Curr Treat Options Psych (2022) 9:151-162

DOI 10.1007/s40501-022-00259-1

Novel Therapeutics in Mood Disorders (R Mansur, Section Editor)

A Possible Antidepressive Effect

of Dietary Interventions: Emergent
Findings and Research Challenges
Gilciane Ceolin, MSc1,2
Vitor Breda, MD, MSc, PhD1,3
Elena Koning, BScH, MSc1
Arun Chinna Meyyappan, BScH1
Fabiano A. Gomes, MD, PhD1,3
Júlia Dubois Moreira, PhD4
Fernando Gerchman, MD, PhD5,6
Elisa Brietzke, MD, MsC, PhD1,3,*
Address
*,1
Centre for Neuroscience Studies (CNS), Queen’s University, Kingston, 752 King
Street West, Kingston, ON K7L 7X3, Canada
Email: [email protected]
2
Postgraduate Program in Nutrition, Universidade Federal de Santa Catarina,
Florianópolis, SC, Brazil
3
Department of Psychiatry, Queen’s University School of Medicine, Kingston, ON, Canada
4
Department of Nutrition, Universidade Federal de Santa Catarina (UFSC),
Florianópolis, SC, Brazil
5
Endocrinology and Metabolism, Hospital de Clínicas de Porto Alegre (HCPA),
Porto Alegre, RS, Brazil
6
Postgraduate Program in Medical Sciences: Endocrinology, Department of Internal
Medicine, Faculty of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS),
Porto Alegre, RS, Brazil

Published online: 23 April 2022

© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022

This article is part of the Topical Collection on Novel Therapeutics in Mood Disorders

Keywords Nutrition · Mood disorders · Bipolar disorder · Depression · Major depressive disorders · Antidepressant

Abstract
Purpose Despite recent advancements in the treatment of depression, the prevalence of
affected individuals continues to grow. The development of new strategies has been required
and emerging evidence has linked a possible antidepressant effect with dietary interventions.

Vol.:(0123456789)
152 Novel Therapeutics in Mood Disorders (R Mansur, Section Editor)

In this review, we discuss recent findings about the possible antidepressant effect of dietary
interventions with an emphasis on the results of randomized controlled trials.
Recent findings A high consumption of refined sugars and saturated fat and a low dietary
content of fruits and vegetables has been associated with the development of depression.
There is evidence supporting a small to moderate beneficial effect of a Mediterranean-
type diet in depression. In addition, new dietary protocols are being studied for their use
as possible interventions, such as the ketogenic diet, Nordic diet, and plant-based diet.
Summary Lifestyle interventions surrounding diet and nutrition are a relatively affordable
way to enhance response to treatment and to be employed as an adjunct in mental health
care. Most studies, however, are limited by the difficulty in controlling for the placebo
effect. Mediterranean-style diets seem to be the most promising as an adjunctive treat-
ment for mood disorders. Larger randomized controlled trials that could assess predictors
of response to dietary interventions are needed to establish a clear positive effect of diet
and guide clinical care and nutritional recommendations concerning mental health care.

Introduction
Mood disorders, including major depressive disorder only important cause of mortality in individuals with
(MDD) and bipolar disorder (BD), are highly preva- mood disorders. Replicated evidence strongly indicates
lent mental illnesses which affect mood, energy lev- that individuals with mood disorders, especially BD,
els, sleep, and cognitive function [1]. Despite recent are disproportionately affected by metabolic condi-
advancements in psychopharmacology, neuromodu- tions, including obesity, prediabetes and type 2 dia-
lation, and evidence-based psychotherapies, the treat- betes, and dyslipidemia [12, 13]. Similarly, it is likely
ment of mood disorders remains clinically challenging that individuals with cancer, chronic pain, HIV, and
[2]. Most guidelines indicate symptomatic remission neurological disorders such as multiple sclerosis and
as the ultimate objective of the treatment of indi- dementia will present with MDD during their lifetime
viduals with mood disorders, yet it is well known in [14]. The results of this particular combination of met-
clinical practice that most patients will deal with no abolic and mood symptoms contribute to increased
response or residual symptoms [3, 4]. In addition, it is morbidity, early mortality, treatment resistance, and
impossible to examine the limitations of antidepres- the need for highly complex treatment approaches
sant and mood-stabilizing treatments without consid- [15, 16]. Furthermore, improvements in medical care
ering that we are currently experiencing an event with and life expectancy in the general population have not
catastrophic proportions: the Covid-19 pandemic. been reflected in individuals with severe mental ill-
The long-term impact of Covid-19 on mental health nesses and the mortality gap continues to increase [17,
remains to be established, but it is possible that men- 18]. In addition to increased mortality and reduced
tal disorders, especially depression, will become even life expectancy, individuals with mood disorders pre-
more prevalent [5–7]. It will be imperative to absorb sent with psychosocial impairment early in their ill-
the personal, societal, and economic costs of mood ness with significant rates of disability and increased
disorder treatment in the post-pandemic world [8]. societal costs [19, 20].
The significant burden of MDD and BD is extensively The biological underpinnings for the association
documented in multiple domains. Individuals with between mood disorders and metabolic abnormalities
mood disorders experience a higher risk of death by remain largely unknown. Notwithstanding, genome-
suicide [9] despite relatively stable rates of suicide in wide association (GWAS) studies suggest a genetic
past decades [10] and even recent decreases in suicide basis for this association, with some genes contribut-
mortality in the USA [11]. However, suicide is not the ing to increased vulnerability to both mood disorders
 A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings Ceolin et al. 153

and obesity/metabolic syndrome [21]. In addition, cognitive performance is well documented in studies
both groups of conditions share environmental risk involving various methodologies ranging from ani-
factors (e.g., exposure to adverse situations in child- mal studies to large epidemiological cohorts [33–35].
hood, substance use, and sleep deprivation) [22, 23]. However, only very recently has psychiatry focused
The integration of genetic and environmental risk on nutrition using more systematic approaches [36,
factors resulted in the contemporaneous causal para- 37]. Lifestyle modifications including physical exer-
digm in mood disorders in which MDD and BD are cises, smoking cessation, sleep hygiene, and dietary
thought to result from the interaction between genes approaches are beginning to be cited in clinical prac-
and environment during neurodevelopment [24, 25], tice guidelines as important initial interventions for
which creates vulnerability for mood episodes [26, individuals with mood disorders [14, 38]. The objec-
27]. Interestingly, mood disorders have been associ- tive of this review is to discuss the emergent litera-
ated with premature aging [28], with different stud- ture on the antidepressant effect of dietary interven-
ies demonstrating telomere shortening and epigenetic tions with an emphasis on the results of randomized
aging in mood disorders [29–31]. controlled trials (RCT). As a rapidly evolving field,
Among the factors involved in neurodevelopment and we also offer insight regarding current challenges
aging, nutrition has been considered a critical one and solutions for advancing the study of nutritional
[32]. The association between early life nutritional approaches in mood disorders.
environment and risk for brain-based illness and poor

Nutrition and health

The nutritional science is considered a recent field of research. Since the discov-
ery of the first vitamin in 1926 until now, we have followed a growing develop-
ment in particular effects of isolated nutrients and, more recently, specific diet
patterns focused on complex non-communicable chronic diseases such as dia-
betes, cardiovascular disease, cancer, obesity, and mental health [39]. Following
the evolutionary transition of industrialization, the introduction of daily intake
of refined carbohydrate and saturated fat accompanied by low intake of fibers,
fruits, and vegetables in modern Westernized societies was accompanied by
the increase of overweight and obesity [40]. This pattern characterized as the
Western Diet has been implicated in the main causes of morbidity and mortal-
ity due to chronic diseases in the USA and most Western countries [41].
On the other hand, some diet patterns such as the Mediterranean diet have
been related with benefits such as cardiovascular health, reduction in the incidence
of obesity, hypertension, metabolic syndrome, and better glycemic control [42].
This pattern is found in civilizations surrounding the Mediterranean Sea and is
characterized by the intake of plant-based foods, nuts, olive oil, whole cereals,
minimally processed and seasonally fresh foods, moderate intake of fish and
poultry, and low intake of red meat [43]. The dietary approaches to stop hyperten-
sion (DASH) was based on studies aiming to decrease blood pressure funded by
the National Institute of Health (NIH). This diet is based on foods rich in protein,
fiber, potassium, magnesium, and calcium, such as fruits, vegetables, beans, nuts,
whole grains, and low-fat dairy. It also limits foods high in saturated fat and sugar
[44, 45]. Another diet, with extensive benefits for treatment resistant epilepsy in
children, the ketogenic diet, has been studied as a possible intervention for depres-
sion and cognitive impairing conditions. The classic ketogenic diet consists of a
154 Novel Therapeutics in Mood Disorders (R Mansur, Section Editor)

high-fat (90%) and low-protein/carbohydrate diet, with restricted calories and

fluids. Nowadays, there are some variations to turn it into a more tolerable and
palatable diet [46].

Dietary interventions as an emergent strategy

in the treatment of mood disorders
Psychiatrists and other mental health professionals frequently receive questions
from their patients about the potential benefit of lifestyle changes in the treat-
ment of depression. If there is some controversy about the benefit of specific
diets [47], little doubts remain about the deleterious impact of an unhealthy
diet on mental health, particularly on depression [48•, 49]. Replicated evidence
suggest that an unhealthy diet, characterized by the ingestion of significant
amounts of processed food, refined grains, sugar, artificial additives, and a low
content of fruits and vegetables, is associated not only with an increased risk
of depressive symptoms in individuals who are otherwise healthy [50], but
also with increased severity of depressive symptoms in individuals with mood
disorders [48•]. A meta-analysis also evidenced an increased risk of depression
related to the consumption of pro-inflammatory foods and Western diets by
45 years and older [48•]. Ecological studies support the notion that several dif-
ferent diets might be considered healthy from a population perspective. Studies
with migrant populations confirm the harm of abandoning healthy dietetic
habits from the original countries and adopting the Western diet [51], which
is often accompanied by unhealthy weight gain [52]. It has been proposed that
the consumption of unhealthy foods induces inflammation and may be one
of the ways in which diet is related to mental health [53, 54].
Although some discussion in the literature about the antidepressant effect
of dietary interventions still persists, in recent years, the results of observational
and interventional studies, including RCTs, support a small to moderate thera-
peutic size effect of dietary interventions in MDD [55•, 56•]. The conduction
of systematic assessments of the antidepressant effect of dietary interventions
was crucial to control for potential confounders and to approximate studies
with nutrition to the scientific rigor adopted in pharmacological interventions.
The most promising dietary intervention for the treatment of depression
in clinical practice is a Mediterranean-style diet. So far, the results of two RCTs
support the superiority of this dietetic approach in reducing the severity of
depressive symptoms after 12 weeks when compared to control groups [57,
58]. Another study with a similar intervention but a shorter follow-up period
(3 weeks) also found similar results [59]. Interestingly, a recent RCT com-
pared the Mediterranean diet supplemented with dairy products to a low-fat
diet, demonstrating improvements in mood and processing speed in adults
aged 45 years or older with cardiovascular risk factors [60].
In the PREDIMED RCT (3 years of follow-up), a Mediterranean diet supple-
mented with extra-virgin olive oil (n = 2543) or nuts (n = 2454) was compared
A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings Ceolin et al. 155

with a low-fat diet (n = 2450) in a community-dwelling high cardiovascular

risk Hispanic population of men aged 55 to 80 years and women aged 60 to
80 years. Although a non-significant protection against depression was found
with the Mediterranean diet, subgroup analysis subjects with diabetes receiv-
ing the Mediterranean diet and nuts (30 g per day of mixed nuts: 15 g walnuts,
7.5 g hazelnuts, and 7.5 g almonds) had a significant protection against the
development of depression (adjusted HR = 0.59; 95% CI 0.36 to 0.98) [61].
The Australian SMILES trial, a parallel-group single-blinded RCT of an
adjunctive dietary intervention for depression, compared a diet support group
(n = 31) with a social support group as control (n = 25). The diet support
aimed to improve the dietary pattern towards a Mediterranean-style diet.
After 12 weeks, the diet support had a significant improvement in depres-
sion symptoms measured by the Montgomery-Asberg Depression Rating Scale
when compared to controls [t (60.7) = 4.38, p < 0.001, Cohen’s d = –1.16] [57].
One of the key challenges with dietary interventions is their implementa-
tion, because of several barriers: low income, socio-cultural traditions, and taste-
preferences. Low-income families are more exposed to dietary patterns consid-
ered unhealthy [62] and healthy diets are more expensive [63]. Those living
in poverty are at a higher risk for mental disorders [64] and would potentially
benefit more from dietetic interventions. Unfortunately, low-socioeconomic
status is also associated with poor treatment adherence [65]. Among the stud-
ies we reviewed, the drop-out rates varied, but overall compliance with the diet
was good, and participants were able to increase the consumption of prescribed
foods. These preliminary data show that implementing dietary changes may
result in significant improvements in affective symptoms and is feasible pro-
vided they are supported by dietitians, although the maintenance of a healthy
diet in the long-term remains an obstacle in some instances.
In addition to the available data, several other studies are currently
being conducted to evaluate the antidepressant effect of other diets [66].
For example, our group is currently conducting an open-label single-arm
interventional study of 12 weeks of medically supervised ketogenic diet in
individuals with MDD who did not properly respond to first-line antide-
pressants (Bambokian et al., submitted). The ketogenic diet is characterized
by reduced carbohydrate content and high-fat consumption and subsequent
use of ketone bodies as the primary energy source, reducing glucose use by
the brain. This diet may have mood-stabilizing properties through altered
excitatory/inhibitory status affecting the signaling of the neurotransmitters
dopamine, GABA, and glutamate, as well as more effective ATP production
with a reduction of reactive oxygen species production [66, 67]. Another
study currently undergoing recruitment is a pilot RCT with 8 weeks of a
healthy Nordic diet versus a control diet for individuals with MDD [68].
The Nordic diet consists of a high intake of vegetables and is associated with
reduced inflammation and improved metabolic markers, insulin sensitivity,
and cognition [68]. In addition, a multi-site RCT implemented the vegan
diet for 18 weeks in which significant improvements in depressive symp-
toms were shown [69]. Plant-based eating seems to promote gut microbi-
ome diversity and anti-inflammatory actions through greater consumption
of plant fibers and proteins [70].
156 Novel Therapeutics in Mood Disorders (R Mansur, Section Editor)

Discussion
Taken together, the results of the interventional trials, most notably RCTs,
support an antidepressant effect of dietary interventions, especially those
which are similar to the Mediterranean diet [57, 58, 71–73]. Notwith-
standing, the results and the experience derived from the conduction of
these studies also bring some interesting and novel topics to discussion.
First, several of them, more or less explicitly, consider that mood
changes and metabolic abnormalities are part of the same syndrome, the
so-called “metabolic-mood syndrome” [74, 75]. An example is the Multi-
country cOllaborative project on the rOle of Diet, FOod-related behav-
ior, and Obesity in the prevention of Depression (MooDFOOD). In this
trial, a large community sample of 1025 overweight adults with depressive
symptoms who are not currently experiencing a major depressive epi-
sode were randomly submitted to daily nutritional supplements or food-
related behavioral activation with the objective to prevent depression [76].
Even without finding results that support the adoption of the interven-
tions under investigation, this approach has become progressively more
accepted [77]. On the other hand, traditional psychiatric treatments, such
as neuromodulatory approaches, have been investigated to target both psy-
chopathology and metabolic variables with some promising results [78].
It is important to consider that mood disorders display vast pheno-
typical heterogeneity, which may inform the application of nutritional
interventions. For example, over 100 different loci have been associ-
ated with the risk of developing MDD, and genetic studies have identi-
fied mood disorder phenotypes based on a variety of risk factors [79,
80]. Altered neural activity and functional connectivity have even been
associated with different risk factors for depression, such as childhood
trauma [81]. Furthermore, appetite in individuals with mood disorders
may present as increased or decreased which has been linked to differ-
ent actions of neuroendocrine hormones and neurotransmitters [82].
A growing body of evidence suggests that the identification of mood
disorder subtypes based on physiology rather than symptom profile is
paramount to improving our understanding of the mechanisms underly-
ing disordered mood.
Emerging projects aim to improve mood disorder characterization and
treatment according to this heterogeneity in physiological disease correlates
[83]. For example, the Research Domain Criteria (RDoC) project involves
the conceptualization of mood disorders as a matrix of symptoms and their
proposed biological underpinnings [84]. Opposed to the application of
pharmacological interventions which is largely symptom-based, nutritional
interventions may integrate with the RDoC to address certain aspects of
mood disorder pathophysiology. For example, some authors postulate that
metabolic and nutritional variables could be more strongly associated to
some domains of the depressive psychopathology (e.g., anhedonia) than
to the general depressive symptomatic expression [85]. Therefore, it may
even become clear that some constructs (e.g., mood changes and metabolic
imbalances) should be treated together. According to the RDoC, treatment
A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings Ceolin et al. 157

selection that considers phenotypic variability in mood disorders is a step

towards improved patient care.
Second, as both depression and metabolic disturbances are multifacto-
rial, there is a trend in the literature to design multimodal interventions,
involving not only dietary protocols, but a combination of diet, physical
exercise, and other lifestyle changes [86, 87]. A recent meta-analysis on
lifestyle interventions targeting modifiable risk factors in young people
(aged 12–25 years) found 14 RCTs, which together found a non-significant
trend towards a protective effect [88]. However, only one of those studies
were conducted in a clinical population [89]. From a meta-analysis with
observational studies, a healthy lifestyle including high-quality diet and
sufficient physical activity was associated with a 50% reduction in the risk
of depressive symptoms [90].
A third point of progress is related to the possible mechanisms of
action involved in the antidepressant effects of dietary interventions
[37]. Findings from several lines of evidence, including animal stud-
ies, support the antioxidant and anti-inflammatory properties of some
diets. As MDD has been considered a condition associated with oxidative
stress and persistent low-grade inflammation, mitochondrial function,
and immune system activity may be relevant targets for intervention
[91]. Among the most recently identified mechanisms, investigations
of gut-brain axis activity are contributing to a more advanced body of
knowledge about the interaction between body health issues and mental
health [92, 93]. There is some evidence that individuals with depres-
sion represent a population with specific bacterial enterotypes or have
a reduction in the diversity of the gut microbiome [94, 95]. Although
some studies targeting the microbiome adopt methods such as probiotic
supplementation or fecal transplant, diet manipulation may also be a
safe and affordable way to change the microbiome [96–99].
The most skeptical observers would likely remind us about the high
rates of placebo effect in any study conducted with populations with
depression, even more so in those including interventions that are dif-
ficult to blind. The placebo effect occurs with any intervention under
investigation for depression, although it seems to be more depend-
ent on the population and the study design than the intervention per
se [100]. However, it is likely that individuals participating in studies
with lifestyle interventions may be physically healthier, present with
less severe illness, and have more motivation to implement dietary
changes. Therefore, larger RCTs with a more diverse patient population
are needed to fully evaluate the therapeutic efficacy of different dietary
interventions. If proven safe and effective, nutritional interventions
may be an important alternative for patients that are not agreeable to
antidepressant treatment for personal reasons or that have concerns
about side effects and/or long-term medication use [56•]. Finally, recent
studies have shown that some depressive symptoms may respond dif-
ferently to diverse treatments, further supporting a role for nutritional
interventions [101, 102]. Future research on predictors of response to
dietary interventions will help tailor treatment selection towards a more
personalized approach [103].
158 Novel Therapeutics in Mood Disorders (R Mansur, Section Editor)

Conclusion
Studies with interventions for depression based on nutritional
approaches and lifestyle interventions with diet as an adjunctive treat-
ment show promising results. According to the literature to date, we can
state that high consumption of sugars and saturated fat, and low con-
sumption of fruits and vegetables are associated with depression. The
development of larger RCTs are needed to assess predictors of response
to dietary interventions and to establish a clear positive effect of diet,
therefore, guiding clinical care and nutritional recommendations for
mental health care.

Author contribution
All authors contributed with the conception and elaboration of this article. The first draft of
the manuscript was written by Elisa Brietzke and Gilciane Ceolin and all authors commented
and edited the further version of the manuscript. All authors read and approved the final
version.

Funding
This study was funded by a Department of Psychiatry Internal Faculty Grant 2021 and a Queen’s Univer-
sity Research Initiation Grant. Gilciane Ceolin has received research support from Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior (CAPES/Brazil) Finance Code 001.

Declarations
Conflict of interest
Gilciane Ceolin declares that she has no conflict of interest. Vitor Breda declares that he has no
conflict of interest. Elena Koning declares that she has no conflict of interest. Arun Chinna Mey-
yappan declares that he has no conflict of interest. Fabiano A. Gomes declares that he has support
from the 2020 Brain and Behaviour Research Foundation (P&S Fund Young Investigator Award),
the Canadian Menopause Society, SEAMO and Queen’s Health Sciences, and received CME mate-
rials honoraria from AbbVie. Júlia Dubois Moreira declares that she has no conflict of interest.
Fernando Gerchman declares that he has no conflict of interest. Elisa Brietzke declares that she has
no conflict of interest.
 A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings Ceolin et al. 159

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