. Another study investigated the
combined effects of ascorbic acid and ethylene diamine
tetra-acetic acid (EDTA) in the treatment of 29 manic and
32 depressed patients using double-blind procedures and
standard treatment regimens [91]. Results indicate that
combined ascorbic acid and EDTA was as effective as the
antidepressant amitriptyline for depressed patients. Also,
the ascorbic acid/EDTA group appeared to respond faster
on the Beck Depression Inventory and global ratings than
the amitriptyline group, suggesting a possible rapid thera-
peutic onset of ascorbic acid. However, manic patients
responded significantly better to lithium than to ascorbic
acid plus ETDA administration. In addition to further
characterization of neurochemical changes induced by
ascorbic in bipolar patients, systematic large-scale clinical
trials are still required. The existing data are controversial,
but suggest that an adequate ascorbic acid intake is of great
importance for psychiatric patients. Clinical trials investi-
gating the effects of ascorbic acid on bipolar disorder are
shown in Table 3.

Table 3 Clinical studies exploring the effects of ascorbic acid in bipolar patients
Study Study design Sample Measurement/intervention Main findings

Milner Placebo- 40 male psychiatric Ascorbic acid (1 g/day) or placebo for Ascorbic acid ; depressive, manic, and
[89] controlled patients with a 3 weeks paranoid symptoms together with an
trial clinical state of improvement in general personality
subscurvy functioning
Naylor Double-blind, Bipolar patients in A single dose of ascorbic acid (3 g) or Illness severity ; slowly during the day in
and placebo- manic (n = 11) placebo the placebo group but faster in the ascorbic
Smith controlled, and depressed acid group. These differences were
[90] crossover (n = 12) phases significant at 3, 4, and 5 h post-ingestion
trial
Kay Double-blind 29 manic and 32 Combined ascorbic acid (4 g) and ethylene The experimental regimen was as effective
et al. trial depressed patients diamine tetra-acetic acid (EDTA) (4 g) or as amitriptyline for depressed patients,
[91] placebo together with standard treatment while manic patients responded better to
regimens for 28 days lithium
; decreased

3 Final Remarks
Several studies have documented that pathophysiological
processes observed in some neuropsychiatric disorders
can be modified by nutritional interventions, a strategy
that has potential as an adjunct to pharmacotherapy and
offers little risk to patients. Much of the existing
research on the impact of nutrition on psychiatric dis-
orders suggests that there is a promising association
between ascorbic acid and these diseases. Interestingly,
ascorbic acid has been demonstrated to be a neuropro-
tective agent in several models of neurodegenerative
diseases [92–96]. Although these effects have not been
discussed in detail here, they seem to be related to the
antioxidant, anti-inflammatory, and antiexcitotoxic
properties of ascorbate [92, 94–97].
The potential use of ascorbic acid for the management
of neuropathologies is particularly interesting consider-
ing that it is a very affordable compound usually
regarded as safe at intakes of B2000 mg/day [98].
However, some small studies suggest that high intakes of
vitamin C, particularly in persons who receive it intra-
venously or who have chronic renal failure, may be
related to the development of oxalate kidney stones [99].
Caution is also advised in people with iron-overload
conditions, such as homozygous hemochromatosis, since
iron absorption may increase with elevated vitamin C
intake [100]. Occasionally, ascorbic acid may cause
diarrhea or mild nausea, especially in high doses; how-
ever, it is important to mention that several hypothesized
adverse effects were examined in detail and were found
to have no substantive basis [78, 81, 101]. Moreover,
few controlled clinical trials are available to conclu-
sively determine the adverse health effects of supple-
mental ascorbic acid consumption; thus, more clinical
trials are required before conclusive inferences can be
made of the health risks to humans.
Figure 1 illustrates some of the hypotheses associated
with the beneficial effect of ascorbic acid in depression
(Fig. 1a) and other diseases mentioned in this article
(Fig. 1b). Other mechanisms have not yet been ade-
quately tested and negative results are also present in the
literature. Rigorously performed trials are mandatory
before clinical acceptance of ascorbic acid as a treatment
for the diseases discussed here. Some data presented in
this review are from case reports [55, 70, 77] or case–
control studies [52, 76], which makes the translation of
results into clinical practice difficult. Even outcomes
from randomized controlled trials must be considered
carefully; some of these studies have small sample sizes
[78, 79] and blinding can be difficult to achieve due to
the distinctive taste of ascorbic acid.
M. Moretti et al.
4 Conclusion
Although some controversial results have been published,
it is undeniable that ascorbic acid is implicated in CNS
homeostasis and may have a role in some neuropatholo-
gies. Therefore, the neuroprotective properties of this
compound should be explored to elucidate the neuro-
chemical basis of its effects and to help in the search for
more effective clinical treatments for neuropsychiatric
disorders. New mechanistic basic research and well-de-
signed clinical studies need to be performed to determine
efficacy and appropriate doses of ascorbic acid adminis-
tration to these patients.
Compliance with Ethical Standards
Funding Dr. Rodrigues is a ‘‘National Counsel of Technological and
Scientific Development (CNPq)’’ Research Fellow. Dr. Rodrigues’
studies are supported by Grants from CNPq (Grant Numbers
#308723/2013-9 and #449436/2014-4), Coordenação de Aperfeiçoa-
mento de Pessoal de Ensino Superior (CAPES), and NENASC Project
(PRONEX-FAPESC/CNPq) #1262/2012-9.
Conflicts of interest Morgana Moretti, Daiane Bittencourt Fraga,
and Ana Lúcia S. Rodrigues declare that no financial support or
compensation has been received from any individual or corporate
entity over the past 3 years for research or professional service and
there are no personal financial holdings that could be perceived as
constituting a potential conflict of interest.
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