Content uploaded by Masaru Tanaka
Author content
All content in this area was uploaded by Masaru Tanaka on May 05, 2025
Content may be subject to copyright.
Review Not peer-reviewed version
Neuroinflammation and Natural
Antidepressants: Balancing Fire with
Flora
Ana Clara Figueiredo Godoy , Fernanda Fortes Frota , Larissa Parreira Araújo , Vitor E. Valenti ,
Eliana de Souza Bastos Mazuqueli Pereira , Claudia Rucco P. Detregiachi , Cristiano M. Galhardo ,
Flávia Cristina Caracio , Rafael S. A. Haber , Lucas Fornari Laurindo , Masaru Tanaka * , Sandra M. Barbalho *
Posted Date: 5 May 2025
doi: 10.20944/preprints202504.0573.v3
Keywords: major depressive disorder (MDD); plant-based therapeutics; neuroinflammation; oxidative stress;
natural antidepressants; tryptophan; kynurenine; brain-derived neurotrophic factor
(BDNF); mitochondrial dysfunction; curcumin
Preprints.org is a free multidisciplinary platform providing preprint service
that is dedicated to making early versions of research outputs permanently
available and citable. Preprints posted at Preprints.org appear in Web of
Science, Crossref, Google Scholar, Scilit, Europe PMC.
Copyright: This open access article is published under a Creative Commons CC BY 4.0
license, which permit the free download, distribution, and reuse, provided that the author
and preprint are cited in any reuse.
Review
Neuroinflammation and Natural Antidepressants:
Balancing Fire with Floras
Ana Clara Figueiredo Godoy 1, Fernanda Fortes Frota 1, Larissa Parreira Araújo 1,
Vitor E. Valenti 2, Eliana de Souza Bastos Mazuqueli Pereira 1,3, Claudia Rucco P. Detregiachi 1,3,
Cristiano M. Galhardo 1, Flávia Cristina Caracio 3,4, Rafael S. A. Haber 1, Lucas Fornari Laurindo 3,
Masaru Tanaka 5,*,† and Sandra M. Barbalho 1,3,6,*,†
1 Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília
17525-902, São Paulo, Brazil
2 Autonomic Nervous System Center, São Paulo State University, School of Philosophy and Sciences, Marília, SP, Brazil
3 Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de
Marília (UNIMAR), Marília 17525-902, São Paulo, Brazil
4 School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília 17519-030, SP, Brazil
5 HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged, Danube
Neuroscience Research Laboratory, Tisza Lajos krt. 113, H-6725 Szeged, Hungary
6 Research Coordinator at UNIMAR Charity Hospital - Marília 17525-902, São Paulo, Brazil
* Correspondence: tanaka.masaru.1@med.u-szeged.hu (M.T.); smbarbalho@gmail.com (S.M.B.);
Tel.: +36-62-342-847 (M.T.); Tel.: (+5514) 99655-3190 (S.M.B.)
† These authors contributed equally to this work.
Abstract: Background/Objectives: Major depressive disorder (MDD) is a major global health concern that is
intimately linked to neuroinflammation, oxidative stress, mitochondrial dysfunction, and complicated metabolic
abnormalities. Traditional antidepressants frequently fail short, highlighting the urgent need for new, safer, and
more acceptable therapeutic techniques. Phytochemicals, or natural antidepressants derived from plants, are
emerging as powerful plant-based therapies capable of targeting many pathogenic pathways at the same time.
Summary: This narrative review synthesizes evidence from preclinical and clinical studies on the efficacy of
phytochemicals such as curcumin, polyphenols, flavonoids, and alkaloids in lowering depressed symptoms.
Consistent data show that these substances have neuroprotective, anti-inflammatory, and antioxidant proper-
ties, altering neuroimmune interactions, reducing oxidative damage, and improving mitochondrial resilience.
Particularly, polyphenols and flavonoids have great therapeutic potential because of their capacity to penetrate
the blood-brain barrier, inhibit cytokine activity, and encourage neuroplasticity mediated by brain-derived neu-
rotrophic factor (BDNF). Despite promising results, the heterogeneity in study designs, phytochemical formula-
tions, and patient demographics highlights the importance of thorough, standardized clinical studies. Conclu-
sion: This review identifies phytochemicals as compelling adjuvant or independent therapies in depression
treatment, providing multimodal mechanisms and enhanced tolerability. Additional research into improved
dose, pharmacokinetics, long-term safety, and integrative therapy approaches is essential. Using phytothera-
peutics could considerably improve holistic and customized depression care, encouraging new research routes
in integrative neuroscience and clinical psychiatry.
Keywords: major depressive disorder (MDD); plant-based therapeutics; neuroinflammation; oxidative stress;
natural antidepressants; tryptophan; kynurenine; brain-derived neurotrophic factor (BDNF); mitochondrial dys-
function; curcumin
1. Introduction
Major depressive disorder (MDD) is a common and debilitating mental condition characterized
by persistent low mood, anhedonia, cognitive dysfunction, and severe impairments in occupational,
social, and interpersonal functioning [1]. Aside from its impact on quality of life, MDD remains the
leading psychiatric contributor to global suicide mortality, with core symptoms including diminished
self-worth, excessive guilt, psychomotor changes, and sleep disturbances—factors that collectively
contribute to increased all-cause mortality rates [2]. Patients with MDD often show persistent
Disclaimer/Publisher’s Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and
contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting
from any ideas, methods, instructions, or products referred to in the content.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
© 2025 by the author(s). Distributed under a Creative Commons CC BY license.
2 of 6
negative cognitive biases, social withdrawal, and impaired emotional regulation [3]. Epidemiological
data reveal an increasing global burden, presently impacting over 350 million individuals, with
World Health Organization forecasts indicating that MDD would emerge as the foremost cause of
disability worldwide by 2030 [4,5]. Vulnerable populations, such as pregnant women, the elderly,
and children, have disproportionately high incidence rates, emphasizing the role of psychological
stressors, genetic predisposition, and environmental adversity in its etiology [6–9]. Chronic stress, in
particular, has been linked to the pathophysiology of MDD because of its ability to disrupt neuro-
plastic processes, resulting in neuronal atrophy, synaptic loss, and volumetric changes in key brain
regions such as the hippocampus and prefrontal cortex, all of which contribute to the disorder's af-
fective, cognitive, and behavioral symptoms [10–12]. Figure 1 summarizes the primary neurobiolog-
ical mechanisms involved in MDD pathogenesis. The purpose of this state-of-the-art critical narrative
review is to integrate disparate mechanistic, pre-clinical, and clinical data into a coherent conceptual
model of phytochemical action in depression, rather than to catalogue every published study.
Figure 1. Neurobiological contributors to the onset and progression of major depressive disorder (MDD). Mul-
tiple interacting systems—including genetic predisposition, chronic psychosocial stress, systemic comorbidities,
and immune dysregulation—converge to disrupt neuroimmune homeostasis. Central to this pathophysiology
are oxidative stress, liver dysfunction, intestinal dysbiosis, and neuroinflammation, driven by activated micro-
glia and astrocytes. These cells increase reactive nitrogen and oxygen species (NO, ROS), impair mitochondrial
function, and alter kynurenine (KYN) pathway dynamics, reducing kynurenic acid (KYNA) and promoting neu-
rotoxicity. Dysregulated serotonin and gamma-aminobutyric acid (GABA) signaling, alongside diminished
brain-derived neurotrophic factor (BDNF), further impair synaptic plasticity and emotional regulation.
Emerging evidence underscores the critical role of neuroinflammatory processes in the patho-
genesis of MDD, positioning central nervous system (CNS) inflammation as a key mechanistic driver
in a subset of patients [13]. A growing body of research implicates dysregulation within the
kynurenine pathway of tryptophan metabolism—a principal biosynthetic route for serotonin—in
contributing to both decreased serotonergic tone and increased production of neurotoxic metabolites
[14]. These metabolic changes not only disrupt neurotransmitter homeostasis, but they also increase
susceptibility to mood dysregulation and cognitive impairment, which are hallmarks of depressive
pathology [15–18]. Furthermore, metabolomic profiling investigations in MDD patients regularly re-
veal abnormalities in a variety of circulating metabolites, including tryptophan, tyrosine, methionine,
valine, phenylalanine, pyruvate, kynurenic acid, and deoxycholic acid [19]. These metabolic disrup-
tions are closely associated with impaired neuroprotective mechanisms, increased oxidative burden,
dysregulated apoptotic signaling, and chronic low-grade inflammation [20–22]. Collectively, these
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
3 of 6
pathophysiological alterations foster a neurobiological environment conducive to the initiation and
persistence of depressive symptoms, particularly through the destabilization of neuronal resilience
and synaptic integrity [23].
While traditional pharmacological treatments, particularly tricyclic antidepressants (TCAs) such
as imipramine, amitriptyline, clomipramine, desipramine, and doxepin, remain essential in the treat-
ment of MDD, their therapeutic efficacy is primarily mediated by modulation of monoaminergic neu-
rotransmission, specifically by increasing synaptic concentrations of serotonin and norepinephrine
[4]. Despite their clinical value, emerging evidence suggests that while antidepressants are consid-
ered first-line therapies, they are not the only effective modality for managing MDD [2]. Notably, in
pediatric and adolescent populations, non-pharmacological strategies such as psychological support,
scheduled physical activity, and dietary optimization have shown clinically relevant preventative
and therapeutic outcomes [24]. Nonetheless, a large proportion of people show partial or complete
resistance to these therapies, emphasizing the importance of complementary or alternative therapy
approaches [25]. Phytotherapeutics have recently rekindled scientific attention due to their historical
use, biological plausibility, cost-effectiveness, and acceptable side-effect profiles. Medicinal plants
have historically provided bioactive chemicals with neuroprotective, anti-inflammatory, and neuro-
modulatory effects [26]. These natural compounds persist in guiding the discovery and development
of innovative pharmacological medicines, presenting a potentially beneficial adjunctive strategy for
persons with treatment-resistant or recurrent depression [27,28].
Phytochemicals are naturally occurring bioactive molecules present in a variety of plants and
food sources that influence their pigmentation, fragrance, and flavor profiles [29]. These chemicals,
which include alkaloids, flavonoids, steroids, coumarins, and terpenoids like eucalyptol, are increas-
ingly recognized for their therapeutic effects, particularly in situations characterized by oxidative
stress and chronic inflammation [30]. Aside from their well-established anti-oxidant and anti-inflam-
matory properties, phytochemicals also have vasoprotective and cardiometabolic effects, making
them prospective agents in the prevention and treatment of complex, multifactorial illnesses [31].
Phytocompounds have received a lot of attention in neuropsychiatry because of their possible role in
altering important neurobiological processes involved in neurodegeneration and mood disorders.
Compounds derived from plants such as Aizoaceae, Acorus, Korthalsella, Astragalus membranaceus,
Sophora flavescens, and Ononis spinosa have long been employed in traditional medicine systems for
their psychotropic and neuromodulatory effects [32–34]. Preclinical research and ongoing clinical tri-
als indicate that several of these botanicals have antidepressant-like properties via processes involv-
ing monoaminergic regulation, neurotrophic signaling, and neuroinflammatory cascade reduction
[35]. As a result, the incorporation of phytocompounds into therapeutic frameworks for MDD is in-
creasingly being investigated, both as standalone treatments and as adjuncts to traditional pharma-
cotherapy [36]. Their ability to address many pathogenic domains at once makes them especially
useful in the context of MDD, which has complex and heterogeneous neuronal bases [37].
It is well established that neurodevelopment intricately shapes emotional regulation and cogni-
tive function, both of which are highly susceptible to disruption by psychiatric and neurological dis-
orders [38]. In recent decades, the global burden of neuropsychiatric conditions—particularly those
with complex, multifactorial etiologies such as MDD—has escalated significantly, placing substantial
pressure on healthcare systems and highlighting the urgent need for innovative, accessible, and well-
tolerated therapeutic strategies [39–41]. Although conventional antidepressants remain central to cur-
rent treatment paradigms, their limitations—namely delayed onset of action, treatment resistance,
and undesirable side effect profiles—have driven the search for alternative and adjunctive interven-
tions that can engage broader neurobiological targets with improved safety margins [42,43].
In this regard, phytocompounds have emerged as intriguing candidates due to their pleiotropic
modes of action, which include anti-inflammatory, antioxidant, and neuromodulatory capabilities
[44]. Recent research has highlighted the intricate connection between phytochemicals, neuroinflam-
mation, and mitochondrial health [22,45]. Yet, no previous analysis has definitively identified the
clinical trial landscape assessing the effectiveness of general phytocompounds in MDD, despite
growing preclinical evidence and sporadic clinical research suggesting their potential usefulness. No-
tably, recent reviews contend that not all trials have yielded favorable outcomes, reinforcing the need
for further research to clarify underlying mechanisms, optimize dosage regimens, assess long-term
safety, and determine the comparative effectiveness of medicinal plants in the treatment of depres-
sion [46]. Addressing this gap, this comprehensive narrative review seeks to illuminate the diverse
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
4 of 6
roles that phytotherapeutics may play in depression management. We hope these insights will not
only guide future investigations on optimal usage and mechanisms of action but also encourage the
meaningful integration of plant-based interventions into established, evidence-based psychiatric
care.
We compiled an expert-guided evidence map: senior authors snowballed references from sem-
inal phytochemical-depression papers and maintained weekly PubMed, Scopus, and Web of Science
keyword alerts (“phytochemical* AND depression OR MDD”) through 28 February 2025. Records
were double-screened and retained only when they advanced mechanistic understanding or held
translational relevance, deliberately privileging depth over exhaustive coverage. This theory-driven
selection underpins the narrative synthesis while avoiding the rigidities of systematic-review proto-
cols. Our theory-driven, expert-guided evidence map inevitably introduces selection bias; some per-
tinent studies may therefore be absent. This trade-off was accepted to prioritize analytic depth over
exhaustive coverage. To improve clarity and avoid redundancy, overlapping descriptions of key
mechanisms such as oxidative stress, mitochondrial dysfunction, and neuroinflammation have been
streamlined. These interconnected processes are now discussed in focused sections with minimal
repetition, ensuring conceptual continuity without diluting analytical depth.
2. Neuroinflammation: A Core Driver of Severe Depression
Emerging data suggests that neuroinflammation plays a critical role in the pathophysiology of
MDD, particularly in its more severe and treatment-resistant forms [47]. With immune-mediated pro-
cesses significantly influencing brain function, inflammation in the CNS is now understood to be a
primary cause of depressive illness rather than a supporting actor [48]. This section investigates how
neuroinflammatory processes, which are characterized by immunological activation, cytokine
dysregulation, and metabolic imbalance, interact with brain areas involved in mood regulation.
Novel therapeutic approaches that target these inflammatory pathways, such as phytochemical ther-
apies, are becoming more popular as promising adjuncts in the treatment of depression as knowledge
grows.
Neuroinflammation, driven by immune activity in the CNS, is intimately associated with de-
pression through elevated levels of pro-inflammatory cytokines and enhanced microglial activation
in the prefrontal cortex, anterior cingulate cortex, and insula [49–54]. Among the key cytokines, in-
terleukin (IL)-1β can interfere with neurotransmitter systems and trigger more inflammatory sub-
stances, while IL-6 often increases in people with depression, affecting the normal function of the
hypothalamic-pituitary-adrenal axis [55,56]. Tumor necrosis factor-α (TNF-α), known for its potent
pro-inflammatory role, influences synaptic transmission and neural plasticity [57]. Interferon-gamma
(IFN-γ) boosts inflammation in the brain, while IL-2, IL-8, and IL-18 create a harmful inflammatory
situation [58,59]. In the prefrontal cortex, microglia adopt a pro-inflammatory phenotype, producing
high levels of cytokines that may impair neuronal health [60]. When these cellular sentinels remain
on high alert, they release toxic mediators that compromise neuronal functioning and hamper com-
munication between circuits [60]. Similar inflammatory activity in the anterior cingulate cortex affects
emotional processing, and overactive microglia in the insula intensify negative emotional states [61].
The hippocampus and amygdala also display maladaptive immune reactivity, undermining neuro-
plasticity and fueling the progression of depressive symptoms [62].
Approximately 30% of persons with MDD have substantial neuroinflammation in the CNS,
which is associated with increased symptom intensity and resistance to standard treatments [63,64].
Neuroinflammation is a key factor in the pathogenesis of MDD, with activation of the NLRP3 inflam-
masome leading to elevated pro-inflammatory cytokines like IL-1β and IL-18, which are linked to
depressive symptoms. [65–67]. Activation of pattern recognition receptors, such as Toll-like receptor
4 (TLR4) on microglia and astrocytes, can induce NF-κB-driven cytokine production when damage
or pathogens are detected [68]. Peripheral immune cells invade the CNS via a weakened blood-brain
barrier, exacerbating local inflammation and neurotoxicity [69]. Chronic inflammation exacerbates
oxidative and nitrosative stress, damages mitochondria, and enhances glutamate excitotoxicity
through reduced astrocytic reuptake, resulting in neuronal injury [70]. Dysfunctional mitochondria
produce pro-inflammatory chemicals, which promote inflammation [71]. Chronic stress-induced cor-
tisol elevations activate microglia, whereas gut-brain axis abnormalities allow bacterial endotoxins
to worsen systemic inflammation [72]. Last but not least, inflammatory kynurenine pathway activa-
tion lowers serotonin synthesis, which feeds a vicious cycle of depression [73].
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
5 of 6
Inflammatory cascades, which are characterized by sustained activation of cytokines and im-
mune responses, are not limited to depression; they are also found in various chronic infections, neu-
rodegenerative disorders such as multiple sclerosis, and perinatal depression, demonstrating their
widespread influence across pathologies [74–80]. Chronic infections continue to excite immune cells,
resulting in elevated amounts of pro-inflammatory cytokines, which contribute to mood and cogni-
tive impairment [81]. Analogously, autoimmune-mediated inflammation is a feature of neurodegen-
erative diseases like multiple sclerosis, in which protracted immune responses harm brain tissue,
aggravating symptoms of depression [82]. In prenatal depression, immunological activation trig-
gered by hormonal and physiological changes greatly increases inflammation, affecting both mater-
nal mood and child outcomes [83]. Furthermore, immunological dysregulation frequently interacts
with metabolic changes such as neuroendocrine dysfunction, gut microbiota dysbiosis, and mito-
chondrial abnormalities, all of which exacerbate depressive states [84–87]. Neuroendocrine disrup-
tions, such as cortisol imbalance due to hypothalamic-pituitary-adrenal axis dysfunction, exacerbate
inflammation and depressive symptoms [88]. Gut dysbiosis promotes systemic inflammation by in-
creasing intestinal permeability and endotoxin exposure, whereas mitochondrial dysfunction im-
pairs cellular energy metabolism and increases oxidative stress [89]. These interconnected inflamma-
tory and metabolic abnormalities highlight the complicated, diverse pathophysiology of depression.
Given the importance of neuroinflammation in the pathogenesis of severe and treatment-re-
sistant depression, identifying effective therapeutic strategies that target inflammation is critical
[47,90]. Notably, accumulating evidence suggests that phytochemical therapies, such as polyphenols,
may provide neuroprotective advantages by inhibiting inflammatory pathways and lowering neu-
ronal death, making them a promising adjunct method for treating MD [74,75]. Natural substances
can protect neurons by modulating inflammation, inhibiting NF-κB activation, and reducing oxida-
tive stress. Furthermore, polyphenols may repair dysregulated neurotransmission and increase mi-
tochondrial function, addressing the basic metabolic abnormalities seen in depressed states [91]. Be-
cause neuroinflammation is so tightly linked to metabolic dysfunction, immunological dysregulation,
and neuronal degeneration, therapies that target numerous inflammatory and apoptotic pathways at
the same time may produce better therapeutic results [92]. Future research should emphasize inves-
tigating the entire therapeutic potential of phytochemicals and comparable molecules as supple-
mental treatments, which could improve outcomes for people suffering from severe, inflammation-
related depression.
3. Oxidative Stress: A Silent Driver of Depression
Amid the complex web of MDD pathology, oxidative stress has emerged as a subtle yet powerful
contributor deserving closer scrutiny [92]. Characterized by an imbalance between reactive oxygen
species (ROS) and antioxidant defenses, oxidative stress quietly undermines neuronal integrity and
brain function [93]. Intriguingly, mounting evidence suggests that this biochemical imbalance not
only parallels depressive symptoms but may actively drive their persistence and severity [94]. From
antioxidant depletion to mitochondrial dysfunction, oxidative stress orchestrates a cascade of cellular
disruptions [95]. In this section, we explore the biochemical undercurrents of oxidative stress and its
far-reaching implications in the development and progression of depression.
Oxidative stress occurs when ROS and other free radicals exceed the body's capacity to neutral-
ize them through antioxidant defenses, leading to cellular harm via the degradation of essential bio-
molecules such as proteins, lipids, and nucleic acids [96,97]. In individuals with depression, this im-
balance is particularly pronounced due to significantly reduced levels of key antioxidants, including
zinc, vitamin E, and coenzyme Q10, amplifying cellular vulnerability and intensifying neurodegen-
erative processes [98,99]. These antioxidant deficits facilitate oxidative damage to neuronal mem-
branes, impair mitochondrial function, and disrupt neurotransmission, further exacerbating depres-
sive symptoms [100]. Zinc deficiency, for example, diminishes neuroplasticity and impairs glutama-
tergic signaling, whereas insufficient vitamin E reduces neuronal protection against lipid peroxida-
tion [101]. Likewise, low levels of coenzyme Q10 impair mitochondrial respiration, increasing ROS
production and energy deficits in neurons [102]. Collectively, this heightened oxidative state pro-
motes neuronal apoptosis and inflammation, reinforcing a destructive cycle that sustains and deep-
ens depressive pathology [103]. Thus, addressing oxidative imbalances through antioxidant supple-
mentation or dietary interventions could potentially mitigate cellular damage and improve therapeu-
tic outcomes in MDD.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
6 of 6
Alterations in tryptophan metabolism significantly contribute to oxidative stress in MDD, pri-
marily by shifting this amino acid toward the kynurenine pathway rather than serotonin synthesis.
When inflammation activates enzymes such as indoleamine 2,3-dioxygenase (IDO), tryptophan is
increasingly converted into kynurenine metabolites, which not only reduce serotonin availability but
also generate neurotoxic byproducts like quinolinic acid [19,104,105]. These toxic intermediates pro-
mote neuronal damage through enhanced generation of ROS, exacerbating oxidative stress and ac-
celerating cellular injury within vulnerable brain regions [99]. Furthermore, reduced tryptophan
availability itself can intensify the formation of free radicals, damaging essential biomolecules includ-
ing deoxyribonucleic acid (DNA), lipids, and proteins [106]. This cascade creates a destructive cycle of
oxidative damage, inflammation, and impaired neurotransmission, significantly correlating with in-
creased severity of depressive symptoms [99]. The resulting neuronal dysfunction, loss of synaptic
plasticity, and impaired mitochondrial performance contribute to the pathophysiology of depression
[107]. Therapeutic interventions targeting the kynurenine pathway or enhancing tryptophan availa-
bility thus hold considerable potential for reducing oxidative damage and alleviating depressive
symptoms.
Mitochondrial dysfunction—including structural alterations and disrupted energy metabo-
lism—significantly escalates ROS production, directly promoting neuroinflammation and cognitive
decline in depressive disorders [108–111]. Accumulation of dysfunctional mitochondria further exac-
erbates neuronal damage, perpetuating chronic inflammatory cycles within the brain [112,113]. Spe-
cifically, impaired mitophagy hampers the removal of damaged mitochondria, allowing toxic debris
to accumulate and activate inflammatory complexes, notably the NLRP3 inflammasome, leading to
increased pro-inflammatory cytokine production [114]. Disrupted mitochondrial calcium buffering
elevates intracellular calcium, triggering oxidative damage, microglial activation, and amplified in-
flammatory signaling [115]. Moreover, mitochondrial energy deficits dysregulate AMP-activated
protein kinase (AMPK) signaling, causing aberrant mammalian target of rapamycin (mTOR) activa-
tion that sustains inflammatory responses [116]. Increased ROS production triggers transcription fac-
tors such as NF-κB, leading to ongoing release of inflammatory cytokines (IL-6, TNF-α) [117]. Re-
duced mitochondrial health also lowers NAD⁺ levels, which weakens protective sirtuin signaling,
while imbalanced iron levels encourage ferroptosis, worsening oxidative damage [118,119]. Conse-
quently, impaired neurogenesis and reduced synaptic plasticity intensify cognitive deficits, reinforc-
ing a destructive feedback loop of mitochondrial-driven inflammation in depression [113].
Obesity-induced inflammation significantly heightens oxidative stress by increasing adipokine
secretion—such as IL-6, IL-1, and tumor necrosis factor-alpha—while simultaneously impairing in-
sulin regulation, thus elevating risks for type 2 diabetes and depression [120–122]. Chronic obesity
also fosters leptin resistance, amplifying microglial activation and further promoting inflammatory
cascades within the brain [123]. Moreover, lifestyle factors, particularly high-fat diets and sedentary
behaviors, escalate ROS production through enhanced mitochondrial β-oxidation and activation of
nuclear factor kappa B (NF-κB) signaling, reinforcing inflammation and neuronal stress pathways
[124–128]. Dietary saturated fats directly stimulate inflammasome complexes like NLRP3, causing
excessive IL-1β release and perpetuating neuroinflammation [129]. Additionally, obesity-related hy-
perglycemia accelerates formation of advanced glycation end-products (AGEs), activating inflamma-
tory responses via AGE receptors on microglia [130]. High-fat diets exacerbate gut microbiota dis-
ruption, increasing endotoxin leakage into circulation and systemic inflammation, while simultane-
ously lowering BDNF levels, impairing neuronal resilience [131]. These interconnected metabolic,
inflammatory, and behavioral mechanisms underscore the critical role of dietary antioxidants and
regular physical exercise in mitigating inflammation-induced depressive pathology.
Oxidative stress stands as a potent yet often overlooked force driving the progression and per-
sistence of MDD [97]. Rather than being a mere consequence of other pathological changes, it plays
an active role in linking mitochondrial dysfunction, immune activation, metabolic disturbances, and
adverse lifestyle factors [132]. Through sustained production of ROS and insufficient antioxidant de-
fenses, oxidative stress damages cellular structures, fuels neuroinflammation, and disrupts key neu-
ral circuits involved in mood regulation [97]. Its impact extends from molecular disruption to large-
scale cognitive decline and emotional dysregulation [133]. Addressing this underlying imbalance—
via antioxidant therapies, metabolic support, and targeted lifestyle changes—offers a promising di-
rection for enhancing treatment response and improving long-term outcomes in individuals with
depression.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
7 of 6
4. Depression’s Mitochondrial Roots and Repair Strategies
Far beyond their role as mere energy suppliers, mitochondria are now recognized as pivotal
regulators of brain health and emotional resilience [134]. In the context of MDD, mitochondrial dys-
function has garnered growing attention as a hidden yet potent driver of neurobiological disruption
[119]. From impaired energy metabolism to excessive ROS production, mitochondrial abnormalities
appear to fuel the progression of depressive symptoms [103]. This section delves into the emerging
landscape of mitochondrial pathology in depression—alongside innovative repair strategies—high-
lighting a compelling shift in how we understand and potentially treat this multifaceted disorder.
Mitochondria also play a pivotal role in regulating neuroinflammation, positioning them as key
contributors to both the onset and persistence of MDD [87]. In individuals with MDD, mitochondrial
abnormalities—such as structural degradation, disrupted mitochondrial DNA (mtDNA), and im-
paired electron transport chain (ETC) function—lead to excessive production of ROS, destabilizing
neurotransmitter systems and exacerbating depressive symptoms [109,135–137]. These disturbances
are intensified by additional mitochondrial impairments [138]. Oxidative damage to mtDNA impairs
the synthesis of ETC components, while dysregulated biogenesis reduces the formation of healthy
mitochondria [139]. Imbalances in fusion and fission dynamics further fragment the mitochondrial
network, diminishing metabolic capacity and increasing susceptibility to cell death [140]. Chronic
stress-related calcium overload, inhibition of ETC complexes, and glucocorticoid-induced suppres-
sion of mitochondrial maintenance genes all contribute to dysfunction [141]. Moreover, a disrupted
NAD⁺/NADH ratio and persistent exposure to pro-inflammatory cytokines impair mitochondrial res-
piration, DNA repair, and anti-inflammatory signaling [142]. Together, these interconnected mecha-
nisms establish a vicious cycle of mitochondrial breakdown, oxidative stress, and neuroinflammation
that drives the neurobiological deterioration seen in MDD.
While psychosocial stressors undoubtedly contribute to the onset MDD, a growing body of evi-
dence highlights the role of biochemical markers—particularly those tied to mitochondrial health—
in its pathophysiology [108]. One such marker, methylmalonic acid (MMA), is elevated in cases of
vitamin B12 deficiency and has been shown to impair succinate dehydrogenase activity, thereby in-
creasing ROS production and promoting neuronal injury [143–147]. Additional biomarkers further
implicate mitochondrial dysfunction in MDD. Elevated homocysteine, another consequence of B-vit-
amin deficiency, induces oxidative stress and compromises mitochondrial DNA repair [148]. In-
creased brain lactate and pyruvate levels suggest a shift from oxidative phosphorylation to inefficient
anaerobic metabolism [149]. Accumulation of acylcarnitines reflects disrupted fatty acid oxidation,
while elevated ammonia impairs mitochondrial respiration and contributes to neurotoxicity [150].
Depletion of glutathione (GSH), the mitochondria’s frontline antioxidant, leaves cells vulnerable to
ROS, and heightened levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) indicate mtDNA damage
[151]. Deficiencies in Coenzyme Q10 and imbalances in the NAD⁺/NADH ratio further hinder ATP
production and stress resilience [152]. Together, these markers underscore the biochemical complex-
ity and mitochondrial vulnerability underlying depressive disorders. These observations resonate
with broader neurodegenerative research frameworks, which emphasize the integration of imaging
biomarkers, inflammatory profiles, and metabolic signatures to characterize disease subtypes and
guide personalized intervention strategies [153].
Recent studies underscore several promising therapeutic strategies aimed at correcting mito-
chondrial dysfunction in MDD [154]. Among them, mitochondrial transplantation—either by replac-
ing damaged mitochondria or introducing healthy mitochondrial DNA and related proteins—has
emerged as a novel approach to restoring cellular energy balance and reversing neuronal damage
[155]. Similarly, inhibiting the renin-angiotensin system with angiotensin receptor blockers has
shown potential in reducing neuroinflammation and oxidative stress, both key drivers of depressive
pathology [156,157]. Beyond these, mitochondria-targeted antioxidants like MitoQ and SkQ1 directly
neutralize ROS within mitochondria, improving membrane potential and behavioral outcomes [158].
Supplementation with NAD⁺ precursors (e.g., nicotinamide riboside) enhances mitochondrial bio-
genesis and DNA repair via sirtuin activation [159]. Coenzyme Q10 boosts ATP production, while
PGC-1α activators such as resveratrol and AMPK activators promote mitochondrial renewal
[160,161]. Other emerging strategies include inhibition of the mitochondrial permeability transition
pore (mPTP), ketogenic diets to optimize mitochondrial fuel use, sirtuin activators to dampen inflam-
mation, and L-carnitine derivatives that support fatty acid oxidation [162–165]. Gene therapies
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
8 of 6
targeting mtDNA mutations offer future avenues for correcting mitochondrial defects at their source
[166].
Ultimately, restoring mitochondrial health offers a compelling path forward in the treatment of
MDD. By integrating phytochemicals and other multimodal strategies—ranging from targeted anti-
oxidants to metabolic and genetic interventions—it may be possible to reduce oxidative damage, en-
hance energy metabolism, and reinforce neuronal resilience [108]. These approaches hold promise
not only for symptom relief but also for addressing the cellular dysfunctions at the core of depres-
sion’s pathology. Importantly, mitochondrial fragility does not occur in isolation. Caloric excess, in-
sulin resistance, and adipose-derived cytokines impose a chronic oxidative-inflammatory load that
further erodes mitochondrial ATP output and calcium buffering in limbic neurons. In turn, energy-
starved mitochondria dysregulate appetite and glucose homeostasis via hypothalamic circuits, creat-
ing a vicious cycle in which metabolic inflammation and mitochondrial dysfunction co-amplify de-
pressive pathology. This bidirectional loop sets the stage for examining obesity-linked inflammation
in greater detail.
5. Nutrition, Inflammation, and Depressive Spirals
While nutrition and lifestyle factors clearly shape metabolic risk and modulate inflammation
relevant to MDD, a detailed discussion lies beyond the core focus of this review. We briefly highlight
key findings to underscore how diet quality, physical activity, and sleep patterns influence neuroim-
mune health. These modifiable behaviors may complement pharmacological and phytochemical
strategies, but a full exploration of their therapeutic applications warrants separate, dedicated anal-
ysis. Nutrition lies at the crossroads of physical and mental health, yet its role in MDD is often un-
derestimated [167]. Increasingly, research points to a vicious cycle in which poor dietary habits not
only reflect depressive states but actively intensify them through metabolic disruption and chronic
inflammation [168]. As nutrient deficiencies and unhealthy food choices fuel neurobiological stress,
depressive symptoms may deepen, further eroding motivation for self-care [169]. This section ex-
plores how diet, lifestyle, and inflammation intertwine in self-perpetuating spirals—offering both a
cautionary tale and a hopeful lens on how strategic nutritional interventions may help break the cy-
cle.
Recent lines of evidence highlight those dietary behaviors, modulated by psychological factors,
significantly shape obesity risk and depressive symptoms by influencing nutrient availability and
metabolic function [170–172]. In particular, inadequate consumption of vitamin B12, zinc, magne-
sium, folic acid, and vitamin B6 has been associated with elevated susceptibility to MDD [15]. More-
over, diets dominated by high-fat convenience foods often coincide with lower intake of fruits, veg-
etables, lean proteins, and whole grains, fueling systemic inflammation and oxidative stress linked
to depression pathogenesis [173–175]. These findings underscore the multifaceted interplay among
dietary patterns, nutritional deficiencies, and mood disorders, suggesting that suboptimal eating hab-
its may potentiate neurobiological pathways underlying depression [176]. By integrating these in-
sights into clinical practice, researchers and clinicians can more effectively target modifiable lifestyle
factors in conjunction with pharmacotherapy or psychotherapy [177]. Ultimately, developing evi-
dence-based nutritional interventions, particularly those emphasizing nutrient-rich whole foods,
could mitigate depressive symptom severity while reducing broader metabolic risk [178]. This com-
prehensive approach holds promise for reducing disease burden and improving patient outcomes in
MDD.
Obesity is increasingly recognized as a critical comorbidity in depression, given that excess adi-
posity promotes a pro-inflammatory milieu and metabolic dysregulation, potentially exacerbating
psychiatric symptomatology [85,86]. In parallel, emerging data indicate that individuals with severe
depressive disorders often exhibit behaviors that intensify these physiological burdens, such as
smoking, physical inactivity, and insufficient sleep [179,180]. These lifestyle factors further elevate
systemic inflammation and oxidative stress, reinforcing a feedback loop that intensifies both mood
disturbances and metabolic risk [64]. Notably, recent studies underscore that even modest reductions
in body mass index or targeted interventions to improve sleep quality can substantially attenuate
neuroinflammatory processes linked to depression [181]. By highlighting these interdependent mech-
anisms, the present review affirms the need for comprehensive management approaches that address
not only psychological distress but also modifiable health behaviors [177]. Tailored interventions that
incorporate nutritional counseling, physical activity regimens, and sleep hygiene may thus hold
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
9 of 6
therapeutic promise, mitigating the dual burden of metabolic and mental health complications
[182,183]. Advancing this integrative perspective could ultimately refine treatment algorithms and
inform future research directions in translational psychiatric care.
Emerging data consistently underscore the potential for lifestyle modifications to alleviate
mood-related symptomatology and address comorbid metabolic disorders in individuals with de-
pression [177]. Notably, adopting healthier diets characterized by nutrient-dense foods, minimized
refined sugars, and balanced macronutrient intake appears to diminish systemic inflammation and
improve metabolic regulation [184]. When combined with regular physical activity, such dietary pat-
terns may enhance neuroplasticity through increased neurotrophic factor release, supporting neu-
ronal resilience [185]. Stress management techniques, including mindfulness-based practices and
cognitive-behavioral strategies, further mitigate hypothalamic-pituitary-adrenal axis dysregulation,
thereby moderating pro-inflammatory responses and bolstering mental health [172,186,187]. Alt-
hough these findings remain preliminary, they collectively suggest that targeted lifestyle programs
can serve as essential components of comprehensive treatment plans [188]. Moreover, recent random-
ized controlled trials affirm that multifaceted approaches integrating nutritional counseling, behav-
ioral interventions, and exercise regimens yield meaningful improvements in depressive symptoms
and metabolic risk profiles [189]. This perspective highlights the need to broaden therapeutic frame-
works beyond pharmacological paradigms to address the complex interplay among diet, behavior,
and psychological well-being in depression [190].
Collectively, these findings illuminate how poor dietary habits can instigate a vicious cycle in
which chronic inflammation exacerbates depressive pathology, further eroding motivation for
healthy behavior [168]. By perpetuating neurobiological stress, this spiral intensifies symptom sever-
ity and increases metabolic risk, reinforcing suboptimal eating patterns [168]. Adopting balanced,
nutrient-rich diets, regular physical activity, and evidence-based stress management may disrupt this
harmful feedback loop, thereby enhancing neurotransmitter balance, mitigating systemic inflamma-
tion, and restoring metabolic homeostasis [177]. Although rigorous trials remain necessary to pin-
point optimal protocols, strategic nutritional interventions hold considerable promise for curtailing
the depressive spiral and advancing patient-centered treatment paradigms in MDD [191].
6. Rethinking Depression Care: Drugs and Natural Options
As our understanding of MDD deepens, so too does the landscape of its treatment—now evolv-
ing beyond traditional pharmacotherapy toward more integrative, personalized care [192]. While es-
tablished medications like SSRIs and SNRIs remain central, their side effect profiles and limitations
prompt a reexamination of what comprehensive care can look like [193]. Intriguingly, nature itself
may offer untapped solutions [194]. From time-honored botanicals to novel phytochemicals, natural
compounds are gaining recognition as adjunctive or alternative treatments with promising efficacy
and improved tolerability [195]. This section explores the growing synergy between conventional
drugs and natural options in the quest for more holistic depression care.
Pharmacological and non-pharmacological therapies for MDD are increasingly being delivered
through multidisciplinary care teams, reflecting a shift toward more holistic, patient-centered treat-
ment models [196,197]. These teams typically include psychiatrists—who oversee diagnosis, medica-
tion management, and complex case coordination—and clinical psychologists or psychotherapists,
who deliver evidence-based therapies such as CBT, IPT, and mindfulness-based interventions
[198,199]. Nutritionists or dietitians also play a key role by addressing nutritional deficiencies and
promoting anti-inflammatory dietary patterns that support mitochondrial and mental health
[198,200]. Exercise physiologists or physical therapists prescribe tailored physical activity regimens
to reduce depressive symptoms and improve neurobiological function [198,199]. Primary care phy-
sicians manage medical comorbidities that often worsen mood disorders, while pharmacists ensure
medication safety and adherence [201]. Complementary and integrative health practitioners may in-
troduce acupuncture, yoga, or nutraceutical support to reduce oxidative stress [202]. Social workers
and case managers address psychosocial barriers and improve continuity of care, and peer support
specialists offer lived-experience insights that build trust and engagement [203]. This interdiscipli-
nary approach is especially effective in treatment-resistant or complex cases, offering a comprehen-
sive strategy that integrates biological, psychological, and social dimensions of depression [204–206].
Among pharmacological options for MDD, selective serotonin reuptake inhibitors (SSRIs) re-
main the preferred first-line treatment due to their efficacy and relative tolerability. However,
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
10 of 6
alternative classes such as serotonin–norepinephrine reuptake inhibitors (SNRIs), TCAs, monoamine
oxidase inhibitors (MAOIs), and N-methyl-D-aspartate (NMDA) antagonists provide additional ther-
apeutic pathways, especially in treatment-resistant cases [10,207–209]. Despite their benefits, these
agents are associated with a range of adverse effects [210]. SSRIs can cause gastrointestinal disturb-
ances, insomnia, sexual dysfunction, and in some cases, QTc prolongation—particularly with cital-
opram [211]. SNRIs like venlafaxine and duloxetine may induce hypertension, hepatotoxicity, and
withdrawal symptoms [212]. TCAs carry anticholinergic burdens (e.g., dry mouth, constipation) and
significant cardiovascular risks, including arrhythmias [213]. MAOIs, though effective, are limited by
dietary restrictions and the risk of hypertensive crises or serotonin syndrome [214]. Atypical antide-
pressants such as bupropion and mirtazapine offer varied mechanisms but introduce risks like in-
somnia, weight gain, or seizure potential [215]. Novel agents, including NMDA antagonists like es-
ketamine, present dissociative and cardiovascular side effects [216]. Given these diverse profiles,
careful, individualized treatment planning is essential [215,217–220]. The limitations of conventional
antidepressants, such as the risk of hyponatremia in older adults and individuals taking diuretics,
underscore the need for safer and more tolerable treatment options [221,222].
These safety concerns have prompted increasing interest in alternative and complementary
strategies that can enhance efficacy while reducing adverse effects [223]. Herbal medicines are gain-
ing recognition as potential adjuncts in the treatment of MDD [224]. These natural compounds may
exert neuroprotective, anti-inflammatory, and mood-regulating effects while offering better tolera-
bility and fewer side effects compared to standard medications [225–227]. By improving safety pro-
files and supporting long-term adherence, herbal therapies may help address some of the limitations
associated with conventional pharmacological approaches [228]. Their integration into clinical prac-
tice could also support a more holistic and individualized model of care [229]. As research continues
to explore these compounds' mechanisms and clinical potential, combining pharmacological and nat-
ural interventions may represent a promising path toward more comprehensive and patient-centered
depression management.
7. Plant-Based Therapies: Natural Allies Against Depression
As science turns its gaze toward nature’s pharmacopoeia, plant-based therapies are emerging as
exciting frontiers in the treatment of MDD [230]. Rich in bioactive compounds, plants offer a diverse
array of phytochemicals capable of modulating the same neurobiological pathways targeted by con-
ventional antidepressants—often with fewer side effects [231]. From polyphenols and flavonoids to
carotenoids and alkaloids, these natural agents show potential to combat oxidative stress, inflamma-
tion, and neurodegeneration [232]. This section delves into the growing body of evidence supporting
phytotherapies as integrative, multifaceted allies in the fight against depression—opening the door
to greener, gentler innovations in mental health care.
Phytochemicals, bioactive compounds naturally derived from plants, have attracted increasing
interest for their ability to modulate key neurobiological pathways involved in MDD [37,233]. Among
them, polyphenols are particularly noteworthy for their ability to cross the blood-brain barrier and
exert neuroprotective, antioxidant, and anti-inflammatory effects, thereby attenuating cytokine ac-
tivity and reducing neuronal apoptosis [75,234]. Within this class, flavonoids such as luteolin effec-
tively scavenge free radicals and suppress neuroinflammation [234–236], while carotenoids offer sim-
ilar antidepressant benefits through antioxidant and anti-inflammatory mechanisms [237–240]. These
effects align with the growing evidence that enhancing BDNF signaling improves synaptic plasticity
and emotional regulation. Compounds like curcumin and resveratrol have demonstrated the ability
to upregulate BDNF in animal models, contributing to mood stabilization and resilience [241–243].
Additional polyphenols—including quercetin, EGCG, fisetin, apigenin, and baicalein—further rein-
force these effects by modulating inflammatory signaling, reducing oxidative stress, and promoting
mitochondrial function [244–247]. Collectively, these natural agents represent promising adjunctive
therapies for improving clinical outcomes in MDD through multimodal neuroprotective actions.
Additional phytochemicals found in medicinal plants such as Panax ginseng, Mitragyna speciosa,
Astragalus membranaceus, and species within the Acorus genus have shown antidepressant-like effects
primarily through their anti-inflammatory and antioxidant properties [32,34,248–250]. These effects
are echoed in other plant-derived compounds that act on convergent molecular pathways [137].
Withanolides from Withania somnifera modulate the HPA axis, reduce pro-inflammatory cytokines
like IL-6 and TNF-α, and elevate BDNF levels, enhancing stress resilience [251]. Hericenones and
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
11 of 6
erinacines from Hericium erinaceus stimulate nerve growth factor synthesis, reduce oxidative stress,
and improve monoaminergic balance [252]. Ginsenosides from Panax ginseng and bacopasides from
Bacopa monnieri both boost mitochondrial efficiency, suppress neuroinflammation, and promote neu-
roplasticity [137,253]. Other promising agents include honokiol from Magnolia officinalis, paeoniflorin
from Paeonia lactiflora, and berberine from Berberis species, all of which influence oxidative, inflam-
matory, and neurotransmitter systems [254–256]. Rhynchophylline and salidroside further contribute
to this phytochemical network by protecting neurons and regulating mood circuits [257]. Collec-
tively, these compounds offer diverse mechanisms for mitigating the multifaceted pathways under-
lying mood disorders by reducing inflammation, alleviating oxidative stress, fine-tuning neurotrans-
mitter balance, and fostering neuroplasticity, thereby highlighting their integrative therapeutic po-
tential.
Although plant-based interventions often exhibit fewer side effects than conventional antide-
pressants, their clinical application still requires deeper investigation to refine optimal dosing, clarify
underlying mechanisms, and ensure long-term safety [258,259]. Nonetheless, mounting evidence
supports the potential of phytotherapeutics as effective, integrative strategies for addressing the com-
plex and multifactorial nature of MDD [260]. By targeting neuroinflammation, oxidative stress, mi-
tochondrial dysfunction, and neurotransmitter imbalances, these compounds offer a multi-pronged
approach to mood regulation [261]. Their ability to enhance neurotrophic factors, such as BDNF, fur-
ther strengthens their therapeutic value [262]. As the field of psychoneuropharmacology evolves, in-
corporating plant-derived compounds into treatment frameworks may improve outcomes for pa-
tients who are unresponsive or intolerant to traditional therapies [263]. Collectively, these findings
highlight the critical need for continued clinical research on phytomedicines in mood disorder man-
agement [264]. Figure 2 illustrates select phytochemicals and their modulatory effects on brain me-
tabolism and neural function, underscoring their relevance as natural allies in depression care.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
12 of 6
Figure 2. Phytochemicals and the role in brain health and reduction of depression. HPA: hypothalamic-pituitary-
adrenal; BDNF: Brain-derived neurotrophic factor. a: hypericin; b: coumarin; c: eucalyptol; d: resveratrol; e: cur-
cumin; f: gallic acid; g: epicathechin.
8. From Curcumin to Cocoa: Plant-Based Mood Solutions
The following interventional studies reveal a promising, though heterogeneous, body of evi-
dence regarding the therapeutic potential of phytocompounds in MDD. These trials examined a wide
range of phytochemicals, including curcumin, quercetin, polyphenols, anthocyanins, isoflavones,
proanthocyanidins, and flavonoid-rich extracts, often administered in monotherapy or adjunctive
formats. Although sample sizes, duration, and design quality varied, most studies used validated
depression scales and biochemical endpoints, supporting a neurobiological rationale for clinical
translation.
In a well-structured randomized controlled trial, Soltani et al. [25] evaluated the impact of
nanocurcumin supplementation in individuals with coronary slow flow phenomenon (CSFP). The
intervention led to improvements in depressive symptoms, physical and psychological health-related
quality of life, and cardiometabolic parameters, with biochemical assays confirming anti-inflamma-
tory and antioxidant effects [265]. Conversely, the double-blind, placebo-controlled study by Jalili et
al. (2020) examining quercetin failed to find significant antidepressant effects. Moreover, the
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
13 of 6
intervention group reported notable adverse effects—abdominal discomfort, paresthesia, and head-
aches—raising concerns about tolerability in psychiatric populations [266].
Methodological strengths such as stratified randomization and biomarker analysis were evident
in the study by Hajiluian et al. [34], which demonstrated reduced depressive symptoms in individu-
als with Multiple Sclerosis following polyphenol-rich interventions. However, its narrow population
limits generalizability to broader MDD cohorts [267]. In a similarly well-structured clinical trial, Choi
et al. [27] examined the effects of flavonoid-enriched orange juice in healthy adults. Improvements in
depressive symptoms were paralleled by increased serum BDNF and reduced zonulin levels, indi-
cating neuromodulatory and gut-brain axis effects. Despite robust biochemical correlates, the sample
size of 40 reduced statistical power [27].
Maeda-Yamamoto et al. [35] assessed the impact of anthocyanin-rich Solanum tuberosum L. on
stress and mesenchymal stem cell proliferation. Although qualitative outcomes were positive, the
trial was limited by its very small sample (n=15) and short duration (8 weeks), which precluded long-
term conclusions. Similarly, Barfoot et al. [36] conducted a randomized study during the COVID-19
pandemic, which introduced significant confounding related to global psychological stress. While
randomization via software strengthened validity, high dropout rates impaired data reliability.
Parilli-Moser et al. [37] explored the effects of botanical cognitive enhancers on depressive symp-
toms. Although standardized cognitive assessments were used, low group sizes and a lack of blind-
ing limited interpretive strength, and COVID-19-related disruptions likely impacted outcome validit.
In contrast, the RISTOMED study by Bourdel-Marchasson et al. [38] assessed a dietary protocol rich
in antioxidants and polyphenols. After 2 months, reductions in depressive symptoms were observed,
but these were found to be independent of inflammatory biomarker changes, suggesting mechanisms
beyond systemic inflammation.
Kontogianni et al. [268] investigated high versus low polyphenol diets in the PPhIT trial, noting
improved psychological wellbeing in the high-polyphenol group using standardized lifestyle and
mood assessments. Park, Choi, and Lee [268] similarly conducted a placebo-controlled flavonoid
study using orange juice and observed improvements in depression alongside increased serum ser-
otonin, BDNF, and reduced CRP—though the small sample again limits external validity.
Smetanka et al. [268] focused on the potential for Pycnogenol to mitigate SSRI-induced sexual
dysfunction in patients taking escitalopram. However, the open-label design and simultaneous phar-
macologic interventions created confounding that weakens causal inference. In the curcumin trial by
Kanchanatawan et al. [40],methodological strengths included matched placebo capsules and double-
blinding, although prior treatments continued during the trial, potentially masking true curcumin
effects.
The study by Esmaily et al. [41] observed only marginal reductions in anxiety and depressive
symptoms in response to saffron extract, with effects limited to a single outcome measure—suggest-
ing potential underpowering or scale insensitivity. In a postmenopausal population, Terauchi et al.
[33] demonstrated that grape seed proanthocyanidins reduced depressive symptoms in a dose-de-
pendent manner, using validated questionnaires. However, the short duration (8 weeks) and modest
sample size limit generalizability.
Equol and resveratrol were evaluated in a longitudinal 12-week study on menopausal women
aged 50–55, where supplementation improved mood as assessed by the Hamilton depression rating
scale (HAM-D) [269]. Hirose et al. [270] explored low-dose isoflavone aglycone for postmenopausal
symptoms, including depression and anxiety, using HADS and AIS. Despite positive outcomes, lack
of adverse event documentation and small sample size limit clinical confidence.
Cognitive-affective benefits of blueberry-derived flavonoids were tested in a crossover design
by Khalid et al. [270], involving both children and young adults. Stratified analysis revealed reduc-
tions in depressogenic cognitive patterns two hours post-consumption, supporting the acute neuro-
modulatory potential of these compounds.
Lastly, Sathyapalan et al. [270] evaluated chocolate rich in cocoa liquor and polyphenols versus
low-polyphenol control chocolate in patients with chronic fatigue syndrome. Participants in the high-
cocoa group reported improvements in depressive and fatigue symptoms, supporting flavonoid ef-
ficacy in neuropsychological syndromes. Pase et al. [11] reported mood-enhancing effects of cocoa
polyphenols but no cognitive improvements after 30 days of supplementation.
Overall, these studies reviewed underscore the emerging promise of phytocompounds as ad-
junctive or standalone interventions for MDD. While most trials reported clinically meaningful
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
14 of 6
reductions in depressive symptoms, variability in methodological rigor, sample size, and treatment
duration limited the generalizability of these findings. Notably, studies incorporating double-blind,
placebo-controlled designs and objective biomarkers (e.g., inflammatory mediators, neurotrophic
factors) provided stronger evidence for neuromodulatory and neuroprotective mechanisms. Never-
theless, several investigations reported inconclusive or modest effects, indicating the necessity of im-
proved trial designs and larger, more diverse samples. Given the heterogeneous nature of depression,
a multi-targeted approach—such as that offered by phytochemicals—holds particular relevance. Fu-
ture research efforts should focus on optimizing dosage regimens, exploring synergistic effects with
standard antidepressants, and elucidating long-term safety profiles to solidify phytocompounds’
place in evidence-based psychiatric care.
Table 1. Summary of Interventional Studies Evaluating the Therapeutic Effects of Phytocompounds in Major
Depressive Disorder (MDD). This table presents a structured synthesis of the 19 clinical trials included in the
systematic review, selected according to PRISMA guidelines. Each study is characterized by its design, geo-
graphic location, sample demographics, intervention type, control conditions, outcome measures, and reported
adverse events. The interventions include a range of phytocompounds—such as curcumin, flavonoids, anthocy-
anins, and isoflavones—administered in monotherapy or adjunctive formats. Outcomes were assessed via vali-
dated psychometric scales and, where applicable, supported by biochemical and neurotrophic markers. This
compilation provides a comparative overview of study quality, efficacy, and safety in the clinical application of
phytochemicals for MDD.
Study [ref.]
Country
Population
Intervention
Outcomes
Side Effects
Soltani et al. [265]
Iran
42 patients (CSFP) aged
35–70
Nano-curcumin 80
mg/day, 12 weeks
Improved depression &
quality of life
Nausea, headache,
diarrhea
Dehghani et al. [266]
Iran
76 individuals aged 35–
65
Quercetin 500 mg/day, 8
weeks
Marginal depression
improvement
Headache, joint
pain, abdominal
discomfort
Hajiluian et al. [267]
Iran
50 MS patients with de-
pression, aged 18-55
Ellagic acid 180 mg/day,
12 weeks
Reduced inflammation
& depression
None significant
Choi et al. [271]
South Korea
40 young adults aged
18-29 with MDD
Flavonoid-rich orange
juice, 8 weeks
Significant improve-
ment in depressive
scores
None significant
Maeda-Yamamoto et al.
[272]
Japan
15 older adults aged 50-
70
Anthocyanin-rich pota-
toes, 8 weeks
Improved psychological
stress response
None significant
Parilli-Moser et al. [273]
UK
38 new mothers
High-flavonoid diet, 2
weeks
Reduced anxiety, im-
proved social relation-
ships
None significant
Barfoot et al. [274]
Spain
63 young overweight
adults
Roasted peanuts & pea-
nut butter, 6-7 months
Significant depression
reduction
Digestive symp-
toms, softer stools
Bourdel-Marchasson et al.
[275]
Europe
125 elderly adults aged
~70
Antioxidant-rich diet, 2
months
Reduced depressive
symptoms
None serious
Kontogianni et al. [268]
UK
99 mildly hypertensive
adults aged 40-65
High vs low polyphenol
diet, 8 weeks
Improved depressive
symptoms
Not reported
Park et al. [276]
South Korea
40 healthy adults (20–30
y)
Flavonoid-rich (FR) or
Flavonoid-low (FL)
drinks, 190 mL twice
daily for 8 week
↓ Depressive symptoms
(CES-D <20)
None significant
Smetanka et al. [277]
Slovakia
67 adults with MDD,
aged 18-65
Pycnogenol with escital-
opram, 12 weeks
No additional benefit
compared to escital-
opram alone
None significant
Kanchanatawan et al. [278]
Multinational
61 adults aged 18-63
with MDD history
Curcumin 500-1500
mg/day, 12-16 weeks
Improved depression
scores (MADRS)
Dizziness, nausea,
insomnia, diarrhea
Terauchi et al. [269]
Italy
60 menopausal women
aged 50-55
Equol & resveratrol, 12
weeks
Reduced depressive
symptoms (HAM-D)
Mild diarrhea
Khalid et al. [279]
UK
Young adults & chil-
dren
Wild blueberry drink (fla-
vonoids), acute admin-
istration
Improved positive af-
fect shortly after con-
sumption
None significant
Hirose et al. [270]
Japan
87 menopausal women
aged 40-60
Isoflavone aglycones, 8
weeks
Improved anxiety, mod-
est depression changes
None significant
Sathyapalan et al. [280]
UK, Iran
30 obese adults
Curcumin 1 g/day, 30
days
Reduced anxiety, no
significant depression
improvement
None significant
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
15 of 6
Terauch et al. [281]
Japan
91 menopausal women
(40–60 y)
GSPE (100 or 200 mg/day)
vs placebo, 8 weeks
↓ Anxiety (dose-de-
pendent); no effect on
depression
None significant
Pase et al. [11]
Australia
Adults aged 40-65
Cocoa polyphenols 250-
500 mg/day, 30 days
Improved mood, calm-
ness
None
Clinical pilot [282]
UK
10 adults
High-polyphenol choco-
late, crossover
Improved anxiety and
depression scores
None
AE: Adverse events; AIS: Athens Insomnia Scale; BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory;
BDI-II: Beck Depression Inventory-II; BDNF: Brain-derived neurotrophic fator; CB: control butter; CES-D: Center
for Epidemiological Studies Depression Scale; EDSS: expanded disability status scales; ESC: Escitalopram; FL:
low flavonoid orange cordial group; FR: group of orange juice rich in flavonoids; GSPE: grape seed proanthocy-
anidin extract; HADS: Hospital Anxiety and Depression Scale; HAMD/ HAMD -17: Hamilton Depression Rating
Scale; IFN-γ: gamma interferon; IQR: range between quartiles; MADRS: Montgomery - Asberg Depression Rat-
ing Scale; MDD: major depressive disorder; MSC: mesenchymal stem cells; MSS: Menopause Symptom Scale;
MS: multiple sclerosis; NO: nitric oxide; PA: Positive Affect; PB: peanut butter; PR: time interval between the
beginning of atrial depolarization and the beginning of ventricular depolarization; PYC: Pycnogenol; QRS: de-
polarization of the ventricles, consisting of Q, R and S waves; SQ: Shadow Queen; SRP: roasted peanuts in shell;
WBB: The wild blueberry drink; y: years.
8. Discussion
MDD remains a complex, multifaceted psychiatric condition that resists simple explanations or
treatments [283]. The primary goal of this review was to explore how phytochemicals—naturally
occurring plant-derived compounds—may offer a biologically plausible and clinically relevant ap-
proach to modulating the intricate neurobiological disruptions observed in MDD [260]. Central to the
disorder’s pathophysiology are sustained neuroinflammation, oxidative stress, mitochondrial dys-
function, and metabolic disturbances, which interact to compromise neuronal integrity, synaptic
plasticity, and emotional regulation [284]. While monoaminergic deficits have long dominated de-
pression theories, current evidence indicates these downstream effects may be fueled by deeper cel-
lular and immune dysregulation [285]. Phytocompounds such as polyphenols, flavonoids, and alka-
loids appear to influence these upstream processes by attenuating pro-inflammatory cytokines, scav-
enging ROS, restoring mitochondrial dynamics, and modulating neurotrophic signaling [143]. In do-
ing so, they challenge conventional paradigms and suggest a more integrative neuropsychiatric
model—one that views depression through the lens of systemic inflammation and neuroenergetic
compromise, rather than solely neurotransmitter depletion [286].
A central finding of this review is the growing body of evidence supporting the antidepressant
potential of phytochemicals, particularly polyphenols, flavonoids, and alkaloid-rich plant extracts.
Compounds such as curcumin, resveratrol, quercetin, and luteolin consistently demonstrate antide-
pressant-like effects across preclinical models and emerging clinical studies. These benefits are me-
diated through a combination of neuroprotective, anti-inflammatory, and antioxidant mechanisms.
Notably, curcumin has been shown to downregulate pro-inflammatory cytokines (e.g., IL-1β, TNF-
α), reduce lipid peroxidation, and enhance BDNF expression—key pathways implicated in MDD.
Similarly, flavonoids such as quercetin and luteolin attenuate microglial activation, restore mitochon-
drial function, and improve synaptic plasticity. These multi-target effects distinguish phytochemicals
from traditional antidepressants, which primarily modulate monoamine reuptake and often require
several weeks to achieve symptom relief. Moreover, phytochemicals tend to have more favorable
safety profiles, presenting a lower risk of side effects such as sexual dysfunction, weight gain, or
hyponatremia. For individuals with treatment-resistant depression or intolerance to conventional
therapies, these natural agents may offer a promising adjunct or alternative approach. Their ability
to modulate upstream drivers of MDD rather than solely downstream neurotransmitter imbalances
reflects a potentially paradigm-shifting advance in how we conceptualize and manage depression.
The therapeutic potential of phytochemicals in MDD is rooted in their ability to engage a broad
array of molecular targets implicated in the neurobiology of depression [287]. One of the most prom-
inent mechanisms is the upregulation of BDNF, a key molecule in synaptic plasticity, neurogenesis,
and neuronal survival [288]. Phytocompounds such as curcumin, resveratrol, and apigenin have been
shown to elevate BDNF expression in preclinical models, countering the synaptic deficits commonly
observed in depression [289]. Another critical mechanism involves the inhibition of the NLRP3 in-
flammasome, a key driver of neuroinflammation [284]. Polyphenols like quercetin and baicalein sup-
press this pathway, leading to decreased release of pro-inflammatory cytokines such as IL-1β and IL-
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
16 of 6
18 [290]. These compounds also reduce oxidative stress by enhancing endogenous antioxidant de-
fenses (e.g., upregulation of Nrf2 and glutathione pathways), protecting neurons from ROS-induced
apoptosis [291]. Importantly, many of these phytochemicals—especially flavonoids and terpenoids—
demonstrate the capacity to cross the blood-brain barrier due to their lipophilic structures and low
molecular weight [292]. Once in the CNS, they can stabilize mitochondrial function, modulate cal-
cium homeostasis, and maintain membrane potential, all of which are disrupted in MDD [293]. These
mechanistic actions align closely with contemporary neurobiological models of depression, which
emphasize the roles of neuroinflammation, mitochondrial dysfunction, and impaired neuroplasticity
over simplistic monoamine depletion theories [91]. By targeting upstream cellular stressors and re-
storing homeostatic balance across neuroimmune and neurometabolic pathways, phytochemicals
represent a compelling therapeutic modality that resonates with the current shift toward systems-
based approaches in psychiatric research. Complementing this systems-level approach, recent in-
sights into quinoline-based drug design suggest that subtle structural modifications, such as halo-
genation or esterification, can meaningfully modulate excitotoxicity and immunoactivity signaling
relevant to depression pathophysiology [294].
The incorporation of phytochemicals into clinical treatment strategies for MDD presents several
promising implications for practice [260]. Unlike conventional antidepressants, which often carry a
high burden of side effects—such as sexual dysfu nction, weight gain, insomnia, or gastrointestinal
disturbances—phytochemicals typically exhibit favorable safety and tolerability profiles [264]. This
reduced side effect burden may significantly enhance patient adherence, particularly among individ-
uals who are medication-sensitive, elderly, or managing comorbid conditions [295]. Furthermore,
many phytocompounds, such as curcumin, resveratrol, and quercetin, are available in standardized
formulations and have shown efficacy when used alongside standard antidepressant regimens, sup-
porting their role as adjunctive therapies [296]. Their natural origin also makes them appealing to
patients seeking holistic or integrative approaches to mental health [297]. To maximize the benefits
of phytochemical interventions, multidisciplinary care teams—comprising psychiatrists, psycholo-
gists, nutritionists, pharmacists, and exercise specialists—are essential [298]. These teams can tailor
phytochemical strategies to the individual's biological and psychosocial profile, monitor for herb-
drug interactions, and integrate them into broader lifestyle and behavioral interventions [299]. This
integrative model not only broadens therapeutic options but aligns with growing interest in person-
alized medicine, where treatment is adapted to the individual's unique physiological and lifestyle
context [300].
Despite encouraging findings, several challenges and limitations temper the immediate clinical
translation of phytochemicals for depression [301]. A primary concern lies in the methodological var-
iability across studies [264]. Many preclinical and clinical trials differ widely in terms of dosage, treat-
ment duration, and formulation, making it difficult to establish standardized protocols [260]. Sample
sizes are often small, with limited representation across age groups, genders, and ethnic back-
grounds, reducing the generalizability of results [302]. Moreover, key pharmacokinetic parameters—
such as bioavailability, half-life, and tissue distribution—remain poorly characterized for many phy-
tochemicals [303]. This complicates efforts to optimize dosage and timing for maximum therapeutic
effect [304]. Additionally, the long-term safety of chronic phytochemical use is not well understood,
particularly when used in combination with conventional antidepressants, raising concerns about
potential herb-drug interactions [305]. These knowledge gaps highlight the need for rigorously de-
signed, large-scale randomized controlled trials that incorporate standardized extract preparations,
dose-ranging studies, and biomarker-based outcome measures [306]. Future research should also em-
phasize population diversity and assess pharmacogenomic factors that may influence individual re-
sponses [307]. Addressing these limitations is essential for moving phytochemicals from promising
adjuncts to reliable, evidence-based components of depression treatment protocols.
Future research on phytochemicals in the treatment of MDD should prioritize rigorously de-
signed clinical trials and translational studies that bridge the gap between laboratory findings and
real-world clinical application [308]. Large-scale, placebo-controlled trials are essential to validate the
antidepressant efficacy of individual phytochemicals, establish optimal dosing strategies, and assess
long-term safety [309]. In addition to studying single compounds, future investigations should ex-
plore the therapeutic potential of phytochemical combinations [259]. Many plant-derived compounds
act on overlapping molecular targets, and their synergistic effects on neuroinflammation, oxidative
stress, and mitochondrial dysfunction may offer enhanced efficacy compared to isolated agents [310].
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
17 of 6
Combinatorial approaches could mirror the polypharmacological nature of depression, targeting its
multifactorial pathophysiology more effectively [232]. Moreover, research should move toward pre-
cision medicine models that account for individual differences in genetic makeup, metabolic profiles,
gut microbiota composition, and inflammatory status [311]. Stratifying participants based on these
biomarkers could identify responders and non-responders to specific phytochemicals, allowing for
more personalized treatment [312]. Integrating omics technologies—such as metabolomics, tran-
scriptomics, and pharmacogenomics—into trial designs will enhance mechanistic understanding and
treatment customization[313]. Finally, future studies should include robust secondary endpoints that
assess cognitive function, quality of life, and functional recovery, not just symptom reduction [206].
By embracing these strategies, the field can move toward the development of targeted, effective, and
biologically grounded phytochemical interventions that expand the therapeutic landscape for de-
pression.
Effective management of MDD increasingly requires a multidisciplinary approach that inte-
grates biological, psychological, and lifestyle-based strategies [314]. Collaborative care teams—com-
prising psychiatrists, psychologists, nutritionists, pharmacists, and exercise specialists—are well-po-
sitioned to deliver comprehensive, personalized treatment plans [315]. Phytochemical supplementa-
tion can be particularly valuable when embedded within this broader therapeutic framework [316].
Nutritionists can guide dietary modifications that reinforce the anti-inflammatory and antioxidant
actions of phytocompounds, while exercise specialists can prescribe physical activity regimens that
synergize with phytochemicals to enhance mitochondrial health and neuroplasticity [317]. Psycholo-
gists can provide cognitive-behavioral or mindfulness-based therapies that further modulate stress-
related pathways implicated in MDD [318]. Literature from integrated care models demonstrates that
combining pharmacological and non-pharmacological interventions—such as in collaborative care
or lifestyle psychiatry frameworks—improves clinical outcomes, enhances patient satisfaction, and
reduces relapse rates [319]. For example, interventions that pair dietary polyphenols with structured
aerobic exercise and therapy have shown additive effects on depressive symptom reduction and cog-
nitive function [320]. This integrated model not only reflects the multifactorial nature of depression
but also offers a pragmatic pathway to improve treatment adherence, reduce polypharmacy, and
promote long-term mental wellness [321]. Phytochemicals, when coordinated with other interven-
tions, may serve as powerful components of such a multidimensional care strategy.
This review illuminates the multifaceted nature of MDD and the potential utility of phytocom-
pounds in its management. Recent evidence reveals that MDD involves not only monoaminergic
dysregulation but also neuroinflammatory processes, oxidative stress, and mitochondrial dysfunc-
tion, implicating diverse pathophysiological pathways [322]. By evaluating interventional studies
centered on phytochemicals—including polyphenols, flavonoids, and alkaloids—this review high-
lights their potential neuroprotective, anti-inflammatory, and antioxidant properties [22]. These ef-
fects align with emerging translational research suggesting that multi-targeted strategies may offer
enhanced therapeutic outcomes in complex mood disorders [80,323]. Nevertheless, the heterogeneity
of study designs, phytocompound formulations, and patient populations underscores the need for
more robust trials with standardized protocols [324–326]. This discussion aims to synthesize the
mechanistic underpinnings and clinical implications of phytocompound use in MDD, situating these
findings within broader neuropsychiatric research and outlining key directions for future investiga-
tion. Taken together, these insights reaffirm the value of phytochemicals as complementary or alter-
native therapies in MDD, particularly given their favorable safety profiles, multimodal mechanisms
of action, and promise for treatment-resistant populations. Continued clinical exploration of these
natural interventions may significantly enhance holistic, personalized approaches to depression care
and expand the future of integrative psychiatric treatment.
5. Conclusions
Emerging data suggest that specific plant-derived compounds can influence the neuro-immune
interface and mitochondrial health in major depressive disorder, yet these signals remain prelimi-
nary. Wide variation in extract standardization, dosing protocols, study designs, and participant pro-
files hampers direct comparison, and most trials enroll modest, geographically limited samples. To
translate early promise into clinical practice, large phase-III studies with rigorous pharmacokinetic
assessment, active comparators, and extended safety follow-up are essential. Nonetheless, the litera-
ture reviewed here highlights the distinctive neuroprotective, anti-inflammatory, and antioxidant
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
18 of 6
capacities of phytochemicals—attributes that align well with the complex biology of depression, ex-
tending therapeutic thinking beyond monoamine modulation alone. Although several investigations
report meaningful symptom relief with minimal adverse effects, methodological shortcomings—
small cohorts, heterogeneous interventions, and inconsistent endpoints—preclude definitive guid-
ance. Future research must emphasize harmonized formulations, adequately powered populations,
and mechanistic biomarkers to clarify durability, optimal dosing, and synergy with standard antide-
pressants. Collectively, the current evidence positions phytocompounds as promising adjuncts, war-
ranting continued, methodologically robust exploration to fully harness their translational potential.
Author Contributions: Conceptualization, S.M.B., M.T., and L.F.L.; methodology, A.C.F.G.; investigation, F.F.F.,
V.E.V., L.P.A., C.R.P.D., and F.C.C., and L.F.L.; writing—original draft preparation, S.M.B., L.F.L., L.P.A., and
M.T.; writing—review and editing, S.M.B., F.F.F., V.E.L., C.M.G., E.S.B.M.P., and R.S.A.H.; visualization, S.M.B.,
M.T., and F.F.F.; supervision, S.M.B. and M.T.; project administration, S.M.B.; funding acquisition, S.M.B. and
M.T. All authors agreed to the final version of this manuscript.
Funding: This work was supported by the HUN-REN Hungarian Research Network to M.T.
Acknowledgments: Images were built with biorender.com, Free.Pick.com, canva, and pixabay.com
Conflicts of Interest: The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript:
BDNF
brain-derived neurotrophic factor
CNS
central nervous system
DNA
deoxyribonucleic acid
HAM-D
Hamilton depression rating scale
IL
Interleukin
MMA
methylmalonic acid
MDD
major depressive disorder
mtDNA
mitochondrial deoxyribonucleic acid
NF-κB
nuclear factor kappa B
ROS
reactive oxygen species
SSRI
selective serotonin reuptake inhibitor
TCA
tricyclic antidepressant
References
1. Manosso, L.M.; Arent, C.O.; Borba, L.A.; Abelaira, H.M.; Réus, G.Z. Natural Phytochemicals for the
Treatment of Major Depressive Disorder: A Mini-Review of Pre- and Clinical Studies. CNS Neurol Disord
Drug Targets 2023, 22, 237–254. https://doi.org/10.2174/1570159X20666220329143804.
2. Kim, J.W.; Suzuki, K.; Kavalali, E.T.; Monteggia, L.M. Ketamine: Mechanisms and Relevance to Treatment
of Depression. Annu Rev Med 2024, 75, 129–143. https://doi.org/10.1146/annurev-med-051322-120608.
3. Schoeller, F.; Jain, A.; Adrien, V.; Maes, P.; Reggente, N. Aesthetic chills mitigate maladaptive cognition in
depression. BMC Psychiatry 2024, 24, 40. https://doi.org/10.1186/s12888-023-05476-3.
4. Averina, O.V.; Poluektova, E.U.; Zorkina, Y.A.; Kovtun, A.S.; Danilenko, V.N. Human Gut Microbiota for
Diagnosis and Treatment of Depression. Int J Mol Sci 2024, 25. https://doi.org/10.3390/ijms25115782.
5. Yan, G.; Zhang, Y.; Wang, S.; Yan, Y.; Liu, M.; Tian, M.; Tian, W. Global, regional, and national temporal
trend in burden of major depressive disorder from 1990 to 2019: An analysis of the global burden of disease
study. Psychiatry Res. 2024, 337, 115958.
6. Bagby, S.P.; Martin, D.; Chung, S.T.; Rajapakse, N. From the outside in: biological mechanisms linking
social and environmental exposures to chronic disease and to health disparities. Am. J. Public Health 2019,
109, S56–S63.
7. Fusar-Poli, P.; Tantardini, M.; De Simone, S.; Ramella-Cravaro, V.; Oliver, D.; Kingdon, J.; Kotlicka-Antczak,
M.; Valmaggia, L.; Lee, J.; Millan, M. Deconstructing vulnerability for psychosis: meta-analysis of
environmental risk factors for psychosis in subjects at ultra high-risk. Eur. Psychiatry 2017, 40, 65–75.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
19 of 6
8. Lesch, K.-P. When the serotonin transporter gene meets adversity: the contribution of animal models to
understanding epigenetic mechanisms in affective disorders and resilience. Mol. Funct. Models
Neuropsychiatry 2011, 251-280.
9. Simons, R.L.; Lei, M.K.; Stewart, E.A.; Beach, S.R.; Brody, G.H.; Philibert, R.A.; Gibbons, F.X. Social
adversity, genetic variation, street code, and aggression: A genetically informed model of violent behavior.
Youth Violence Juv. Justice 2012, 10, 3–24.
10. Cui, L.; Li, S.; Wang, S.; Wu, X.; Liu, Y.; Yu, W.; Wang, Y.; Tang, Y.; Xia, M.; Li, B. Major depressive disorder:
hypothesis, mechanism, prevention and treatment. Signal Transduct Target Ther 2024, 9, 30.
https://doi.org/10.1038/s41392-024-01738-y.
11. Pase, M.P.; Scholey, A.B.; Pipingas, A.; Kras, M.; Nolidin, K.; Gibbs, A.; Wesnes, K.; Stough, C. Cocoa
polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-
controlled trial. J. Psychopharmacol. (Oxf. Engl. ) 2013, 27, 451–458. https://doi.org/10.1177/0269881112473791.
12. Jia, S.; Hou, Y.; Wang, D.; Zhao, X. Flavonoids for depression and anxiety: a systematic review and meta-
analysis. Crit. Rev. Food Sci. Nutr. 2023, 63, 8839–8849. https://doi.org/10.1080/10408398.2022.2057914.
13. Tang, M.; Liu, T.; Jiang, P.; Dang, R. The interaction between autophagy and neuroinflammation in major
depressive disorder: from pathophysiology to therapeutic implications. Pharmacol. Res. 2021, 168, 105586.
14. Bertollo, A.G.; Mingoti, M.E.D.; Ignácio, Z.M. Neurobiological mechanisms in the kynurenine pathway and
major depressive disorder. Rev. Neurosci. 2025, 36, 169–187.
15. Wang, Y.; Cai, X.; Ma, Y.; Yang, Y.; Pan, C.W.; Zhu, X.; Ke, C. Metabolomics on depression: A comparison
of clinical and animal research. J Affect Disord 2024, 349, 559–568. https://doi.org/10.1016/j.jad.2024.01.053.
16. Barbalho, S.M.; Leme Boaro, B.; da Silva Camarinha Oliveira, J.; Patočka, J.; Barbalho Lamas, C.; Tanaka,
M.; Laurindo, L.F. Molecular Mechanisms Underlying Neuroinflammation Intervention with Medicinal
Plants: A Critical and Narrative Review of the Current Literature. Pharm. (Basel) 2025, 18.
https://doi.org/10.3390/ph18010133.
17. de Lima, E.P.; Laurindo, L.F.; Catharin, V.C.S.; Direito, R.; Tanaka, M.; Jasmin Santos German, I.; Lamas,
C.B.; Guiguer, E.L.; Araújo, A.C.; Fiorini, A.M.R.; et al. Polyphenols, Alkaloids, and Terpenoids Against
Neurodegeneration: Evaluating the Neuroprotective Effects of Phytocompounds Through a
Comprehensive Review of the Current Evidence. Metabolites 2025, 15.
https://doi.org/10.3390/metabo15020124.
18. de Lima, E.P.; Tanaka, M.; Lamas, C.B.; Quesada, K.; Detregiachi, C.R.P.; Araújo, A.C.; Guiguer, E.L.;
Catharin, V.; de Castro, M.V.M.; Junior, E.B.; et al. Vascular Impairment, Muscle Atrophy, and Cognitive
Decline: Critical Age-Related Conditions. Biomedicines 2024, 12.
https://doi.org/10.3390/biomedicines12092096.
19. Pearson, K.; Beier, K.; Mardis, T.; Munoz, B.; Zaidi, A. The Neurochemistry of Depression: The Good, The
Bad and The Ugly. Mo Med 2024, 121, 68–75.
20. Ullah, R.; Khan, M.; Shah, S.A.; Saeed, K.; Kim, M.O. Natural antioxidant anthocyanins—A hidden
therapeutic candidate in metabolic disorders with major focus in neurodegeneration. Nutrients 2019, 11,
1195.
21. Jin, W.; Xu, X.; Chen, X.; Qi, W.; Lu, J.; Yan, X.; Zhao, D.; Cong, D.; Li, X.; Sun, L. Protective effect of pig
brain polypeptides against corticosterone-induced oxidative stress, inflammatory response, and apoptosis
in PC12 cells. Biomed. Pharmacother. 2019, 115, 108890.
22. Wang, J.; Song, Y.; Chen, Z.; Leng, S.X. Connection between systemic inflammation and neuroinflammation
underlies neuroprotective mechanism of several phytochemicals in neurodegenerative diseases. Oxidative
Med. Cell. Longev. 2018, 2018, 1972714.
23. Battaglia, S.; Avenanti, A.; Vécsei, L.; Tanaka, M. Neural correlates and molecular mechanisms of memory
and learning. 2024, 25, 2724.
24. Yoder, R.; Michaud, A.; Feagans, A.; Hinton-Froese, K.E.; Meyer, A.; Powers, V.A.; Stalnaker, L.; Hord, M.K.
Family-Based Treatment for Anxiety, Depression, and ADHD for a Parent and Child. Int J Env. Res Public
Health 2024, 21. https://doi.org/10.3390/ijerph21040504.
25. Moreira, J.; Machado, M.; Dias-Teixeira, M.; Ferraz, R.; Delerue-Matos, C.; Grosso, C. The neuroprotective
effect of traditional Chinese medicinal plants—A critical review. Acta Pharm. Sin. B 2023, 13, 3208–3237.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
20 of 6
26. Ajao, A.A.-n.; Sabiu, S.; Balogun, F.O.; Adekomi, D.A.; Saheed, S.A. The Ambit of Phytotherapy in
Psychotic Care. In Psychosis-Biopsychosocial and Relational Perspectives; IntechOpen: 2018.
27. Rajpal, V.R.; Koul, H.K.; Raina, S.N.; Kumar, H.M.S.; Qazi, G.N. Phytochemicals for Human Health: The
Emerging Trends and Prospects. Curr Top Med Chem 2024, 24, v-vi,.
https://doi.org/10.2174/156802662404240226094145.
28. Kumar, H.M.S.; Rajpal, V.R.; Koul, H.K.; Raina, S.N.; Qazi, G.N. Phytochemicals for Human Health: The
Emerging Trends and Prospects, Part-3. Curr Top Med Chem 2024, 24, 1011–1012.
https://doi.org/10.2174/156802662412240506092824.
29. Xiao, J.; Bai, W. Bioactive phytochemicals. Crit. Rev. Food Sci. Nutr. 2019, 59, 827–829.
30. Fais, A.; Era, B. Phytochemical Composition and Biological Activity. Plants (Basel) 2024, 13.
https://doi.org/10.3390/plants13030331.
31. Muscolo, A.; Mariateresa, O.; Giulio, T.; Mariateresa, R. Oxidative Stress: The Role of Antioxidant
Phytochemicals in the Prevention and Treatment of Diseases. Int J Mol Sci 2024, 25.
https://doi.org/10.3390/ijms25063264.
32. Zhao, Y.; Li, J.; Cao, G.; Zhao, D.; Li, G.; Zhang, H.; Yan, M. Ethnic, Botanic, Phytochemistry and
Pharmacology of the. Molecules 2023, 28. https://doi.org/10.3390/molecules28207117.
33. Reddy, K.; Stafford, G.I.; Makunga, N.P. Skeletons in the closet? Using a bibliometric lens to visualise
phytochemical and pharmacological activities linked to. Front Plant Sci 2024, 15, 1268101.
https://doi.org/10.3389/fpls.2024.1268101.
34. Gong, G.; Ganesan, K.; Wang, Y.; Zhang, Z.; Liu, Y.; Wang, J.; Yang, F.; Zheng, Y. Ononin ameliorates
depression-like behaviors by regulating BDNF-TrkB-CREB signaling in vitro and in vivo. J Ethnopharmacol
2024, 320, 117375. https://doi.org/10.1016/j.jep.2023.117375.
35. Tanaka, M.; Vécsei, L. From Lab to Life: Exploring Cutting-Edge Models for Neurological and Psychiatric
Disorders. Biomedicines 2024, 12, 613.
36. Seung, H.-B.; Kwon, H.-J.; Kwon, C.-Y.; Kim, S.-H. Neuroendocrine Biomarkers of Herbal Medicine for
Major Depressive Disorder: A Systematic Review and Meta-Analysis. Pharmaceuticals 2023, 16, 1176.
37. Jaberi, K.R.; Alamdari-Palangi, V.; Savardashtaki, A.; Vatankhah, P.; Jamialahmadi, T.; Tajbakhsh, A.;
Sahebkar, A. Modulatory Effects of Phytochemicals on Gut-Brain Axis: Therapeutic Implication. Curr Dev
Nutr 2024, 8, 103785. https://doi.org/10.1016/j.cdnut.2024.103785.
38. Liloia, D.; Zamfira, D.A.; Tanaka, M.; Manuello, J.; Crocetta, A.; Keller, R.; Cozzolino, M.; Duca, S.; Cauda,
F.; Costa, T. Disentangling the role of gray matter volume and concentration in autism spectrum disorder:
A meta-analytic investigation of 25 years of voxel-based morphometry research. Neurosci. Biobehav. Rev.
2024, 105791.
39. Davis, C.C.; Choisy, P. Medicinal plants meet modern biodiversity science. Curr Biol 2024, 34, R158-R173,.
https://doi.org/10.1016/j.cub.2023.12.038.
40. Kakarla, R.; Karuturi, P.; Siakabinga, Q.; Kasi Viswanath, M.; Dumala, N.; Guntupalli, C.; Nalluri, B.N.;
Venkateswarlu, K.; Prasanna, V.S.; Gutti, G.; et al. Current understanding and future directions of
cruciferous vegetables and their phytochemicals to combat neurological diseases. Phytother Res 2024, 38,
1381–1399. https://doi.org/10.1002/ptr.8122.
41. Chandel, P.; Thapa, K.; Kanojia, N.; Rani, L.; Singh, T.G.; Rohilla, P. Exploring Therapeutic Potential of
Phytoconstituents as a Gut Microbiota Modulator in the Management of Neurological and Psychological
Disorders. Neuroscience 2024, 551, 69–78. https://doi.org/10.1016/j.neuroscience.2024.05.002.
42. Tanaka, M. From Serendipity to Precision: Integrating AI, Multi-Omics, and Human-Specific Models for
Personalized Neuropsychiatric Care. Biomedicines 2025, 13, 167.
43. Tanaka, M. Beyond the boundaries: Transitioning from categorical to dimensional paradigms in mental
health diagnostics. Adv. Clin. Exp. Med. 2024, 33, 1295–1301.
44. Cordeiro, M.L.d.S.; Martins, V.G.d.Q.A.; Silva, A.P.d.; Rocha, H.A.O.; Rachetti, V.d.P.S.; Scortecci, K.C.
Phenolic acids as antidepressant agents. Nutrients 2022, 14, 4309.
45. Rahman, M.A.; Rahman, M.H.; Biswas, P.; Hossain, M.S.; Islam, R.; Hannan, M.A.; Uddin, M.J.; Rhim, H.
Potential therapeutic role of phytochemicals to mitigate mitochondrial dysfunctions in Alzheimer’s disease.
Antioxidants 2020, 10, 23.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
21 of 6
46. Fazilat, S.; Tahmasbi, F.; Mirzaei, M.R.; Sanaie, S.; Yousefi, Z.; Asnaashari, S.; Yaqoubi, S.; Mohammadi,
A.B.; Araj-khodaei, M. A systematic review on the use of phytotherapy in managing clinical depression.
BioImpacts 2024, 15, 30532–30532.
47. Hassamal, S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological
mechanisms and emerging anti-inflammatories. Front. Psychiatry 2023, 14, 1130989.
48. Troubat, R.; Barone, P.; Leman, S.; Desmidt, T.; Cressant, A.; Atanasova, B.; Brizard, B.; El Hage, W.; Surget,
A.; Belzung, C. Neuroinflammation and depression: A review. Eur. J. Neurosci. 2021, 53, 151–171.
49. Wu, A.; Zhang, J. Neuroinflammation, memory, and depression: new approaches to hippocampal
neurogenesis. J Neuroinflammation 2023, 20, 283. https://doi.org/10.1186/s12974-023-02964-x.
50. Jurcau, A.; Simion, A. Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From
Pathophysiology to Therapeutic Strategies. Int J Mol Sci 2021, 23. https://doi.org/10.3390/ijms23010014.
51. Fornari Laurindo, L.; Aparecido Dias, J.; Cressoni Araújo, A.; Torres Pomini, K.; Machado Galhardi, C.;
Rucco Penteado Detregiachi, C.; Santos de Argollo Haber, L.; Donizeti Roque, D.; Dib Bechara, M.; Vialogo
Marques de Castro, M.; et al. Immunological dimensions of neuroinflammation and microglial activation:
exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression. Front
Immunol 2023, 14, 1305933. https://doi.org/10.3389/fimmu.2023.1305933.
52. Laurindo, L.F.; Barbalho, S.M.; Araújo, A.C.; Guiguer, E.L.; Mondal, A.; Bachtel, G.; Bishayee, A. Açaí
(Euterpe oleracea Mart.) in Health and Disease: A Critical Review. Nutrients 2023, 15.
https://doi.org/10.3390/nu15040989.
53. Laurindo, L.F.; Simili, O.A.G.; Araújo, A.C.; Guiguer, E.L.; Direito, R.; Valenti, V.E.; de Oliveira, V.; de
Oliveira, J.S.; Yanaguizawa Junior, J.L.; Dias, J.A.; et al. Melatonin from Plants: Going Beyond Traditional
Central Nervous System Targeting-A Comprehensive Review of Its Unusual Health Benefits. Biol. (Basel)
2025, 14. https://doi.org/10.3390/biology14020143.
54. Tanaka, M.; Tuka, B.; Vécsei, L. Navigating the Neurobiology of Migraine: From pathways to potential
therapies. 2024, 13, 1098.
55. Rizzo, F.R.; Musella, A.; De Vito, F.; Fresegna, D.; Bullitta, S.; Vanni, V.; Guadalupi, L.; Stampanoni Bassi,
M.; Buttari, F.; Mandolesi, G. Tumor necrosis factor and interleukin-1β modulate synaptic plasticity during
neuroinflammation. Neural Plast. 2018, 2018, 8430123.
56. Turnbull, A.V.; Prehar, S.; Kennedy, A.R.; Little, R.A.; Hopkins, S.J. Interleukin-6 is an afferent signal to the
hypothalamo-pituitary-adrenal axis during local inflammation in mice. Endocrinology 2003, 144, 1894–1906.
57. Kawasaki, Y.; Zhang, L.; Cheng, J.-K.; Ji, R.-R. Cytokine mechanisms of central sensitization: distinct and
overlapping role of interleukin-1β, interleukin-6, and tumor necrosis factor-α in regulating synaptic and
neuronal activity in the superficial spinal cord. J. Neurosci. 2008, 28, 5189–5194.
58. De Simoni, M.; Terreni, L.; Chiesa, R.; Mangiarotti, F.; Forloni, G. Interferon-γ potentiates interleukin (IL)-
6 and tumor necrosis factor-α but not IL-1β induced by endotoxin in the brain. Endocrinology 1997, 138,
5220–5226.
59. Chaves, F.M.; Mansano, N.S.; Frazão, R.; Donato Jr, J. Tumor necrosis factor α and interleukin-1β acutely
inhibit AgRP neurons in the arcuate nucleus of the hypothalamus. Int. J. Mol. Sci. 2020, 21, 8928.
60. Li, B.; Yang, W.; Ge, T.; Wang, Y.; Cui, R. Stress induced microglial activation contributes to depression.
Pharmacol. Res. 2022, 179, 106145.
61. Jia, X.; Gao, Z.; Hu, H. Microglia in depression: current perspectives. Sci. China Life Sci. 2021, 64, 911–925.
62. Turkin, A.; Tuchina, O.; Klempin, F. Microglia function on precursor cells in the adult hippocampus and
their responsiveness to serotonin signaling. Front. Cell Dev. Biol. 2021, 9, 665739.
63. Zanella, I. Neuroinflammation: From Molecular Basis to Therapy. Int J Mol Sci 2024, 25.
https://doi.org/10.3390/ijms25115973.
64. Hassamal, S. Chronic stress, neuroinflammation, and depression: an overview of pathophysiological
mechanisms and emerging anti-inflammatories. Front Psychiatry 2023, 14, 1130989.
https://doi.org/10.3389/fpsyt.2023.1130989.
65. Poletti, S.; Mazza, M.G.; Benedetti, F. Inflammatory mediators in major depression and bipolar disorder.
Transl Psychiatry 2024, 14, 247. https://doi.org/10.1038/s41398-024-02921-z.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
22 of 6
66. Xia, C.Y.; Guo, Y.X.; Lian, W.W.; Yan, Y.; Ma, B.Z.; Cheng, Y.C.; Xu, J.K.; He, J.; Zhang, W.K. The NLRP3
inflammasome in depression: Potential mechanisms and therapies. Pharmacol Res 2023, 187, 106625.
https://doi.org/10.1016/j.phrs.2022.106625.
67. Han, Q.; Li, W.; Chen, P.; Wang, L.; Bao, X.; Huang, R.; Liu, G.; Chen, X. Microglial NLRP3 inflammasome-
mediated neuroinflammation and therapeutic strategies in depression. Neural Regen Res 2024, 19, 1890–
1898. https://doi.org/10.4103/1673-5374.390964.
68. Bearoff, F.; Dhavale, D.; Kotzbauer, P.; Kortagere, S. Aggregated Alpha-Synuclein Activates Pro-
Inflammatory NFKB Signaling Pathways Through TLR-Dependent and Independent Mechanisms in
Peripheral Monocytic Cells. FASEB J. 2022, 36.
69. Huang, X.; Hussain, B.; Chang, J. Peripheral inflammation and blood–brain barrier disruption: effects and
mechanisms. CNS Neurosci. Ther. 2021, 27, 36–47.
70. Wang, X.; Antony, V.; Wang, Y.; Wu, G.; Liang, G. Pattern recognition receptor-mediated inflammation in
diabetic vascular complications. Med. Res. Rev. 2020, 40, 2466–2484.
71. Barrera, M.-J.; Aguilera, S.; Castro, I.; Carvajal, P.; Jara, D.; Molina, C.; González, S.; González, M.-J.
Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role
in Sjögren’s syndrome. Autoimmun. Rev. 2021, 20, 102867.
72. Wang, Y.; Lai, H.; Zhang, T.; Wu, J.; Tang, H.; Liang, X.; Ren, D.; Huang, J.; Li, W. Mitochondria of intestinal
epithelial cells in depression: Are they at a crossroads of gut-brain communication? Neurosci. Biobehav. Rev.
2023, 153, 105403.
73. Sipahi, H.; Mat, A.F.; Ozhan, Y.; Aydin, A. The interrelation between oxidative stress, depression and
inflammation through the kynurenine pathway. Curr. Top. Med. Chem. 2023, 23, 415–425.
74. Wakasugi, D.; Kondo, S.; Ferdousi, F.; Mizuno, S.; Yada, A.; Tominaga, K.; Takahashi, S.; Isoda, H. A rare
olive compound oleacein functions as a TrkB agonist and mitigates neuroinflammation both in vitro and
in vivo. Cell Commun Signal 2024, 22, 309. https://doi.org/10.1186/s12964-024-01691-x.
75. Guo, Y.; Yang, Y. Progress of plant polyphenol extracts in treating depression by anti-neuroinflammatory
mechanism: A review. Med. (Baltim. ) 2024, 103, e37151. https://doi.org/10.1097/MD.0000000000037151.
76. Bruno, A.; Dolcetti, E.; Rizzo, F.R.; Fresegna, D.; Musella, A.; Gentile, A.; De Vito, F.; Caioli, S.; Guadalupi,
L.; Bullitta, S.; et al. Corrigendum: Inflammation-Associated Synaptic Alterations as Shared Threads in
Depression and Multiple Sclerosis. Front Cell Neurosci 2020, 14, 647259.
https://doi.org/10.3389/fncel.2020.647259.
77. Sha, Q.; Escobar Galvis, M.L.; Madaj, Z.B.; Keaton, S.A.; Smart, L.; Edgerly, Y.M.; Anis, E.; Leach, R.;
Osborne, L.M.; Achtyes, E.; et al. Dysregulated placental expression of kynurenine pathway enzymes is
associated with inflammation and depression in pregnancy. Brain Behav Immun 2024, 119, 146–153.
https://doi.org/10.1016/j.bbi.2024.03.042.
78. Achtyes, E.; Keaton, S.A.; Smart, L.; Burmeister, A.R.; Heilman, P.L.; Krzyzanowski, S.; Nagalla, M.;
Guillemin, G.J.; Escobar Galvis, M.L.; Lim, C.K.; et al. Inflammation and kynurenine pathway
dysregulation in post-partum women with severe and suicidal depression. Brain Behav Immun 2020, 83,
239–247. https://doi.org/10.1016/j.bbi.2019.10.017.
79. Tanaka, M.; Vécsei, L. Revolutionizing our understanding of Parkinson’s disease: Dr. Heinz Reichmann’s
pioneering research and future research direction. J. Neural Transm. 2024, 1-21.
80. Tanaka, M.; Vécsei, L. A decade of dedication: pioneering perspectives on neurological diseases and mental
illnesses. 2024, 12, 1083.
81. Chesnokova, V.; Pechnick, R.N.; Wawrowsky, K. Chronic peripheral inflammation, hippocampal
neurogenesis, and behavior. Brain Behav. Immun. 2016, 58, 1–8.
82. Bruno, A.; Dolcetti, E.; Rizzo, F.R.; Fresegna, D.; Musella, A.; Gentile, A.; De Vito, F.; Caioli, S.; Guadalupi,
L.; Bullitta, S. Inflammation-associated synaptic alterations as shared threads in depression and multiple
sclerosis. Front. Cell. Neurosci. 2020, 14, 169.
83. Gustafsson, H.C.; Sullivan, E.L.; Nousen, E.K.; Sullivan, C.A.; Huang, E.; Rincon, M.; Nigg, J.T.; Loftis, J.M.
Maternal prenatal depression predicts infant negative affect via maternal inflammatory cytokine levels.
Brain Behav. Immun. 2018, 73, 470–481.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
23 of 6
84. Pontillo, G.; Cepas, M.B.; Broeders, T.A.A.; Koubiyr, I.; Schoonheim, M.M. Network Analysis in Multiple
Sclerosis and Related Disorders. Neuroimaging Clin N Am 2024, 34, 375–384.
https://doi.org/10.1016/j.nic.2024.03.008.
85. Liu, P.; Liu, Z.; Wang, J.; Gao, M.; Zhang, Y.; Yang, C.; Zhang, A.; Li, G.; Li, X.; Liu, S.; et al.
Immunoregulatory role of the gut microbiota in inflammatory depression. Nat Commun 2024, 15, 3003.
https://doi.org/10.1038/s41467-024-47273-w.
86. Molina Galindo, L.S.; Gonzalez-Escamilla, G.; Fleischer, V.; Grotegerd, D.; Meinert, S.; Ciolac, D.; Person,
M.; Stein, F.; Brosch, K.; Nenadić, I.; et al. Concurrent inflammation-related brain reorganization in multiple
sclerosis and depression. Brain Behav Immun 2024, 119, 978–988. https://doi.org/10.1016/j.bbi.2024.05.015.
87. Qin, P.; Sun, Y.; Li, L. Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review). Int J
Mol Med 2024, 53. https://doi.org/10.3892/ijmm.2024.5371.
88. Cui, J.-J.; Huang, Z.-Y.; Xie, Y.-H.; Wu, J.-B.; Xu, G.-H.; Li, C.-F.; Zhang, M.-M.; Yi, L.-T. Gut microbiota
mediated inflammation, neuroendocrine and neurotrophic functions involved in the antidepressant-like
effects of diosgenin in chronic restraint stress. J. Affect. Disord. 2023, 321, 242–252.
89. Morris, G.; Reiche, E.M.V.; Murru, A.; Carvalho, A.F.; Maes, M.; Berk, M.; Puri, B.K. Multiple immune-
inflammatory and oxidative and nitrosative stress pathways explain the frequent presence of depression
in multiple sclerosis. Mol. Neurobiol. 2018, 55, 6282–6306.
90. Adzic, M.; Brkic, Z.; Mitic, M.; Francija, E.; Jovicic, M.J.; Radulovic, J.; Maric, N.P. Therapeutic strategies for
treatment of inflammation-related depression. Curr. Neuropharmacol. 2018, 16, 176–209.
91. Khan, M.; Baussan, Y.; Hebert-Chatelain, E. Connecting dots between mitochondrial dysfunction and
depression. Biomolecules 2023, 13, 695.
92. Casaril, A.M.; Dantzer, R.; Bas-Orth, C. Neuronal mitochondrial dysfunction and bioenergetic failure in
inflammation-associated depression. Front. Neurosci. 2021, 15, 725547.
93. Correia, A.S.; Cardoso, A.; Vale, N. Oxidative stress in depression: the link with the stress response,
neuroinflammation, serotonin, neurogenesis and synaptic plasticity. Antioxidants 2023, 12, 470.
94. Black, C.N.; Bot, M.; Scheffer, P.G.; Cuijpers, P.; Penninx, B.W. Is depression associated with increased
oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 2015, 51, 164–175.
95. Czarny, P.; Wigner, P.; Galecki, P.; Sliwinski, T. The interplay between inflammation, oxidative stress, DNA
damage, DNA repair and mitochondrial dysfunction in depression. Prog. Neuro-Psychopharmacol. Biol.
Psychiatry 2018, 80, 309–321.
96. Yoshikawa, T.; You, F. Oxidative Stress and Bio-Regulation. Int J Mol Sci 2024, 25.
https://doi.org/10.3390/ijms25063360.
97. Bhatt, S.; Nagappa, A.N.; Patil, C.R. Role of oxidative stress in depression. Drug Discov Today 2020, 25, 1270–
1276. https://doi.org/10.1016/j.drudis.2020.05.001.
98. Li, K.; Deng, Z.; Lei, C.; Ding, X.; Li, J.; Wang, C. The Role of Oxidative Stress in Tumorigenesis and
Progression. Cells 2024, 13. https://doi.org/10.3390/cells13050441.
99. Correia, A.S.; Cardoso, A.; Vale, N. Oxidative Stress in Depression: The Link with the Stress Response,
Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity. Antioxid. (Basel) 2023, 12.
https://doi.org/10.3390/antiox12020470.
100. Bhatt, S.; Nagappa, A.N.; Patil, C.R. Role of oxidative stress in depression. Drug Discov. Today 2020, 25,
1270–1276.
101. Anderson, G.; Maes, M. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression:
treatment implications. Curr. Pharm. Des. 2014, 20, 3812–3847.
102. Manzar, H.; Abdulhussein, D.; Yap, T.E.; Cordeiro, M.F. Cellular Consequences of Coenzyme Q10
Deficiency in Neurodegeneration of the Retina and Brain. Int J Mol Sci 2020, 21.
https://doi.org/10.3390/ijms21239299.
103. Khan, M.; Baussan, Y.; Hebert-Chatelain, E. Connecting Dots between Mitochondrial Dysfunction and
Depression. Biomolecules 2023, 13. https://doi.org/10.3390/biom13040695.
104. Ilavská, L.; Morvová, M.; Paduchová, Z.; Muchová, J.; Garaiova, I.; Ďuračková, Z.; Šikurová, L.; Trebatická,
J. The kynurenine and serotonin pathway, neopterin and biopterin in depressed children and adolescents:
an impact of omega-3 fatty acids, and association with markers related to depressive disorder. A
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
24 of 6
randomized, blinded, prospective study. Front Psychiatry 2024, 15, 1347178.
https://doi.org/10.3389/fpsyt.2024.1347178.
105. Szabó, Á.; Galla, Z.; Spekker, E.; Szűcs, M.; Martos, D.; Takeda, K.; Ozaki, K.; Inoue, H.; Yamamoto, S.;
Toldi, J. Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine
Aminotransferase Knock-out Mice: A Novel Model for Experience-Based Depression and Post-Traumatic
Stress Disorder. 2024.
106. Czarny, P.; Wigner, P.; Galecki, P.; Sliwinski, T. The interplay between inflammation, oxidative stress, DNA
damage, DNA repair and mitochondrial dysfunction in depression. Prog Neuropsychopharmacol Biol
Psychiatry 2018, 80, 309–321. https://doi.org/10.1016/j.pnpbp.2017.06.036.
107. Tönnies, E.; Trushina, E. Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease. J Alzheimers Dis
2017, 57, 1105–1121. https://doi.org/10.3233/jad-161088.
108. Larrea, A.; Sánchez-Sánchez, L.; Diez-Martin, E.; Elexpe, A.; Torrecilla, M.; Astigarraga, E.; Barreda-Gómez,
G. Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment
Options. J Clin Med 2024, 13. https://doi.org/10.3390/jcm13061727.
109. Chen, H.; Lu, M.; Lyu, Q.; Shi, L.; Zhou, C.; Li, M.; Feng, S.; Liang, X.; Zhou, X.; Ren, L. Mitochondrial
dynamics dysfunction: Unraveling the hidden link to depression. Biomed Pharmacother 2024, 175, 116656.
https://doi.org/10.1016/j.biopha.2024.116656.
110. Martos, D.; Lőrinczi, B.; Szatmári, I.; Vécsei, L.; Tanaka, M. The impact of C-3 side chain modifications on
Kynurenic Acid: a behavioral analysis of its analogs in the Motor Domain. Int. J. Mol. Sci. 2024, 25, 3394.
111. Battaglia, S.; Avenanti, A.; Vécsei, L.; Tanaka, M. Neurodegeneration in cognitive impairment and mood
disorders for experimental, clinical and translational neuropsychiatry. 2024, 12, 574.
112. Cao, Y.; Chen, H.; Tan, Y.; Yu, X.D.; Xiao, C.; Li, Y.; Reilly, J.; He, Z.; Shu, X. Protection of p-Coumaric acid
against chronic stress-induced neurobehavioral deficits in mice via activating the PKA-CREB-BDNF
pathway. Physiol Behav 2024, 273, 114415. https://doi.org/10.1016/j.physbeh.2023.114415.
113. Song, Y.; Cao, H.; Zuo, C.; Gu, Z.; Huang, Y.; Miao, J.; Fu, Y.; Guo, Y.; Jiang, Y.; Wang, F. Mitochondrial
dysfunction: A fatal blow in depression. Biomed Pharmacother 2023, 167, 115652.
https://doi.org/10.1016/j.biopha.2023.115652.
114. Zhao, Y.; Huang, S.; Liu, J.; Wu, X.; Zhou, S.; Dai, K.; Kou, Y. Mitophagy Contributes to the Pathogenesis
of Inflammatory Diseases. Inflammation 2018, 41, 1590–1600. https://doi.org/10.1007/s10753-018-0835-2.
115. Matuz-Mares, D.; González-Andrade, M.; Araiza-Villanueva, M.G.; Vilchis-Landeros, M.M.; Vázquez-
Meza, H. Mitochondrial Calcium: Effects of Its Imbalance in Disease. Antioxid. (Basel) 2022, 11.
https://doi.org/10.3390/antiox11050801.
116. Han, S.; Zhang, M.; Jeong, Y.Y.; Margolis, D.J.; Cai, Q. The role of mitophagy in the regulation of
mitochondrial energetic status in neurons. Autophagy 2021, 17, 4182–4201.
https://doi.org/10.1080/15548627.2021.1907167.
117. Visentin, A.P.V.; Colombo, R.; Scotton, E.; Fracasso, D.S.; da Rosa, A.R.; Branco, C.S.; Salvador, M.
Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further
Challenges. Oxid Med Cell Longev 2020, 2020, 2972968. https://doi.org/10.1155/2020/2972968.
118. Casaril, A.M.; Dantzer, R.; Bas-Orth, C. Neuronal Mitochondrial Dysfunction and Bioenergetic Failure in
Inflammation-Associated Depression. Front Neurosci 2021, 15, 725547.
https://doi.org/10.3389/fnins.2021.725547.
119. Bansal, Y.; Kuhad, A. Mitochondrial Dysfunction in Depression. Curr Neuropharmacol 2016, 14, 610–618.
https://doi.org/10.2174/1570159x14666160229114755.
120. Masenga, S.K.; Kabwe, L.S.; Chakulya, M.; Kirabo, A. Mechanisms of Oxidative Stress in Metabolic
Syndrome. Int J Mol Sci 2023, 24. https://doi.org/10.3390/ijms24097898.
121. Li, H.; Ren, J.; Li, Y.; Wu, Q.; Wei, J. Oxidative stress: The nexus of obesity and cognitive dysfunction in
diabetes. Front Endocrinol (Lausanne) 2023, 14, 1134025. https://doi.org/10.3389/fendo.2023.1134025.
122. Ramírez-Garza, S.L.; Laveriano-Santos, E.P.; Moreno, J.J.; Bodega, P.; de Cos-Gandoy, A.; de Miguel, M.;
Santos-Beneit, G.; Fernández-Alvira, J.M.; Fernández-Jiménez, R.; Martínez-Gómez, J.; et al. Metabolic
syndrome, adiposity, diet, and emotional eating are associated with oxidative stress in adolescents. Front
Nutr 2023, 10, 1216445. https://doi.org/10.3389/fnut.2023.1216445.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
25 of 6
123. Heiss, C.N.; Mannerås-Holm, L.; Lee, Y.S.; Serrano-Lobo, J.; Håkansson Gladh, A.; Seeley, R.J.; Drucker,
D.J.; Bäckhed, F.; Olofsson, L.E. The gut microbiota regulates hypothalamic inflammation and leptin
sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism. Cell Rep 2021, 35, 109163.
https://doi.org/10.1016/j.celrep.2021.109163.
124. Li, H.; Song, L.; Cen, M.; Fu, X.; Gao, X.; Zuo, Q.; Wu, J. Oxidative balance scores and depressive symptoms:
Mediating effects of oxidative stress and inflammatory factors. J Affect Disord 2023, 334, 205–212.
https://doi.org/10.1016/j.jad.2023.04.134.
125. Tan, B.L.; Norhaizan, M.E. Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response
and Cognitive Function. Nutrients 2019, 11. https://doi.org/10.3390/nu11112579.
126. Nunes, Y.C.; Mendes, N.M.; Pereira de Lima, E.; Chehadi, A.C.; Lamas, C.B.; Haber, J.F.S.; Dos Santos
Bueno, M.; Araújo, A.C.; Catharin, V.C.S.; Detregiachi, C.R.P.; et al. Curcumin: A Golden Approach to
Healthy Aging: A Systematic Review of the Evidence. Nutrients 2024, 16.
https://doi.org/10.3390/nu16162721.
127. Pagotto, G.L.O.; Santos, L.; Osman, N.; Lamas, C.B.; Laurindo, L.F.; Pomini, K.T.; Guissoni, L.M.; Lima,
E.P.; Goulart, R.A.; Catharin, V.; et al. Ginkgo biloba: A Leaf of Hope in the Fight against Alzheimer's
Dementia: Clinical Trial Systematic Review. Antioxid. (Basel) 2024, 13.
https://doi.org/10.3390/antiox13060651.
128. Takeda, L.N.; Omine, A.; Laurindo, L.F.; Araújo, A.C.; Machado, N.M.; Dias, J.A.; Kavalakatt, J.; Banerjee,
S.; de Alvares Goulart, R.; Atanasov, A.G.; et al. Brazil nut (Bertholletia excelsa Bonpl.) in health and
disease: A narrative review. Food Chem 2025, 477, 143425. https://doi.org/10.1016/j.foodchem.2025.143425.
129. Corraliza-Gómez, M.; Gallardo, A.B.; Díaz-Marrero, A.R.; de la Rosa, J.M.; D'Croz, L.; Darias, J.; Arranz, E.;
Cózar-Castellano, I.; Ganfornina, M.D.; Cueto, M. Modulation of Glial Responses by Furanocembranolides:
Leptolide Diminishes Microglial Inflammation in Vitro and Ameliorates Gliosis In Vivo in a Mouse Model
of Obesity and Insulin Resistance. Mar Drugs 2020, 18. https://doi.org/10.3390/md18080378.
130. Tucsek, Z.; Toth, P.; Sosnowska, D.; Gautam, T.; Mitschelen, M.; Koller, A.; Szalai, G.; Sonntag, W.E.;
Ungvari, Z.; Csiszar, A. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation,
and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid
generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci 2014, 69, 1212–1226.
https://doi.org/10.1093/gerona/glt177.
131. Zhang, P.; Yu, Y.; Qin, Y.; Zhou, Y.; Tang, R.; Wang, Q.; Li, X.; Wang, H.; Weston-Green, K.; Huang, X.F.;
et al. Alterations to the microbiota-colon-brain axis in high-fat-diet-induced obese mice compared to diet-
resistant mice. J Nutr Biochem 2019, 65, 54–65. https://doi.org/10.1016/j.jnutbio.2018.08.016.
132. Tobe, E.H. Mitochondrial dysfunction, oxidative stress, and major depressive disorder. Neuropsychiatr Dis
Treat 2013, 9, 567–573. https://doi.org/10.2147/ndt.S44282.
133. Maurya, P.K.; Noto, C.; Rizzo, L.B.; Rios, A.C.; Nunes, S.O.; Barbosa, D.S.; Sethi, S.; Zeni, M.; Mansur, R.B.;
Maes, M.; et al. The role of oxidative and nitrosative stress in accelerated aging and major depressive
disorder. Prog Neuropsychopharmacol Biol Psychiatry 2016, 65, 134–144.
https://doi.org/10.1016/j.pnpbp.2015.08.016.
134. Allen, J.; Romay-Tallon, R.; Brymer, K.J.; Caruncho, H.J.; Kalynchuk, L.E. Mitochondria and Mood:
Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression. Front Neurosci 2018, 12, 386.
https://doi.org/10.3389/fnins.2018.00386.
135. Li, W.; Zhu, L.; Chen, Y.; Zhuo, Y.; Wan, S.; Guo, R. Association between mitochondrial DNA levels and
depression: a systematic review and meta-analysis. BMC Psychiatry 2023, 23, 866.
https://doi.org/10.1186/s12888-023-05358-8.
136. Jiang, M.; Wang, L.; Sheng, H. Mitochondria in depression: The dysfunction of mitochondrial energy
metabolism and quality control systems. CNS Neurosci Ther 2024, 30, e14576.
https://doi.org/10.1111/cns.14576.
137. Valotto Neto, L.J.; Reverete de Araujo, M.; Moretti Junior, R.C.; Mendes Machado, N.; Joshi, R.K.; Dos
Santos Buglio, D.; Barbalho Lamas, C.; Direito, R.; Fornari Laurindo, L.; Tanaka, M.; et al. Investigating the
Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
26 of 6
Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis. Antioxid. (Basel) 2024, 13.
https://doi.org/10.3390/antiox13040393.
138. Rezin, G.T.; Amboni, G.; Zugno, A.I.; Quevedo, J.; Streck, E.L. Mitochondrial dysfunction and psychiatric
disorders. Neurochem Res 2009, 34, 1021–1029. https://doi.org/10.1007/s11064-008-9865-8.
139. Miwa, S.; Kashyap, S.; Chini, E.; von Zglinicki, T. Mitochondrial dysfunction in cell senescence and aging.
J Clin Invest 2022, 132. https://doi.org/10.1172/jci158447.
140. Guo, Y.; Guan, T.; Shafiq, K.; Yu, Q.; Jiao, X.; Na, D.; Li, M.; Zhang, G.; Kong, J. Mitochondrial dysfunction
in aging. Ageing Res Rev 2023, 88, 101955. https://doi.org/10.1016/j.arr.2023.101955.
141. Zhou, B.; Tian, R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest 2018, 128,
3716–3726. https://doi.org/10.1172/jci120849.
142. Chapman, J.; Fielder, E.; Passos, J.F. Mitochondrial dysfunction and cell senescence: deciphering a complex
relationship. FEBS Lett 2019, 593, 1566–1579. https://doi.org/10.1002/1873-3468.13498.
143. Scaini, G.; Mason, B.L.; Diaz, A.P.; Jha, M.K.; Soares, J.C.; Trivedi, M.H.; Quevedo, J. Dysregulation of
mitochondrial dynamics, mitophagy and apoptosis in major depressive disorder: Does inflammation play
a role? Mol. Psychiatry 2022, 27, 1095–1102.
144. Zhan, F.; Lin, G.; Su, L.; Xue, L.; Duan, K.; Chen, L.; Ni, J. The association between methylmalonic acid, a
biomarker of mitochondrial dysfunction, and cause-specific mortality in Alzheimer's disease and
Parkinson's disease. Heliyon 2024, 10, e29357. https://doi.org/10.1016/j.heliyon.2024.e29357.
145. Guo, J.; Wang, S.; Wan, X.; Liu, X.; Wang, Z.; Liang, C.; Zhang, Z.; Wang, Y.; Yan, M.; Wu, P.; et al.
Mitochondria-derived methylmalonic acid aggravates ischemia-reperfusion injury by activating reactive
oxygen species-dependent ferroptosis. Cell Commun Signal 2024, 22, 53. https://doi.org/10.1186/s12964-024-
01479-z.
146. Cao, B.; Xiao, Y.; Liu, D. Associations of methylmalonic acid and depressive symptoms with mortality: a
population-based study. Transl Psychiatry 2024, 14, 297. https://doi.org/10.1038/s41398-024-03015-6.
147. Huang, Q.N.; Watanabe, F.; Koseki, K.; He, R.E.; Lee, H.L.; Chiu, T.H.T. Effect of roasted purple laver (nori)
on vitamin B(12) nutritional status of vegetarians: a dose-response trial. Eur. J. Nutr. 2024, 63, 3269–3279.
https://doi.org/10.1007/s00394-024-03505-9.
148. Chen, S.; Dong, Z.; Zhao, Y.; Sai, N.; Wang, X.; Liu, H.; Huang, G.; Zhang, X. Homocysteine induces
mitochondrial dysfunction involving the crosstalk between oxidative stress and mitochondrial pSTAT3 in
rat ischemic brain. Sci Rep 2017, 7, 6932. https://doi.org/10.1038/s41598-017-07112-z.
149. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative
Diseases. Molecules 2019, 24. https://doi.org/10.3390/molecules24081583.
150. de Moraes, M.S.; Guerreiro, G.; Sitta, A.; de Moura Coelho, D.; Manfredini, V.; Wajner, M.; Vargas, C.R.
Oxidative damage in mitochondrial fatty acids oxidation disorders patients and the in vitro effect of l-
carnitine on DNA damage induced by the accumulated metabolites. Arch Biochem Biophys 2020, 679, 108206.
https://doi.org/10.1016/j.abb.2019.108206.
151. Butkowski, E.G.; Al-Aubaidy, H.A.; Jelinek, H.F. Interaction of homocysteine, glutathione and 8-hydroxy-
2'-deoxyguanosine in metabolic syndrome progression. Clin Biochem 2017, 50, 116–120.
https://doi.org/10.1016/j.clinbiochem.2016.10.006.
152. Zhao, X.; Abulikemu, A.; Lv, S.; Qi, Y.; Duan, J.; Zhang, J.; Chen, R.; Guo, C.; Li, Y.; Sun, Z. Oxidative stress-
and mitochondrial dysfunction-mediated cytotoxicity by silica nanoparticle in lung epithelial cells from
metabolomic perspective. Chemosphere 2021, 275, 129969.
https://doi.org/10.1016/j.chemosphere.2021.129969.
153. Tanaka, M.; Battaglia, S.; Liloia, D. Navigating Neurodegeneration: Integrating Biomarkers,
Neuroinflammation, and Imaging in Parkinson’s, Alzheimer’s, and Motor Neuron Disorders. 2025, 13, 1045.
154. Park, A.; Oh, M.; Lee, S.J.; Oh, K.J.; Lee, E.W.; Lee, S.C.; Bae, K.H.; Han, B.S.; Kim, W.K. Mitochondrial
Transplantation as a Novel Therapeutic Strategy for Mitochondrial Diseases. Int J Mol Sci 2021, 22.
https://doi.org/10.3390/ijms22094793.
155. Riou, A.; Broeglin, A.; Grimm, A. Mitochondrial transplantation in brain disorders: Achievements,
methods, and challenges. Neurosci Biobehav Rev 2025, 169, 105971.
https://doi.org/10.1016/j.neubiorev.2024.105971.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
27 of 6
156. Zong, Y.; Li, H.; Liao, P.; Chen, L.; Pan, Y.; Zheng, Y.; Zhang, C.; Liu, D.; Zheng, M.; Gao, J. Mitochondrial
dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther 2024, 9, 124.
https://doi.org/10.1038/s41392-024-01839-8.
157. Ali, N.H.; Al-Kuraishy, H.M.; Al-Gareeb, A.I.; Albuhadily, A.K.; Hamad, R.S.; Alexiou, A.; Papadakis, M.;
Saad, H.M.; Batiha, G.E. Role of brain renin-angiotensin system in depression: A new perspective. CNS
Neurosci Ther 2024, 30, e14525. https://doi.org/10.1111/cns.14525.
158. Ramis, M.R.; Esteban, S.; Miralles, A.; Tan, D.X.; Reiter, R.J. Protective Effects of Melatonin and
Mitochondria-targeted Antioxidants Against Oxidative Stress: A Review. Curr Med Chem 2015, 22, 2690–
2711. https://doi.org/10.2174/0929867322666150619104143.
159. Koh, J.H.; Kim, J.Y. Role of PGC-1α in the Mitochondrial NAD(+) Pool in Metabolic Diseases. Int J Mol Sci
2021, 22. https://doi.org/10.3390/ijms22094558.
160. Hidalgo-Gutiérrez, A.; González-García, P.; Díaz-Casado, M.E.; Barriocanal-Casado, E.; López-Herrador,
S.; Quinzii, C.M.; López, L.C. Metabolic Targets of Coenzyme Q10 in Mitochondria. Antioxid. (Basel) 2021,
10. https://doi.org/10.3390/antiox10040520.
161. Abu Shelbayeh, O.; Arroum, T.; Morris, S.; Busch, K.B. PGC-1α Is a Master Regulator of Mitochondrial
Lifecycle and ROS Stress Response. Antioxid. (Basel) 2023, 12. https://doi.org/10.3390/antiox12051075.
162. Briston, T.; Selwood, D.L.; Szabadkai, G.; Duchen, M.R. Mitochondrial Permeability Transition: A
Molecular Lesion with Multiple Drug Targets. Trends Pharmacol Sci 2019, 40, 50–70.
https://doi.org/10.1016/j.tips.2018.11.004.
163. Tao, J.; Chen, H.; Wang, Y.J.; Qiu, J.X.; Meng, Q.Q.; Zou, R.J.; Li, L.; Huang, J.G.; Zhao, Z.K.; Huang, Y.L.;
et al. Ketogenic Diet Suppressed T-Regulatory Cells and Promoted Cardiac Fibrosis via Reducing
Mitochondria-Associated Membranes and Inhibiting Mitochondrial Function. Oxid Med Cell Longev 2021,
2021, 5512322. https://doi.org/10.1155/2021/5512322.
164. Yang, Y.; Wang, W.; Tian, Y.; Shi, J. Sirtuin 3 and mitochondrial permeability transition pore (mPTP): A
systematic review. Mitochondrion 2022, 64, 103–111. https://doi.org/10.1016/j.mito.2022.03.004.
165. Xue, Y.; Liu, H.; Yang, X.X.; Pang, L.; Liu, J.; Ng, K.T.P.; Yeung, O.W.H.; Lam, Y.F.; Zhang, W.Y.; Lo, C.M.;
et al. Inhibition of Carnitine Palmitoyltransferase 1A Aggravates Fatty Liver Graft Injury via Promoting
Mitochondrial Permeability Transition. Transplantation 2021, 105, 550–560.
https://doi.org/10.1097/tp.0000000000003437.
166. Kalani, K.; Yan, S.F.; Yan, S.S. Mitochondrial permeability transition pore: a potential drug target for
neurodegeneration. Drug Discov Today 2018, 23, 1983–1989. https://doi.org/10.1016/j.drudis.2018.08.001.
167. Khiroya, K.; Sekyere, E.; McEwen, B.; Bayes, J. Nutritional considerations in major depressive disorder:
current evidence and functional testing for clinical practice. Nutr Res Rev 2023, 1-12.
https://doi.org/10.1017/s0954422423000276.
168. Bernier, V.; Debarge, M.H.; Hein, M.; Ammendola, S.; Mungo, A.; Loas, G. Major Depressive Disorder,
Inflammation, and Nutrition: A Tricky Pattern? Nutrients 2023, 15. https://doi.org/10.3390/nu15153438.
169. Ortega, M.A.; Fraile-Martínez, Ó.; García-Montero, C.; Alvarez-Mon, M.A.; Lahera, G.; Monserrat, J.;
Llavero-Valero, M.; Mora, F.; Rodríguez-Jiménez, R.; Fernandez-Rojo, S.; et al. Nutrition, Epigenetics, and
Major Depressive Disorder: Understanding the Connection. Front Nutr 2022, 9, 867150.
https://doi.org/10.3389/fnut.2022.867150.
170. Muha, J.; Schumacher, A.; Campisi, S.C.; Korczak, D.J. Depression and emotional eating in children and
adolescents: A systematic review and meta-analysis. Appetite 2024, 200, 107511.
https://doi.org/10.1016/j.appet.2024.107511.
171. Ekinci, G.N.; Sanlier, N. The relationship between nutrition and depression in the life process: A mini-
review. Exp Gerontol 2023, 172, 112072. https://doi.org/10.1016/j.exger.2022.112072.
172. Chrzastek, Z.; Guligowska, A.; Sobczuk, P.; Kostka, T. Dietary factors, risk of developing depression, and
severity of its symptoms in older adults-A narrative review of current knowledge. Nutrition 2023, 106,
111892. https://doi.org/10.1016/j.nut.2022.111892.
173. Lane, M.M.; Gamage, E.; Travica, N.; Dissanayaka, T.; Ashtree, D.N.; Gauci, S.; Lotfaliany, M.; O'Neil, A.;
Jacka, F.N.; Marx, W. Ultra-Processed Food Consumption and Mental Health: A Systematic Review and
Meta-Analysis of Observational Studies. Nutrients 2022, 14. https://doi.org/10.3390/nu14132568.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
28 of 6
174. Ejtahed, H.S.; Mardi, P.; Hejrani, B.; Mahdavi, F.S.; Ghoreshi, B.; Gohari, K.; Heidari-Beni, M.; Qorbani, M.
Association between junk food consumption and mental health problems in adults: a systematic review
and meta-analysis. BMC Psychiatry 2024, 24, 438. https://doi.org/10.1186/s12888-024-05889-8.
175. Malmir, H.; Mahdavi, F.S.; Ejtahed, H.S.; Kazemian, E.; Chaharrahi, A.; Mohammadian Khonsari, N.;
Mahdavi-Gorabi, A.; Qorbani, M. Junk food consumption and psychological distress in children and
adolescents: a systematic review and meta-analysis. Nutr Neurosci 2023, 26, 807–827.
https://doi.org/10.1080/1028415X.2022.2094856.
176. Aly, J.; Engmann, O. The Way to a Human's Brain Goes Through Their Stomach: Dietary Factors in Major
Depressive Disorder. Front Neurosci 2020, 14, 582853. https://doi.org/10.3389/fnins.2020.582853.
177. Kunugi, H. Depression and lifestyle: Focusing on nutrition, exercise, and their possible relevance to
molecular mechanisms. Psychiatry Clin Neurosci 2023, 77, 420–433. https://doi.org/10.1111/pcn.13551.
178. Swainson, J.; Reeson, M.; Malik, U.; Stefanuk, I.; Cummins, M.; Sivapalan, S. Diet and depression: A
systematic review of whole dietary interventions as treatment in patients with depression. J Affect Disord
2023, 327, 270–278. https://doi.org/10.1016/j.jad.2023.01.094.
179. Selvaraj, R.; Selvamani, T.Y.; Zahra, A.; Malla, J.; Dhanoa, R.K.; Venugopal, S.; Shoukrie, S.I.; Hamouda,
R.K.; Hamid, P. Association Between Dietary Habits and Depression: A Systematic Review. Cureus 2022,
14, e32359. https://doi.org/10.7759/cureus.32359.
180. Gorbachev, D.; Markina, E.; Chigareva, O.; Gradinar, A.; Borisova, N.; Syunyakov, T. Dietary Patterns as
Modifiable Risk Factors for Depression: a Narrative Review. Psychiatr Danub 2023, 35, 423–431.
181. Zhang, Q.; Yi, J.; Wu, Y. Oxidative stress and inflammation mediate the association between elevated
oxidative balance scores and improved sleep quality: evidence from NHANES. Front Nutr 2024, 11, 1469779.
https://doi.org/10.3389/fnut.2024.1469779.
182. Wilson, D.; Driller, M.; Winwood, P.; Clissold, T.; Johnston, B.; Gill, N. The Effectiveness of a Combined
Healthy Eating, Physical Activity, and Sleep Hygiene Lifestyle Intervention on Health and Fitness of
Overweight Airline Pilots: A Controlled Trial. Nutrients 2022, 14. https://doi.org/10.3390/nu14091988.
183. Bolognese, M.A.; Franco, C.B.; Ferrari, A.; Bennemann, R.M.; Lopes, S.M.A.; Bertolini, S.; Júnior, N.N.;
Branco, B.H.M. Group Nutrition Counseling or Individualized Prescription for Women With Obesity? A
Clinical Trial. Front Public Health 2020, 8, 127. https://doi.org/10.3389/fpubh.2020.00127.
184. Mehdi, S.; Wani, S.U.D.; Krishna, K.L.; Kinattingal, N.; Roohi, T.F. A review on linking stress, depression,
and insulin resistance via low-grade chronic inflammation. Biochem Biophys Rep 2023, 36, 101571.
https://doi.org/10.1016/j.bbrep.2023.101571.
185. Pickersgill, J.W.; Turco, C.V.; Ramdeo, K.; Rehsi, R.S.; Foglia, S.D.; Nelson, A.J. The Combined Influences
of Exercise, Diet and Sleep on Neuroplasticity. Front Psychol 2022, 13, 831819.
https://doi.org/10.3389/fpsyg.2022.831819.
186. Magzal, F.; Turroni, S.; Fabbrini, M.; Barone, M.; Vitman Schorr, A.; Ofran, A.; Tamir, S. A personalized
diet intervention improves depression symptoms and changes microbiota and metabolite profiles among
community-dwelling older adults. Front Nutr 2023, 10, 1234549. https://doi.org/10.3389/fnut.2023.1234549.
187. Yu, Y.; Zhou, W.; Zhu, X.; Hu, Z.; Li, S.; Zheng, B.; Xu, H.; Long, W.; Xiong, X. Association between dietary
intake and symptoms of depression and anxiety in pregnant women: Evidence from a community-based
observational study. Food Sci Nutr 2023, 11, 7555–7564. https://doi.org/10.1002/fsn3.3675.
188. Serrano Ripoll, M.J.; Oliván-Blázquez, B.; Vicens-Pons, E.; Roca, M.; Gili, M.; Leiva, A.; García-Campayo,
J.; Demarzo, M.P.; García-Toro, M. Lifestyle change recommendations in major depression: Do they work?
J Affect Disord 2015, 183, 221–228. https://doi.org/10.1016/j.jad.2015.04.059.
189. Ip, A.K.; Ho, F.Y.; Yeung, W.F.; Chung, K.F.; Ng, C.H.; Oliver, G.; Sarris, J. Effects of a group-based lifestyle
medicine for depression: A pilot randomized controlled trial. PLoS One 2021, 16, e0258059.
https://doi.org/10.1371/journal.pone.0258059.
190. Sarris, J.; O'Neil, A.; Coulson, C.E.; Schweitzer, I.; Berk, M. Lifestyle medicine for depression. BMC
Psychiatry 2014, 14, 107. https://doi.org/10.1186/1471-244x-14-107.
191. Firth, J.; Marx, W.; Dash, S.; Carney, R.; Teasdale, S.B.; Solmi, M.; Stubbs, B.; Schuch, F.B.; Carvalho, A.F.;
Jacka, F.; et al. The Effects of Dietary Improvement on Symptoms of Depression and Anxiety: A Meta-
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
29 of 6
Analysis of Randomized Controlled Trials. Psychosom Med 2019, 81, 265–280.
https://doi.org/10.1097/psy.0000000000000673.
192. Dale, E.; Bang-Andersen, B.; Sánchez, C. Emerging mechanisms and treatments for depression beyond
SSRIs and SNRIs. Biochem Pharmacol 2015, 95, 81–97. https://doi.org/10.1016/j.bcp.2015.03.011.
193. Fagiolini, A.; Florea, I.; Loft, H.; Christensen, M.C. Effectiveness of Vortioxetine on Emotional Blunting in
Patients with Major Depressive Disorder with inadequate response to SSRI/SNRI treatment. J Affect Disord
2021, 283, 472–479. https://doi.org/10.1016/j.jad.2020.11.106.
194. Zhao, Y.; Xu, D.; Wang, J.; Zhou, D.; Liu, A.; Sun, Y.; Yuan, Y.; Li, J.; Guo, W. The pharmacological
mechanism of chaihu-jia-longgu-muli-tang for treating depression: integrated meta-analysis and network
pharmacology analysis. Front Pharmacol 2023, 14, 1257617. https://doi.org/10.3389/fphar.2023.1257617.
195. Zhichao, H.; Ching, L.W.; Huijuan, L.; Liang, Y.; Zhiyu, W.; Weiyang, H.; Zhaoxiang, B.; Linda, Z.L.D. A
network meta-analysis on the effectiveness and safety of acupuncture in treating patients with major
depressive disorder. Sci Rep 2021, 11, 10384. https://doi.org/10.1038/s41598-021-88263-y.
196. Qaseem, A.; Owens, D.K.; Etxeandia-Ikobaltzeta, I.; Tufte, J.E.; Cross, J.T.; Wilt, T.J.; Physicians,
C.G.C.f.t.A.C.o. Nonpharmacologic and Pharmacologic Treatments of Adults in the Acute Phase of Major
Depressive Disorder: A Living Clinical Guideline From the American College of Physicians (Version 1,
Update Alert 2). Ann Intern Med 2024. https://doi.org/10.7326/ANNALS-24-00593.
197. Direito, R.; Barbalho, S.M.; Sepodes, B.; Figueira, M.E. Plant-Derived Bioactive Compounds: Exploring
Neuroprotective, Metabolic, and Hepatoprotective Effects for Health Promotion and Disease Prevention.
Pharmaceutics 2024, 16. https://doi.org/10.3390/pharmaceutics16050577.
198. Marx, W.; Manger, S.H.; Blencowe, M.; Murray, G.; Ho, F.Y.; Lawn, S.; Blumenthal, J.A.; Schuch, F.; Stubbs,
B.; Ruusunen, A.; et al. Clinical guidelines for the use of lifestyle-based mental health care in major
depressive disorder: World Federation of Societies for Biological Psychiatry (WFSBP) and Australasian
Society of Lifestyle Medicine (ASLM) taskforce. World J Biol Psychiatry 2023, 24, 333–386.
https://doi.org/10.1080/15622975.2022.2112074.
199. Smith, R.D.; Dang, W.; Shen, S.; Hung, S.C.; Lam, I.H.; Kwok, J.Y.Y.; Choi, E.P.H.; Fong, D.Y.T.; Ali, S.;
Wilson, C.A.; et al. Comparative effectiveness of interventions for the prevention and treatment of perinatal
depression: A systematic review and network meta-analysis. Asian J Psychiatr 2025, 103, 104316.
https://doi.org/10.1016/j.ajp.2024.104316.
200. Sarris, J.; Logan, A.C.; Akbaraly, T.N.; Amminger, G.P.; Balanzá-Martínez, V.; Freeman, M.P.; Hibbeln, J.;
Matsuoka, Y.; Mischoulon, D.; Mizoue, T.; et al. Nutritional medicine as mainstream in psychiatry. Lancet
Psychiatry 2015, 2, 271–274. https://doi.org/10.1016/s2215-0366(14)00051-0.
201. Voineskos, D.; Daskalakis, Z.J.; Blumberger, D.M. Management of Treatment-Resistant Depression:
Challenges and Strategies. Neuropsychiatr Dis Treat 2020, 16, 221–234. https://doi.org/10.2147/ndt.S198774.
202. Al-Harbi, K.S. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient
Prefer Adherence 2012, 6, 369–388. https://doi.org/10.2147/ppa.S29716.
203. McIntyre, R.S.; Alsuwaidan, M.; Baune, B.T.; Berk, M.; Demyttenaere, K.; Goldberg, J.F.; Gorwood, P.; Ho,
R.; Kasper, S.; Kennedy, S.H.; et al. Treatment-resistant depression: definition, prevalence, detection,
management, and investigational interventions. World Psychiatry 2023, 22, 394–412.
https://doi.org/10.1002/wps.21120.
204. McIntyre, R.S.; Filteau, M.J.; Martin, L.; Patry, S.; Carvalho, A.; Cha, D.S.; Barakat, M.; Miguelez, M.
Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect
Disord 2014, 156, 1–7. https://doi.org/10.1016/j.jad.2013.10.043.
205. De Raedt, R.; Vanderhasselt, M.A.; Baeken, C. Neurostimulation as an intervention for treatment resistant
depression: From research on mechanisms towards targeted neurocognitive strategies. Clin Psychol Rev
2015, 41, 61–69. https://doi.org/10.1016/j.cpr.2014.10.006.
206. Amasi-Hartoonian, N.; Pariante, C.M.; Cattaneo, A.; Sforzini, L. Understanding treatment-resistant
depression using "omics" techniques: A systematic review. J Affect Disord 2022, 318, 423–455.
https://doi.org/10.1016/j.jad.2022.09.011.
207. Bayes, A.; Parker, G. How to choose an antidepressant medication. Acta Psychiatr Scand 2019, 139, 280–291.
https://doi.org/10.1111/acps.13001.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
30 of 6
208. Gillman, P.K. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J
Pharmacol 2007, 151, 737–748. https://doi.org/10.1038/sj.bjp.0707253.
209. Arakawa, R.; Stenkrona, P.; Takano, A.; Svensson, J.; Andersson, M.; Nag, S.; Asami, Y.; Hirano, Y.; Halldin,
C.; Lundberg, J. Venlafaxine ER Blocks the Norepinephrine Transporter in the Brain of Patients with Major
Depressive Disorder: a PET Study Using [18F]FMeNER-D2. Int J Neuropsychopharmacol 2019, 22, 278–285.
https://doi.org/10.1093/ijnp/pyz003.
210. Settle, E.C., Jr. Antidepressant drugs: disturbing and potentially dangerous adverse effects. J Clin Psychiatry
1998, 59 Suppl 16, 25-30; discussion 40-22.
211. Teply, R.M.; Packard, K.A.; White, N.D.; Hilleman, D.E.; DiNicolantonio, J.J. Treatment of Depression in
Patients with Concomitant Cardiac Disease. Prog Cardiovasc Dis 2016, 58, 514–528.
https://doi.org/10.1016/j.pcad.2015.11.003.
212. Wang, S.M.; Han, C.; Bahk, W.M.; Lee, S.J.; Patkar, A.A.; Masand, P.S.; Pae, C.U. Addressing the Side Effects
of Contemporary Antidepressant Drugs: A Comprehensive Review. Chonnam Med J 2018, 54, 101–112.
https://doi.org/10.4068/cmj.2018.54.2.101.
213. Blackwell, B. Adverse effects of antidepressant drugs: part 1: monoamine oxidase inhibitors and tricyclics.
Drugs 1981, 21, 201–219.
214. Feighner, J.P. Mechanism of action of antidepressant medications. J Clin Psychiatry 1999, 60 Suppl 4, 4-11;
discussion 12-13.
215. Zhou, S.; Li, P.; Lv, X.; Lai, X.; Liu, Z.; Zhou, J.; Liu, F.; Tao, Y.; Zhang, M.; Yu, X.; et al. Adverse effects of
21 antidepressants on sleep during acute-phase treatment in major depressive disorder: a systemic review
and dose-effect network meta-analysis. Sleep 2023, 46. https://doi.org/10.1093/sleep/zsad177.
216. Muir, K.W.; Lees, K.R. Clinical experience with excitatory amino acid antagonist drugs. Stroke 1995, 26,
503–513. https://doi.org/10.1161/01.str.26.3.503.
217. Carvalho, A.F.; Sharma, M.S.; Brunoni, A.R.; Vieta, E.; Fava, G.A. The Safety, Tolerability and Risks
Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature.
Psychother Psychosom 2016, 85, 270–288. https://doi.org/10.1159/000447034.
218. Kishi, T.; Ikuta, T.; Sakuma, K.; Okuya, M.; Hatano, M.; Matsuda, Y.; Iwata, N. Antidepressants for the
treatment of adults with major depressive disorder in the maintenance phase: a systematic review and
network meta-analysis. Mol Psychiatry 2023, 28, 402–409. https://doi.org/10.1038/s41380-022-01824-z.
219. Wichniak, A.; Wierzbicka, A.; Walęcka, M.; Jernajczyk, W. Effects of Antidepressants on Sleep. Curr
Psychiatry Rep 2017, 19, 63. https://doi.org/10.1007/s11920-017-0816-4.
220. Beach, S.R.; Kostis, W.J.; Celano, C.M.; Januzzi, J.L.; Ruskin, J.N.; Noseworthy, P.A.; Huffman, J.C. Meta-
analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry 2014, 75,
e441-449,. https://doi.org/10.4088/JCP.13r08672.
221. Gheysens, T.; Van Den Eede, F.; De Picker, L. The risk of antidepressant-induced hyponatremia: A meta-
analysis of antidepressant classes and compounds. Eur Psychiatry 2024, 67, e20.
https://doi.org/10.1192/j.eurpsy.2024.11.
222. Wu, X.; Zhang, W. Reminiscence therapy-based care program alleviates anxiety and depression, as well as
improves the quality of life in recurrent gastric cancer patients. Front Psychol 2023, 14, 1133470.
https://doi.org/10.3389/fpsyg.2023.1133470.
223. Yeung, W.F.; Chung, K.F.; Ng, K.Y.; Yu, Y.M.; Ziea, E.T.; Ng, B.F. A systematic review on the efficacy, safety
and types of Chinese herbal medicine for depression. J Psychiatr Res 2014, 57, 165–175.
https://doi.org/10.1016/j.jpsychires.2014.05.016.
224. Sarris, J. Herbal medicines in the treatment of psychiatric disorders: 10-year updated review. Phytother Res
2018, 32, 1147–1162. https://doi.org/10.1002/ptr.6055.
225. Pellegrini, C.; Fornai, M.; Antonioli, L.; Blandizzi, C.; Calderone, V. Phytochemicals as Novel Therapeutic
Strategies for NLRP3 Inflammasome-Related Neurological, Metabolic, and Inflammatory Diseases. Int J
Mol Sci 2019, 20. https://doi.org/10.3390/ijms20122876.
226. Laurindo, L.F.; de Carvalho, G.M.; de Oliveira Zanuso, B.; Figueira, M.E.; Direito, R.; de Alvares Goulart,
R.; Buglio, D.S.; Barbalho, S.M. Curcumin-Based Nanomedicines in the Treatment of Inflammatory and
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
31 of 6
Immunomodulated Diseases: An Evidence-Based Comprehensive Review. Pharmaceutics 2023, 15.
https://doi.org/10.3390/pharmaceutics15010229.
227. Nishikito, D.F.; Borges, A.C.A.; Laurindo, L.F.; Otoboni, A.; Direito, R.; Goulart, R.A.; Nicolau, C.C.T.;
Fiorini, A.M.R.; Sinatora, R.V.; Barbalho, S.M. Anti-Inflammatory, Antioxidant, and Other Health Effects
of Dragon Fruit and Potential Delivery Systems for Its Bioactive Compounds. Pharmaceutics 2023, 15.
https://doi.org/10.3390/pharmaceutics15010159.
228. Liu, L.Y.; Feng, B.; Chen, J.; Tan, Q.R.; Chen, Z.X.; Chen, W.S.; Wang, P.R.; Zhang, Z.J. Herbal medicine for
hospitalized patients with severe depressive episode: a retrospective controlled study. J Affect Disord 2015,
170, 71–77. https://doi.org/10.1016/j.jad.2014.08.027.
229. Cai, M.Y.; Yang, Z.; Huang, X.J.; Li, J.; Bao, W.Y.; Hurilebagen; Wulanqiqige; Wuyunsiriguleng; Cui, J.W.;
Ma, L.Q.; et al. Mongolian Medicine Areca Thirteen Pill (GY-13) Improved Depressive Syndrome via
upregulating cAMP/PKA/CREB/BDNF signaling pathway. J Ethnopharmacol 2022, 293, 115310.
https://doi.org/10.1016/j.jep.2022.115310.
230. Singh, N.; Garg, M.; Prajapati, P.; Singh, P.K.; Chopra, R.; Kumari, A.; Mittal, A. Adaptogenic property of
Asparagus racemosus: Future trends and prospects. Heliyon 2023, 9, e14932.
https://doi.org/10.1016/j.heliyon.2023.e14932.
231. Mu, D.; Ma, Q. A Review of Antidepressant Effects and Mechanisms of Three Common Herbal Medicines:
Panax ginseng, Bupleurum chinense, and Gastrodia elata. CNS Neurol Disord Drug Targets 2023, 22, 1164–
1175. https://doi.org/10.2174/1871527322666221116164836.
232. Mokhtari, T. Targeting autophagy and neuroinflammation pathways with plant-derived natural
compounds as potential antidepressant agents. Phytother Res 2022, 36, 3470–3489.
https://doi.org/10.1002/ptr.7551.
233. Yoon, S.; Iqbal, H.; Kim, S.M.; Jin, M. Phytochemicals That Act on Synaptic Plasticity as Potential
Prophylaxis against Stress-Induced Depressive Disorder. Biomol Ther (Seoul) 2023, 31, 148–160.
https://doi.org/10.4062/biomolther.2022.116.
234. Wu, X.; Zhou, Y.; Xi, Y.; Zhou, H.; Tang, Z.; Xiong, L.; Qin, D. Polyphenols: Natural Food-Grade
Biomolecules for the Treatment of Nervous System Diseases from a Multi-Target Perspective. Pharm. (Basel)
2024, 17. https://doi.org/10.3390/ph17060775.
235. Wang, T.; Yang, C.; Li, Z.; Li, T.; Zhang, R.; Zhao, Y.; Cheng, T.; Zong, Z.; Ma, Y.; Zhang, D.; et al. Flavonoid
4,4'-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy. Redox Biol 2024,
69, 103017. https://doi.org/10.1016/j.redox.2023.103017.
236. Zhu, M.; Sun, Y.; Su, Y.; Guan, W.; Wang, Y.; Han, J.; Wang, S.; Yang, B.; Wang, Q.; Kuang, H. Luteolin: A
promising multifunctional natural flavonoid for human diseases. Phytother Res 2024, 38, 3417–3443.
https://doi.org/10.1002/ptr.8217.
237. Rasmus, P.; Kozłowska, E. Antioxidant and Anti-Inflammatory Effects of Carotenoids in Mood Disorders:
An Overview. Antioxid. (Basel) 2023, 12. https://doi.org/10.3390/antiox12030676.
238. Barbalho, S.M.; Direito, R.; Laurindo, L.F.; Marton, L.T.; Guiguer, E.L.; Goulart, R.A.; Tofano, R.J.; Carvalho,
A.C.A.; Flato, U.A.P.; Capelluppi Tofano, V.A.; et al. Ginkgo biloba in the Aging Process: A Narrative
Review. Antioxid. (Basel) 2022, 11. https://doi.org/10.3390/antiox11030525.
239. Barbalho, S.M.; Laurindo, L.F.; de Oliveira Zanuso, B.; da Silva, R.M.S.; Gallerani Caglioni, L.; Nunes
Junqueira de Moraes, V.B.F.; Fornari Laurindo, L.; Dogani Rodrigues, V.; da Silva Camarinha Oliveira, J.;
Beluce, M.E.; et al. AdipoRon's Impact on Alzheimer's Disease-A Systematic Review and Meta-Analysis.
Int J Mol Sci 2025, 26. https://doi.org/10.3390/ijms26020484.
240. Buglio, D.S.; Marton, L.T.; Laurindo, L.F.; Guiguer, E.L.; Araújo, A.C.; Buchaim, R.L.; Goulart, R.A.; Rubira,
C.J.; Barbalho, S.M. The Role of Resveratrol in Mild Cognitive Impairment and Alzheimer's Disease: A
Systematic Review. J Med Food 2022, 25, 797–806. https://doi.org/10.1089/jmf.2021.0084.
241. Costa, R.O.; Martins, L.F.; Tahiri, E.; Duarte, C.B. Brain-derived neurotrophic factor-induced regulation of
RNA metabolism in neuronal development and synaptic plasticity. Wiley Interdiscip Rev RNA 2022, 13,
e1713. https://doi.org/10.1002/wrna.1713.
242. Gadad, B.S.; Vargas-Medrano, J.; Ramos, E.I.; Najera, K.; Fagan, M.; Forero, A.; Thompson, P.M. Altered
levels of interleukins and neurotrophic growth factors in mood disorders and suicidality: an analysis from
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
32 of 6
periphery to central nervous system. Transl Psychiatry 2021, 11, 341. https://doi.org/10.1038/s41398-021-
01452-1.
243. Afzal, A.; Batool, Z.; Sadir, S.; Liaquat, L.; Shahzad, S.; Tabassum, S.; Ahmad, S.; Kamil, N.; Perveen, T.;
Haider, S. Therapeutic Potential of Curcumin in Reversing the Depression and Associated Pseudodementia
via Modulating Stress Hormone, Hippocampal Neurotransmitters, and BDNF Levels in Rats. Neurochem
Res 2021, 46, 3273–3285. https://doi.org/10.1007/s11064-021-03430-x.
244. Peng, J.; Yang, Z.; Li, H.; Hao, B.; Cui, D.; Shang, R.; Lv, Y.; Liu, Y.; Pu, W.; Zhang, H.; et al. Quercetin
Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1α Signaling Pathway to Ameliorate
Lipopolysaccharide-Induced Oxidative Damage. Int J Mol Sci 2023, 24. https://doi.org/10.3390/ijms24065542.
245. Wu, J.; Xu, X.; Li, Y.; Kou, J.; Huang, F.; Liu, B.; Liu, K. Quercetin, luteolin and epigallocatechin gallate
alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in
endothelial cells. Eur J Pharmacol 2014, 745, 59–68. https://doi.org/10.1016/j.ejphar.2014.09.046.
246. Hassan, S.S.U.; Samanta, S.; Dash, R.; Karpiński, T.M.; Habibi, E.; Sadiq, A.; Ahmadi, A.; Bunagu, S. The
neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of
oxidative stress. Front Pharmacol 2022, 13, 1015835. https://doi.org/10.3389/fphar.2022.1015835.
247. Jantan, I.; Haque, M.A.; Arshad, L.; Harikrishnan, H.; Septama, A.W.; Mohamed-Hussein, Z.A. Dietary
polyphenols suppress chronic inflammation by modulation of multiple inflammation-associated cell
signaling pathways. J Nutr Biochem 2021, 93, 108634. https://doi.org/10.1016/j.jnutbio.2021.108634.
248. Idayu, N.F.; Hidayat, M.T.; Moklas, M.A.; Sharida, F.; Raudzah, A.R.; Shamima, A.R.; Apryani, E.
Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of
depression. Phytomedicine 2011, 18, 402–407. https://doi.org/10.1016/j.phymed.2010.08.011.
249. Ahmad, I.; Prabowo, W.C.; Arifuddin, M.; Fadraersada, J.; Indriyanti, N.; Herman, H.; Purwoko, R.Y.;
Nainu, F.; Rahmadi, A.; Paramita, S.; et al. Species as Pharmacological Agents: From Abuse to Promising
Pharmaceutical Products. Life (Basel) 2022, 12. https://doi.org/10.3390/life12020193.
250. Chen, L.; Fei, S.; Olatunji, O.J. LC/ESI/TOF-MS Characterization, Anxiolytic and Antidepressant-like Effects
of. Molecules 2022, 27. https://doi.org/10.3390/molecules27072208.
251. Speers, A.B.; Cabey, K.A.; Soumyanath, A.; Wright, K.M. Effects of Withania somnifera (Ashwagandha) on
Stress and the Stress- Related Neuropsychiatric Disorders Anxiety, Depression, and Insomnia. Curr
Neuropharmacol 2021, 19, 1468–1495. https://doi.org/10.2174/1570159x19666210712151556.
252. Szućko-Kociuba, I.; Trzeciak-Ryczek, A.; Kupnicka, P.; Chlubek, D. Neurotrophic and Neuroprotective
Effects of Hericium erinaceus. Int J Mol Sci 2023, 24. https://doi.org/10.3390/ijms242115960.
253. de Oliveira Zanuso, B.; de Oliveira Dos Santos, A.R.; Miola, V.F.B.; Guissoni Campos, L.M.; Spilla, C.S.G.;
Barbalho, S.M. Panax ginseng and aging related disorders: A systematic review. Exp Gerontol 2022, 161,
111731. https://doi.org/10.1016/j.exger.2022.111731.
254. Hou, Y.; Peng, S.; Li, X.; Yao, J.; Xu, J.; Fang, J. Honokiol alleviates oxidative stress-induced neurotoxicity
via activation of Nrf2. ACS Chem. Neurosci. 2018, 9, 3108–3116.
255. Wang, D.; Cao, L.; Zhou, X.; Wang, G.; Ma, Y.; Hao, X.; Fan, H. Mitigation of honokiol on fluoride-induced
mitochondrial oxidative stress, mitochondrial dysfunction, and cognitive deficits through activating
AMPK/PGC-1α/Sirt3. J. Hazard. Mater. 2022, 437, 129381.
256. Lin, X.; Zhang, N. Berberine: Pathways to protect neurons. Phytother. Res. 2018, 32, 1501–1510.
257. Zhang, C.; Xue, Z.; Zhu, L.; Zhou, J.; Zhuo, L.; Zhang, J.; Zhang, X.; Liu, W.; Han, L.; Liao, W.
Rhynchophylline alleviates neuroinflammation and regulates metabolic disorders in a mouse model of
Parkinson's disease. Food Funct. 2023, 14, 3208–3219.
258. Fathinezhad, Z.; Sewell, R.D.E.; Lorigooini, Z.; Rafieian-Kopaei, M. Depression and Treatment with
Effective Herbs. Curr Pharm Des 2019, 25, 738–745. https://doi.org/10.2174/1381612825666190402105803.
259. Lee, G.; Bae, H. Therapeutic Effects of Phytochemicals and Medicinal Herbs on Depression. Biomed Res Int
2017, 2017, 6596241. https://doi.org/10.1155/2017/6596241.
260. Manosso, L.M.; Arent, C.O.; Borba, L.A.; Abelaira, H.M.; Réus, G.Z. Natural Phytochemicals for the
Treatment of Major Depressive Disorder: A Mini-Review of Pre-and Clinical Studies. CNS Neurol. Disord. -
Drug Targets-CNS Neurol. Disord. ) 2023, 22, 237–254.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
33 of 6
261. Kou, Y.; Li, Z.; Yang, T.; Shen, X.; Wang, X.; Li, H.; Zhou, K.; Li, L.; Xia, Z.; Zheng, X. Therapeutic potential
of plant iridoids in depression: a review. Pharm. Biol. 2022, 60, 2167–2181.
262. Xiong, Z.; Jiang, B.; Wu, P.-F.; Tian, J.; Shi, L.-L.; Gu, J.; Hu, Z.-L.; Fu, H.; Wang, F.; Chen, J.-G.
Antidepressant effects of a plant-derived flavonoid baicalein involving extracellular signal-regulated
kinases cascade. Biol. Pharm. Bull. 2011, 34, 253–259.
263. Gupta, J.; Gupta, R.; Varshney, K.K. Emerging mechanisms and potential antidepressant action of
medicinal plants. Int J Pharm Sci Res 2020, 11, 1–3.
264. Picheta, N.; Piekarz, J.; Daniłowska, K.; Mazur, K.; Piecewicz-Szczęsna, H.; Smoleń, A. Phytochemicals in
the treatment of patients with depression: a systemic review. Front. Psychiatry 2024, 15, 1509109.
265. Soltani, M.; Hosseinzadeh-Attar, M.J.; Rezaei, M.; Alipoor, E.; Vasheghani-Farahani, A.; Yaseri, M.; Rezayat,
S.M. Effect of nano-curcumin supplementation on cardiometabolic risk factors, physical and psychological
quality of life, and depression in patients with coronary slow flow phenomenon: a randomized double-
blind clinical trial. Trials 2024, 25, 515. https://doi.org/10.1186/s13063-024-08354-9.
266. Dehghani, F.; Vafa, M.; Ebrahimkhani, A.; Găman, M.A.; Sezavar Seyedi Jandaghi, S.H. Effects of quercetin
supplementation on endothelial dysfunction biomarkers and depression in post-myocardial infarction
patients: A double-blind, placebo-controlled, randomized clinical trial. Clin Nutr ESPEN 2023, 56, 73–80.
https://doi.org/10.1016/j.clnesp.2023.04.019.
267. Hajiluian, G.; Karegar, S.J.; Shidfar, F.; Aryaeian, N.; Salehi, M.; Lotfi, T.; Farhangnia, P.; Heshmati, J.;
Delbandi, A.A. The effects of Ellagic acid supplementation on neurotrophic, inflammation, and oxidative
stress factors, and indoleamine 2, 3-dioxygenase gene expression in multiple sclerosis patients with mild
to moderate depressive symptoms: A randomized, triple-blind, placebo-controlled trial. Phytomedicine 2023,
121, 155094. https://doi.org/10.1016/j.phymed.2023.155094.
268. Kontogianni, M.D.; Vijayakumar, A.; Rooney, C.; Noad, R.L.; Appleton, K.M.; McCarthy, D.; Donnelly, M.;
Young, I.S.; McKinley, M.C.; McKeown, P.P.; et al. A High Polyphenol Diet Improves Psychological Well-
Being: The Polyphenol Intervention Trial (PPhIT). Nutrients 2020, 12. https://doi.org/10.3390/nu12082445.
269. Davinelli, S.; Scapagnini, G.; Marzatico, F.; Nobile, V.; Ferrara, N.; Corbi, G. Influence of equol and
resveratrol supplementation on health-related quality of life in menopausal women: A randomized,
placebo-controlled study. Maturitas 2017, 96, 77–83. https://doi.org/10.1016/j.maturitas.2016.11.016.
270. Hirose, A.; Terauchi, M.; Akiyoshi, M.; Owa, Y.; Kato, K.; Kubota, T. Low-dose isoflavone aglycone
alleviates psychological symptoms of menopause in Japanese women: a randomized, double-blind,
placebo-controlled study. Arch Gynecol Obs. 2016, 293, 609–615. https://doi.org/10.1007/s00404-015-3849-0.
271. Choi, J.; Kim, J.H.; Park, M.; Lee, H.J. Effects of Flavonoid-Rich Orange Juice Intervention on Major
Depressive Disorder in Young Adults: A Randomized Controlled Trial. Nutrients 2022, 15.
https://doi.org/10.3390/nu15010145.
272. Maeda-Yamamoto, M.; Honmou, O.; Sasaki, M.; Haseda, A.; Kagami-Katsuyama, H.; Shoji, T.; Namioka,
A.; Namioka, T.; Magota, H.; Oka, S.; et al. The Impact of Purple-Flesh Potato (Nutrients 2022, 14.
https://doi.org/10.3390/nu14122446.
273. Barfoot, K.L.; Forster, R.; Lamport, D.J. Mental Health in New Mothers: A Randomised Controlled Study
into the Effects of Dietary Flavonoids on Mood and Perceived Quality of Life. Nutrients 2021, 13.
https://doi.org/10.3390/nu13072383.
274. Parilli-Moser, I.; Domínguez-López, I.; Trius-Soler, M.; Castellví, M.; Bosch, B.; Castro-Barquero, S.; Estruch,
R.; Hurtado-Barroso, S.; Lamuela-Raventós, R.M. Consumption of peanut products improves memory and
stress response in healthy adults from the ARISTOTLE study: A 6-month randomized controlled trial. Clin.
Nutr. (Edinb. Scotl. ) 2021, 40, 5556–5567. https://doi.org/10.1016/j.clnu.2021.09.020.
275. Bourdel-Marchasson, I.; Ostan, R.; Regueme, S.C.; Pinto, A.; Pryen, F.; Charrouf, Z.; d'Alessio, P.; Baudron,
C.R.; Guerville, F.; Durrieu, J.; et al. Quality of Life: Psychological Symptoms-Effects of a 2-Month Healthy
Diet and Nutraceutical Intervention; A Randomized, Open-Label Intervention Trial (RISTOMED).
Nutrients 2020, 12. https://doi.org/10.3390/nu12030800.
276. Park, M.; Choi, J.; Lee, H.J. Flavonoid-Rich Orange Juice Intake and Altered Gut Microbiome in Young
Adults with Depressive Symptom: A Randomized Controlled Study. Nutrients 2020, 12.
https://doi.org/10.3390/nu12061815.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
34 of 6
277. Smetanka, A.; Stara, V.; Farsky, I.; Tonhajzerova, I.; Ondrejka, I. Pycnogenol supplementation as an adjunct
treatment for antidepressant-induced sexual dysfunction. Physiol Int 2019, 106, 59–69.
https://doi.org/10.1556/2060.106.2019.02.
278. Kanchanatawan, B.; Tangwongchai, S.; Sughondhabhirom, A.; Suppapitiporn, S.; Hemrunrojn, S.; Carvalho,
A.F.; Maes, M. Add-on Treatment with Curcumin Has Antidepressive Effects in Thai Patients with Major
Depression: Results of a Randomized Double-Blind Placebo-Controlled Study. Neurotox Res 2018, 33, 621–
633. https://doi.org/10.1007/s12640-017-9860-4.
279. Khalid, S.; Barfoot, K.L.; May, G.; Lamport, D.J.; Reynolds, S.A.; Williams, C.M. Effects of Acute Blueberry
Flavonoids on Mood in Children and Young Adults. Nutrients 2017, 9. https://doi.org/10.3390/nu9020158.
280. Esmaily, H.; Sahebkar, A.; Iranshahi, M.; Ganjali, S.; Mohammadi, A.; Ferns, G.; Ghayour-Mobarhan, M.
An investigation of the effects of curcumin on anxiety and depression in obese individuals: A randomized
controlled trial. Chin J Integr Med 2015, 21, 332–338. https://doi.org/10.1007/s11655-015-2160-z.
281. Terauchi, M.; Horiguchi, N.; Kajiyama, A.; Akiyoshi, M.; Owa, Y.; Kato, K.; Kubota, T. Effects of grape seed
proanthocyanidin extract on menopausal symptoms, body composition, and cardiovascular parameters in
middle-aged women: a randomized, double-blind, placebo-controlled pilot study. Menopause 2014, 21, 990–
996. https://doi.org/10.1097/GME.0000000000000200.
282. Sathyapalan, T.; Beckett, S.; Rigby, A.S.; Mellor, D.D.; Atkin, S.L. High cocoa polyphenol rich chocolate
may reduce the burden of the symptoms in chronic fatigue syndrome. Nutr. J. 2010, 9, 55.
https://doi.org/10.1186/1475–2891–9–55.
283. Malau, I.A.; Chang, J.P.-C.; Lin, Y.-W.; Chang, C.-C.; Chiu, W.-C.; Su, K.-P. Omega-3 Fatty Acids and
Neuroinflammation in Depression: Targeting Damage-Associated Molecular Patterns and Neural
Biomarkers. Cells 2024, 13, 1791.
284. Wang, J.; Behl, T.; Rana, T.; Sehgal, A.; Wal, P.; Saxena, B.; Yadav, S.; Mohan, S.; Anwer, M.K.; Chigurupati,
S. Exploring the pathophysiological influence of heme oxygenase-1 on neuroinflammation and depression:
A study of phytotherapeutic-based modulation. Phytomedicine 2024, 155466.
285. Haase, J.; Brown, E. Integrating the monoamine, neurotrophin and cytokine hypotheses of depression—a
central role for the serotonin transporter? Pharmacol. Ther. 2015, 147, 1–11.
286. Halaris, A. Inflammation and depression but where does the inflammation come from? Curr. Opin.
Psychiatry 2019, 32, 422–428.
287. Zhao, R.; Wang, J.; Chung, S.K.; Xu, B. New insights into anti-depression effects of bioactive
phytochemicals. Pharmacol. Res. 2024, 107566.
288. Yoon, S.; Iqbal, H.; Kim, S.M.; Jin, M. Phytochemicals that act on synaptic plasticity as potential prophylaxis
against stress-induced depressive disorder. Biomol. Ther. 2023, 31, 148.
289. Ramos-Hryb, A.B.; Cunha, M.P.; Kaster, M.P.; Rodrigues, A.L.S. Natural polyphenols and terpenoids for
depression treatment: Current status. Stud. Nat. Prod. Chem. 2018, 55, 181–221.
290. Shi, X.; Fu, Y.; Zhang, S.; Ding, H.; Chen, J. Baicalin attenuates subarachnoid hemorrhagic brain injury by
modulating blood-brain barrier disruption, inflammation, and oxidative damage in mice. Oxidative Med.
Cell. Longev. 2017, 2017, 1401790.
291. Zamanian, M.Y.; Soltani, A.; Khodarahmi, Z.; Alameri, A.A.; Alwan, A.M.; Ramírez-Coronel, A.A.; Obaid,
R.F.; Abosaooda, M.; Heidari, M.; Golmohammadi, M. Targeting Nrf2 signaling pathway by quercetin in
the prevention and treatment of neurological disorders: An overview and update on new developments.
Fundam. Clin. Pharmacol. 2023, 37, 1050–1064.
292. Deepika; Maurya, P.K. Health benefits of quercetin in age-related diseases. Molecules 2022, 27, 2498.
293. Grabacka, M.M.; Gawin, M.; Pierzchalska, M. Phytochemical modulators of mitochondria: The search for
chemopreventive agents and supportive therapeutics. Pharmaceuticals 2014, 7, 913–942.
294. Tanaka, M.; Szatmári, I.; Vécsei, L. Quinoline Quest: Kynurenic Acid Strategies for Next-Generation
Therapeutics via Rational Drug Design. 2025.
295. Mu, D.; Ma, Q. A review of antidepressant effects and mechanisms of three common herbal medicines:
Panax ginseng, Bupleurum chinense, and Gastrodia elata. CNS Neurol. Disord. -Drug Targets-CNS Neurol.
Disord. ) 2023, 22, 1164–1175.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
35 of 6
296. Bozzuto, G.; Calcabrini, A.; Colone, M.; Condello, M.; Dupuis, M.L.; Pellegrini, E.; Stringaro, A.
Phytocompounds and nanoformulations for anticancer therapy: A review. Molecules 2024, 29, 3784.
297. Aburel, O.M.; Pavel, I.Z.; Dănilă, M.D.; Lelcu, T.; Roi, A.; Lighezan, R.; Muntean, D.M.; Rusu, L.C.
Pleiotropic effects of eugenol: The good, the bad, and the unknown. Oxidative Med. Cell. Longev. 2021, 2021,
3165159.
298. Khan, A.; Jahan, S.; Imtiyaz, Z.; Alshahrani, S.; Antar Makeen, H.; Mohammed Alshehri, B.; Kumar, A.;
Arafah, A.; Rehman, M.U. Neuroprotection: Targeting multiple pathways by naturally occurring
phytochemicals. Biomedicines 2020, 8, 284.
299. Lippert, A.; Renner, B. Herb–drug interaction in inflammatory diseases: Review of phytomedicine and
herbal supplements. J. Clin. Med. 2022, 11, 1567.
300. Tayeb, B.A.; Kusuma, I.Y.; Osman, A.A.; Minorics, R. Herbal compounds as promising therapeutic agents
in precision medicine strategies for cancer: A systematic review. J. Integr. Med. 2024.
301. Lee, G.; Bae, H. Therapeutic effects of phytochemicals and medicinal herbs on depression. BioMed Res. Int.
2017, 2017, 6596241.
302. Dobrek, L.; Głowacka, K. Depression and its phytopharmacotherapy—a narrative review. Int. J. Mol. Sci.
2023, 24, 4772.
303. Singh, S.K.; Rashid, M.; Chaturvedi, S.; Agarwal, A.; Chauhan, D.; Gayen, J.R.; Wahajuddin, M. Preclinical
pharmacokinetics, absolute bioavailability and dose proportionality evaluation of bioactive phytochemical
Withanone in rats. Bioorganic Chem. 2025, 155, 108128.
304. Barani, M.; Sangiovanni, E.; Angarano, M.; Rajizadeh, M.A.; Mehrabani, M.; Piazza, S.; Gangadharappa,
H.V.; Pardakhty, A.; Mehrbani, M.; Dell’Agli, M. Phytosomes as innovative delivery systems for
phytochemicals: A comprehensive review of literature. Int. J. Nanomed. 2021, 6983-7022.
305. Gouws, C.; Hamman, J.H. What are the dangers of drug interactions with herbal medicines? Expert Opin.
Drug Metab. Toxicol. 2020, 16, 165–167.
306. Holleran, G.; Scaldaferri, F.; Gasbarrini, A.; Currò, D. Herbal medicinal products for inflammatory bowel
disease: A focus on those assessed in double-blind randomised controlled trials. Phytother Res 2020, 34, 77–
93. https://doi.org/10.1002/ptr.6517.
307. Murphy, E.; McMahon, F.J. Pharmacogenetics of antidepressants, mood stabilizers, and antipsychotics in
diverse human populations. Discov Med 2013, 16, 113–122.
308. Zhao, R.; Wang, J.; Chung, S.K.; Xu, B. New insights into anti-depression effects of bioactive
phytochemicals. Pharmacol Res 2025, 212, 107566. https://doi.org/10.1016/j.phrs.2024.107566.
309. Nabavi, S.M.; Daglia, M.; Braidy, N.; Nabavi, S.F. Natural products, micronutrients, and nutraceuticals for
the treatment of depression: A short review. Nutr Neurosci 2017, 20, 180–194.
https://doi.org/10.1080/1028415x.2015.1103461.
310. Iorio, R.; Celenza, G.; Petricca, S. Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the
Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-
Mediated Neuroinflammation. Antioxid. (Basel) 2022, 11. https://doi.org/10.3390/antiox11061199.
311. Magni, G.; Riboldi, B.; Petroni, K.; Ceruti, S. Flavonoids bridging the gut and the brain: Intestinal metabolic
fate, and direct or indirect effects of natural supporters against neuroinflammation and neurodegeneration.
Biochem Pharmacol 2022, 205, 115257. https://doi.org/10.1016/j.bcp.2022.115257.
312. Coen, M.; Want, E.J.; Clayton, T.A.; Rhode, C.M.; Hong, Y.S.; Keun, H.C.; Cantor, G.H.; Metz, A.L.;
Robertson, D.G.; Reily, M.D.; et al. Mechanistic aspects and novel biomarkers of responder and non-
responder phenotypes in galactosamine-induced hepatitis. J Proteome Res 2009, 8, 5175–5187.
https://doi.org/10.1021/pr9005266.
313. Karczewski, K.J.; Snyder, M.P. Integrative omics for health and disease. Nat Rev Genet 2018, 19, 299–310.
https://doi.org/10.1038/nrg.2018.4.
314. Almeida, S.S.; Zizzi, F.B.; Cattaneo, A.; Comandini, A.; Di Dato, G.; Lubrano, E.; Pellicano, C.; Spallone, V.;
Tongiani, S.; Torta, R. Management and Treatment of Patients With Major Depressive Disorder and
Chronic Diseases: A Multidisciplinary Approach. Front Psychol 2020, 11, 542444.
https://doi.org/10.3389/fpsyg.2020.542444.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
36 of 6
315. Pepe, M.; Bartolucci, G.; Marcelli, I.; Pesaresi, F.; Brugnami, A.; Caso, R.; Fischetti, A.; Grisoni, F.; Mazza,
M.; Camardese, G.; et al. The Patient's Perspective on the Effects of Intranasal Esketamine in Treatment-
Resistant Depression. Brain Sci 2023, 13. https://doi.org/10.3390/brainsci13101494.
316. Stolfi, F.; Abreu, H.; Sinella, R.; Nembrini, S.; Centonze, S.; Landra, V.; Brasso, C.; Cappellano, G.; Rocca,
P.; Chiocchetti, A. Omics approaches open new horizons in major depressive disorder: from biomarkers to
precision medicine. Front Psychiatry 2024, 15, 1422939. https://doi.org/10.3389/fpsyt.2024.1422939.
317. Sun, L.; Liu, T.; Liu, J.; Gao, C.; Zhang, X. Physical exercise and mitochondrial function: New therapeutic
interventions for psychiatric and neurodegenerative disorders. Front Neurol 2022, 13, 929781.
https://doi.org/10.3389/fneur.2022.929781.
318. Wilkinson, S.T.; Holtzheimer, P.E.; Gao, S.; Kirwin, D.S.; Price, R.B. Leveraging Neuroplasticity to Enhance
Adaptive Learning: The Potential for Synergistic Somatic-Behavioral Treatment Combinations to Improve
Clinical Outcomes in Depression. Biol Psychiatry 2019, 85, 454–465.
https://doi.org/10.1016/j.biopsych.2018.09.004.
319. Ashdown-Franks, G.; Firth, J.; Carney, R.; Carvalho, A.F.; Hallgren, M.; Koyanagi, A.; Rosenbaum, S.;
Schuch, F.B.; Smith, L.; Solmi, M.; et al. Exercise as Medicine for Mental and Substance Use Disorders: A
Meta-review of the Benefits for Neuropsychiatric and Cognitive Outcomes. Sports Med 2020, 50, 151–170.
https://doi.org/10.1007/s40279-019-01187-6.
320. Ahn, J.; Kim, M. Effects of exercise therapy on global cognitive function and, depression in older adults
with mild cognitive impairment: A systematic review and meta-analysis. Arch Gerontol Geriatr 2023, 106,
104855. https://doi.org/10.1016/j.archger.2022.104855.
321. Gamage, E.; Orr, R.; Travica, N.; Lane, M.M.; Dissanayaka, T.; Kim, J.H.; Grosso, G.; Godos, J.; Marx, W.
Polyphenols as novel interventions for depression: Exploring the efficacy, mechanisms of action, and
implications for future research. Neurosci Biobehav Rev 2023, 151, 105225.
https://doi.org/10.1016/j.neubiorev.2023.105225.
322. Singh, N.; Garg, M.; Prajapati, P.; Singh, P.K.; Chopra, R.; Kumari, A.; Mittal, A. Adaptogenic property of
Asparagus racemosus: Future trends and prospects. Heliyon 2023, 9.
323. Tanaka, M.; Szabó, Á.; Vécsei, L.; Giménez-Llort, L. Emerging translational research in neurological and
psychiatric diseases: from in vitro to in vivo models. 2023, 24, 15739.
324. Kessler, R.C.; van Loo, H.M.; Wardenaar, K.J.; Bossarte, R.M.; Brenner, L.; Ebert, D.; De Jonge, P.;
Nierenberg, A.; Rosellini, A.; Sampson, N. Using patient self-reports to study heterogeneity of treatment
effects in major depressive disorder. Epidemiol. Psychiatr. Sci. 2017, 26, 22–36.
325. Malgaroli, M.; Calderon, A.; Bonanno, G.A. Networks of major depressive disorder: A systematic review.
Clin. Psychol. Rev. 2021, 85, 102000.
326. Mew, E.J.; Monsour, A.; Saeed, L.; Santos, L.; Patel, S.; Courtney, D.B.; Watson, P.N.; Szatmari, P.; Offringa,
M.; Monga, S. Systematic scoping review identifies heterogeneity in outcomes measured in adolescent
depression clinical trials. J. Clin. Epidemiol. 2020, 126, 71–79.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those
of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s)
disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or
products referred to in the content.
Preprints.org (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 May 2025 doi:10.20944/preprints202504.0573.v3
