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Received: 6 April 2025
Revised: 2 May 2025
Accepted: 3 May 2025
Published: 7 May 2025
Citation: Figueiredo Godoy, A.C.;
Frota, F.F.; Araújo, L.P.; Valenti, V.E.;
Pereira, E.d.S.B.M.; Detregiachi, C.R.P.;
Galhardo, C.M.; Caracio, F.C.; Haber,
R.S.A.; Fornari Laurindo, L.; et al.
Neuroinflammation and Natural
Antidepressants: Balancing Fire with
Flora. Biomedicines 2025,13, 1129.
https://doi.org/10.3390/
biomedicines13051129
Copyright: © 2025 by the authors.
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(https://creativecommons.org/
licenses/by/4.0/).
Review
Neuroinflammation and Natural Antidepressants: Balancing Fire
with Flora
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. Galhardi 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,*,†
1Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR),
Marília 17525-902, SP, Brazil; larissaparreiraaraujo@gmail.com (L.P.A.)
2Autonomic Nervous System Center, School of Philosophy and Sciences, São Paulo State University,
Marília 17525-900, SP, Brazil
3Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine,
Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil; lucaslaurindo@unimar.br (L.F.L.)
4School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília 17519-030, SP, Brazil
5Danube Neuroscience Research Laboratory, HUN-REN-SZTE Neuroscience Research Group, Hungarian
Research Network, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
6Research Coordinator at UNIMAR Charity Hospital, Marília 17525-902, SP, Brazil
*Correspondence: tanaka.masaru.1@med.u-szeged.hu (M.T.); smbarbalho@gmail.com (S.M.B.);
Tel.: +36-62-342-847 (M.T.); +55-(14)-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, mitochon-
drial dysfunction, and complicated metabolic abnormalities. Traditional antidepressants
frequently fall short, highlighting the urgent need for new, safer, and more acceptable
therapeutic techniques. Phytochemicals, i.e., 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, polyphe-
nols, flavonoids, and alkaloids in lowering depressed symptoms. Consistent data show
that these substances have neuroprotective, anti-inflammatory, and antioxidant properties,
altering neuroimmune interactions, reducing oxidative damage, and improving mitochon-
drial 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 neurotrophic factor (BDNF).
Despite promising results, the heterogeneity in study designs, phytochemical formulations,
and patient demographics highlights the importance of thorough, standardized clinical
studies. Conclusions: This review identifies phytochemicals as compelling adjuvant or
independent therapies in depression treatment, providing multimodal mechanisms and
enhanced tolerability. Additional research into improved dosage, pharmacokinetics, long-
term safety, and integrative therapy approaches is essential. Using phytotherapeutics 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; neuroinflamma-
tion; oxidative stress; natural antidepressants; tryptophan; kynurenine; brain-derived
neurotrophic factor (BDNF); mitochondrial dysfunction; curcumin
Biomedicines 2025,13, 1129 https://doi.org/10.3390/biomedicines13051129
Biomedicines 2025,13, 1129 2 of 35
1. Introduction
Major depressive disorder (MDD) is a common and debilitating mental condition
characterized by persistent low mood, anhedonia, cognitive dysfunction, and severe im-
pairments in occupational, social, and interpersonal functioning [
1
]. Aside from its impact
on quality of life, MDD remains the leading psychiatric contributor to global suicide mor-
tality, 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 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 will 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 neuroplastic 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 affective, cognitive, and behav-
ioral symptoms [
10
–
12
]. Figure 1summarizes the primary neurobiological mechanisms
involved in MDD pathogenesis. The purpose of this state-of-the-art critical narrative re-
view 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.
Emerging evidence underscores the critical role of neuroinflammatory processes in
the pathogenesis 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 dysreg-
ulation and cognitive impairment, which are hallmarks of depressive pathology [
15
–
18
].
Furthermore, metabolomic profiling investigations in MDD patients regularly reveal abnor-
malities in a variety of circulating metabolites, including tryptophan, tyrosine, methionine,
valine, phenylalanine, pyruvate, kynurenic acid, and deoxycholic acid [
19
]. These metabolic
disruptions are closely associated with impaired neuroprotective mechanisms, increased
oxidative burden, dysregulated apoptotic signaling, and chronic low-grade inflamma-
tion [
20
–
22
]. Collectively, these pathophysiological alterations foster a neurobiological
environment conducive to the initiation and persistence of depressive symptoms, particu-
larly 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, re-
main essential in the treatment of MDD, their therapeutic efficacy is primarily mediated
by modulation of monoaminergic neurotransmission, specifically by increasing synaptic
concentrations of serotonin and norepinephrine [
4
]. Despite their clinical value, emerging
evidence suggests that while antidepressants are considered 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
Biomedicines 2025,13, 1129 3 of 35
alternative therapy approaches [
25
]. Phytotherapeutics have recently rekindled scientific
attention due to their historical use, biological plausibility, cost effectiveness, and accept-
able side-effect profiles. Medicinal plants have historically provided bioactive chemicals
with neuroprotective, anti-inflammatory, and neuromodulatory effects [
26
]. These natural
compounds persist in guiding the discovery and development of innovative pharmaco-
logical medicines, presenting a potentially beneficial adjunctive strategy for persons with
treatment-resistant or recurrent depression [27,28].
Biomedicines 2025, 13, x FOR PEER REVIEW 2 of 37
Keywords: major depressive disorder (MDD); plant-based therapeutics; neuroinflammation;
oxidative stress; natural antidepressants; tryptophan; kynurenine; brain-derived neurotrophic
factor (BDNF); mitochondrial dysfunction; 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 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 will
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
neuroplastic 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 affective, cognitive, and behavioral symptoms [10–12]. Figure
1 summarizes the primary neurobiological 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). Multiple 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 neu-
roinflammation, driven by activated microglia and astrocytes. These cells increase reactive nitrogen
and oxygen species (NO and ROS), impair mitochondrial function, and alter kynurenine (KYN)
pathway dynamics, reducing kynurenic acid (KYNA) and promoting neurotoxicity. Dysregulated
serotonin and gamma-aminobutyric acid (GABA) signaling, alongside diminished brain-derived
neurotrophic factor (BDNF), further impair synaptic plasticity and emotional regulation.
↑
: increase;
↓: decrease.
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 increasingly recognized for their therapeutic effects, particularly in
situations characterized by oxidative stress and chronic inflammation [
30
]. Aside from their
well-established antioxidant and anti-inflammatory properties, phytochemicals also have
vasoprotective and cardiometabolic effects, making them prospective agents in the preven-
tion and treatment of complex, multifactorial illnesses [
31
]. Phytocompounds have received
a lot of attention in neuropsychiatry because of their possible role in altering important neu-
robiological 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
Biomedicines 2025,13, 1129 4 of 35
clinical trials indicate that several of these botanicals have antidepressant-like properties
via processes involving monoaminergic regulation, neurotrophic signaling, and neuroin-
flammatory cascade reduction [
35
]. As a result, the incorporation of phytocompounds into
therapeutic frameworks for MDD is increasingly being investigated both as standalone
treatments and as adjuncts to traditional pharmacotherapy [
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 cognitive function, both of which are highly susceptible to disruption by psychiatric
and neurological disorders [
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 current treatment paradigms,
their limitations—namely delayed onset of action, treatment resistance, and undesirable
side-effect profiles—have driven the search for alternative and adjunctive interventions
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 neuromod-
ulatory capabilities [
44
]. Recent research has highlighted the intricate connection between
phytochemicals, neuroinflammation, 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. Notably, 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 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 seminal 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 protocols. Our theory-driven, expert-
guided evidence map inevitably introduces selection bias; some pertinent 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
were streamlined. These interconnected processes are herein discussed in focused sections
with minimal repetition, ensuring conceptual continuity without diluting analytical depth.
2. Neuroinflammation: A Core Driver of Severe Depression
Emerging data suggest that neuroinflammation plays a critical role in the pathophys-
iology of MDD, particularly in its more severe and treatment-resistant forms [
47
]. With
immune-mediated processes significantly influencing brain function, inflammation in the
Biomedicines 2025,13, 1129 5 of 35
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 charac-
terized 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 therapies, 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 depression 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, interleukin (IL)-1
β
can interfere with neurotransmitter sys-
tems and trigger more inflammatory substances, 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 cellu-
lar sentinels remain on high alert, they release toxic mediators that compromise neuronal
functioning and hamper communication between circuits [
60
]. Similar inflammatory activ-
ity 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 neuroplasticity 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 [
47
,
63
]. Neuroinflammation is a key factor in the pathogenesis of MDD, with
activation of the NLRP3 inflammasome leading to elevated pro-inflammatory cytokines like
IL-1
β
and IL-18, which are linked to depressive symptoms [
64
–
66
]. Activation of pattern
recognition receptors, such as Toll-like receptor 4 (TLR4) on microglia and astrocytes, can
induce NF-
κ
B-driven cytokine production when damage or pathogens are detected [
67
].
Peripheral immune cells invade the CNS via a weakened blood–brain barrier, exacerbating
local inflammation and neurotoxicity [
68
]. Chronic inflammation exacerbates oxidative and
nitrosative stress, damages mitochondria, and enhances glutamate excitotoxicity through
reduced astrocytic reuptake, resulting in neuronal injury [
69
]. Dysfunctional mitochondria
produce pro-inflammatory chemicals, which promote inflammation [
70
]. Chronic stress-
induced cortisol elevations activate microglia, whereas gut–brain axis abnormalities allow
bacterial endotoxins to worsen systemic inflammation [
71
]. Last but not least, inflammatory
kynurenine pathway activation lowers serotonin synthesis, which feeds a vicious cycle of
depression [72].
Inflammatory cascades, which are characterized by sustained activation of cytokines
and immune responses, are not limited to depression; they are also found in various
chronic infections, neurodegenerative disorders such as multiple sclerosis, and peri-
natal depression, demonstrating their widespread influence across pathologies [
73
–
79
].
Chronic infections continue to excite immune cells, resulting in elevated amounts of pro-
inflammatory cytokines, which contribute to mood and cognitive impairment [
80
]. Analo-
gously, autoimmune-mediated inflammation is a feature of neurodegenerative diseases like
multiple sclerosis, in which protracted immune responses harm brain tissue, aggravating
symptoms of depression [
75
]. In prenatal depression, immunological activation triggered by
hormonal and physiological changes greatly increases inflammation, affecting both mater-
nal mood and child outcomes [
81
]. Furthermore, immunological dysregulation frequently
Biomedicines 2025,13, 1129 6 of 35
interacts with metabolic changes such as neuroendocrine dysfunction, gut microbiota dys-
biosis, and mitochondrial abnormalities, all of which exacerbate depressive states [
82
–
85
].
Neuroendocrine disruptions, such as cortisol imbalance due to hypothalamic–pituitary–
adrenal axis dysfunction, exacerbate inflammation and depressive symptoms [
86
]. Gut
dysbiosis promotes systemic inflammation by increasing intestinal permeability and endo-
toxin exposure, whereas mitochondrial dysfunction impairs cellular energy metabolism
and increases oxidative stress [
87
]. These interconnected inflammatory and metabolic
abnormalities highlight the complicated, diverse pathophysiology of depression.
Given the importance of neuroinflammation in the pathogenesis of severe and
treatment-resistant depression, identifying effective therapeutic strategies that target in-
flammation is critical [
47
,
88
]. Notably, accumulating evidence suggests that phytochemical
therapies, such as polyphenols, may provide neuroprotective advantages by inhibiting
inflammatory pathways and lowering neuronal death, making them a promising adjunct
method for treating MD [
73
,
74
]. Natural substances can protect neurons by modulating
inflammation, inhibiting NF-
κ
B activation, and reducing oxidative stress. Furthermore,
polyphenols may repair dysregulated neurotransmission and increase mitochondrial func-
tion, addressing the basic metabolic abnormalities seen in depressed states [
89
]. Because
neuroinflammation is so tightly linked to metabolic dysfunction, immunological dysreg-
ulation, and neuronal degeneration, therapies that target numerous inflammatory and
apoptotic pathways at the same time may produce better therapeutic results [
90
]. Future
research should emphasize investigating the entire therapeutic potential of phytochemicals
and comparable molecules as supplemental 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 [
90
]. Characterized by an imbalance
between reactive oxygen species (ROS) and antioxidant defenses, oxidative stress quietly
undermines neuronal integrity and brain function [
91
]. Intriguingly, mounting evidence
suggests that this biochemical imbalance not only parallels depressive symptoms but may
actively drive their persistence and severity [
92
]. From antioxidant depletion to mitochon-
drial dysfunction, oxidative stress orchestrates a cascade of cellular disruptions [
93
]. 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
neutralize them through antioxidant defenses, leading to cellular harm via the degradation
of essential biomolecules such as proteins, lipids, and nucleic acids [
94
,
95
]. In individuals
with depression, this imbalance is particularly pronounced due to significantly reduced
levels of key antioxidants, including zinc, vitamin E, and coenzyme Q10, amplifying cellular
vulnerability and intensifying neurodegenerative processes [
91
,
96
]. These antioxidant
deficits facilitate oxidative damage to neuronal membranes, impair mitochondrial function,
and disrupt neurotransmission, further exacerbating depressive symptoms [
95
]. Zinc
deficiency, for example, diminishes neuroplasticity and impairs glutamatergic signaling,
whereas insufficient vitamin E reduces neuronal protection against lipid peroxidation [
97
].
Likewise, low levels of coenzyme Q10 impair mitochondrial respiration, increasing ROS
production and energy deficits in neurons [
98
]. Collectively, this heightened oxidative
state promotes neuronal apoptosis and inflammation, reinforcing a destructive cycle that
sustains and deepens depressive pathology [
89
]. Thus, addressing oxidative imbalances
through antioxidant supplementation or dietary interventions could potentially mitigate
cellular damage and improve therapeutic outcomes in MDD.
Biomedicines 2025,13, 1129 7 of 35
Alterations in tryptophan metabolism significantly contribute to oxidative stress
in MDD, primarily 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
,
99
,
100
]. These toxic intermediates promote neuronal damage through
enhanced generation of ROS, exacerbating oxidative stress and accelerating cellular injury
within vulnerable brain regions [
91
]. Furthermore, reduced tryptophan availability itself
can intensify the formation of free radicals, damaging essential biomolecules including
deoxyribonucleic acid (DNA), lipids, and proteins [
93
]. This cascade creates a destructive
cycle of oxidative damage, inflammation, and impaired neurotransmission, significantly
correlating with increased severity of depressive symptoms [
91
]. The resulting neuronal
dysfunction, loss of synaptic plasticity, and impaired mitochondrial performance contribute
to the pathophysiology of depression [
101
]. Therapeutic interventions targeting the kynure-
nine pathway or enhancing tryptophan availability thus hold considerable potential for
reducing oxidative damage and alleviating depressive symptoms.
Mitochondrial dysfunction—including structural alterations and disrupted energy
metabolism—significantly escalates ROS production, directly promoting neuroinflamma-
tion and cognitive decline in depressive disorders [
102
–
105
]. Accumulation of dysfunctional
mitochondria further exacerbates neuronal damage, perpetuating chronic inflammatory
cycles within the brain [
106
,
107
]. Specifically, 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 cy-
tokine production [108]. Disrupted mitochondrial calcium buffering elevates intracellular
calcium, triggering oxidative damage, microglial activation, and amplified inflammatory
signaling [
109
]. Moreover, mitochondrial energy deficits dysregulate AMP-activated pro-
tein kinase (AMPK) signaling, causing aberrant mammalian target of rapamycin (mTOR)
activation that sustains inflammatory responses [
110
]. Increased ROS production triggers
transcription factors such as NF-
κ
B, leading to ongoing release of inflammatory cytokines
(IL-6 and TNF-
α
) [
111
]. Reduced mitochondrial health also lowers NAD
+
levels, which
weakens protective sirtuin signaling, while imbalanced iron levels encourage ferroptosis,
worsening oxidative damage [
90
,
112
]. Consequently, impaired neurogenesis and reduced
synaptic plasticity intensify cognitive deficits, reinforcing a destructive feedback loop of
mitochondrial-driven inflammation in depression [107].
Obesity-induced inflammation significantly heightens oxidative stress by increasing
adipokine secretion—such as IL-6, IL-1, and tumor necrosis factor-alpha—while simul-
taneously impairing insulin regulation, thus elevating risks for type 2 diabetes and de-
pression [
113
–
115
]. Chronic obesity also fosters leptin resistance, amplifying microglial
activation and further promoting inflammatory cascades within the brain [
116
]. Moreover,
lifestyle factors, particularly high-fat diets and sedentary behaviors, escalate ROS produc-
tion through enhanced mitochondrial
β
-oxidation and activation of nuclear factor kappa
B (NF-
κ
B) signaling, reinforcing inflammation and neuronal stress pathways [
117
–
121
].
Dietary saturated fats directly stimulate inflammasome complexes like NLRP3, causing
excessive IL-1
β
release and perpetuating neuroinflammation [
122
]. Additionally, obesity-
related hyperglycemia accelerates formation of advanced glycation end-products (AGEs),
activating inflammatory responses via AGE receptors on microglia [
123
]. High-fat diets
exacerbate gut microbiota disruption, increasing endotoxin leakage into circulation and
systemic inflammation while simultaneously lowering BDNF levels, impairing neuronal
resilience [
124
]. These interconnected metabolic, inflammatory, and behavioral mecha-
Biomedicines 2025,13, 1129 8 of 35
nisms 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 persistence of MDD [
95
]. 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 [
125
]. Through sustained production
of ROS and insufficient antioxidant defenses, oxidative stress damages cellular structures,
fuels neuroinflammation, and disrupts key neural circuits involved in mood regulation [
95
].
Its impact extends from molecular disruption to large-scale cognitive decline and emotional
dysregulation [
126
]. Addressing this underlying imbalance—via antioxidant therapies,
metabolic support, and targeted lifestyle changes—offers a promising direction for enhanc-
ing treatment response and improving long-term outcomes in individuals with depression.
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 [
127
]. In the context of
MDD, mitochondrial dysfunction has garnered growing attention as a hidden yet potent
driver of neurobiological disruption [
112
]. From impaired energy metabolism to excessive
ROS production, mitochondrial abnormalities appear to fuel the progression of depressive
symptoms [
89
]. This section delves into the emerging landscape of mitochondrial pathology
in depression—alongside innovative repair strategies—highlighting 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 [
85
]. In individuals
with MDD, mitochondrial abnormalities—such as structural degradation, disrupted mi-
tochondrial DNA (mtDNA), and impaired electron transport chain (ETC) function—lead
to excessive production of ROS, destabilizing neurotransmitter systems and exacerbat-
ing depressive symptoms [
103
,
128
–
130
]. These disturbances are intensified by additional
mitochondrial impairments [
131
]. Oxidative damage to mtDNA impairs the synthesis
of ETC components, while dysregulated biogenesis reduces the formation of healthy
mitochondria [
132
]. Imbalances in fusion and fission dynamics further fragment the mi-
tochondrial network, diminishing metabolic capacity and increasing susceptibility to cell
death [
133
]. Chronic stress-related calcium overload, inhibition of ETC complexes, and
glucocorticoid-induced suppression of mitochondrial maintenance genes all contribute
to dysfunction [
134
]. Moreover, a disrupted NAD
+
/NADH ratio and persistent expo-
sure to pro-inflammatory cytokines impair mitochondrial respiration, DNA repair, and
anti-inflammatory signaling [
135
]. Together, these interconnected mechanisms 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 of MDD, a growing
body of evidence highlights the role of biochemical markers—particularly those tied to
mitochondrial health—in its pathophysiology [
102
]. One such marker, methylmalonic
acid (MMA), is elevated in cases of vitamin B12 deficiency and has been shown to impair
succinate dehydrogenase activity, thereby increasing ROS production and promoting neu-
ronal injury [
136
–
140
]. Additional biomarkers further implicate mitochondrial dysfunction
in MDD. Elevated homocysteine, another consequence of B-vitamin deficiency, induces
oxidative stress and compromises mitochondrial DNA repair [
141
]. Increased brain lactate
and pyruvate levels suggest a shift from oxidative phosphorylation to inefficient anaerobic
metabolism [
142
]. Accumulation of acylcarnitines reflects disrupted fatty acid oxidation,
while elevated ammonia impairs mitochondrial respiration and contributes to neurotoxic-
Biomedicines 2025,13, 1129 9 of 35
ity [
143
]. 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 [
144
]. Deficiencies in coenzyme Q10 and imbalances in the
NAD
+
/NADH ratio further hinder ATP production and stress resilience [
145
]. Together,
these markers underscore the biochemical complexity and mitochondrial vulnerability
underlying depressive disorders. These observations resonate with broader neurodegen-
erative research frameworks, which emphasize the integration of imaging biomarkers,
inflammatory profiles, and metabolic signatures to characterize disease subtypes and guide
personalized intervention strategies [146].
Recent studies underscore several promising therapeutic strategies aimed at correcting
mitochondrial dysfunction in MDD [
147
]. Among them, mitochondrial transplantation—
either by replacing 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 [
148
]. 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 [
149
,
150
]. Beyond these,
mitochondria-targeted antioxidants like MitoQ and SkQ1 directly neutralize ROS within
mitochondria, improving membrane potential and behavioral outcomes [
151
]. Supple-
mentation with NAD
+
precursors (e.g., nicotinamide riboside) enhances mitochondrial
biogenesis and DNA repair via sirtuin activation [
152
]. Coenzyme Q10 boosts ATP produc-
tion, while PGC-1
α
activators such as resveratrol and AMPK activators promote mitochon-
drial renewal [
153
,
154
]. Other emerging strategies include inhibition of the mitochondrial
permeability transition pore (mPTP), ketogenic diets to optimize mitochondrial fuel use,
sirtuin activators to dampen inflammation, and L-carnitine derivatives that support fatty
acid oxidation [
155
–
158
]. Gene therapies targeting mtDNA mutations offer future avenues
for correcting mitochondrial defects at their source [159].
Ultimately, restoring mitochondrial health offers a compelling path forward in the treat-
ment of MDD. By integrating phytochemicals and other multimodal strategies—ranging
from targeted antioxidants to metabolic and genetic interventions—it may be possible to re-
duce oxidative damage, enhance energy metabolism, and reinforce neuronal resilience [
102
].
These approaches hold promise not only for symptom relief but also for addressing the
cellular dysfunctions at the core of depression’s pathology. Importantly, mitochondrial
fragility does not occur in isolation. Caloric excess, insulin 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 mitochon-
dria dysregulate appetite and glucose homeostasis via hypothalamic circuits, creating a
vicious cycle in which metabolic inflammation and mitochondrial dysfunction co-amplify
depressive 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 inflam-
mation 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 neuroimmune health. These modifiable behaviors may complement
pharmacological and phytochemical strategies, but a full exploration of their therapeutic ap-
plications warrants separate, dedicated analysis. Nutrition lies at the crossroads of physical
and mental health, yet its role in MDD is often underestimated [
160
]. 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 [
161
]. As
Biomedicines 2025,13, 1129 10 of 35
nutrient deficiencies and unhealthy food choices fuel neurobiological stress, depressive
symptoms may deepen, further eroding motivation for self-care [
162
]. This section explores
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 cycle.
Recent lines of evidence highlight that dietary behaviors, modulated by psychological
factors, significantly shape obesity risk and depressive symptoms by influencing nutrient
availability and metabolic function [
163
–
165
]. In particular, inadequate consumption of
vitamin B12, zinc, magnesium, folic acid, and vitamin B6 has been associated with elevated
susceptibility to MDD [
15
]. Moreover, diets dominated by high-fat convenience foods often
coincide with lower intake of fruits, vegetables, lean proteins, and whole grains, fueling
systemic inflammation and oxidative stress linked to depression pathogenesis [
166
–
168
].
These findings underscore the multifaceted interplay among dietary patterns, nutritional
deficiencies, and mood disorders, suggesting that suboptimal eating habits may potentiate
neurobiological pathways underlying depression [
169
]. By integrating these insights into
clinical practice, researchers and clinicians can more effectively target modifiable lifestyle
factors in conjunction with pharmacotherapy or psychotherapy [
170
]. Ultimately, develop-
ing evidence-based nutritional interventions, particularly those emphasizing nutrient-rich
whole foods, could mitigate depressive symptom severity while reducing broader metabolic
risk [
171
]. This comprehensive 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 adiposity promotes a pro-inflammatory milieu and metabolic dysregulation, po-
tentially exacerbating psychiatric symptomatology [
83
,
84
]. 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 insuffi-
cient sleep [
172
,
173
]. These lifestyle factors further elevate systemic inflammation and
oxidative stress, reinforcing a feedback loop that intensifies both mood disturbances and
metabolic risk [
47
]. Notably, recent studies underscore that even modest reductions in
body mass index or targeted interventions to improve sleep quality can substantially at-
tenuate neuroinflammatory processes linked to depression [
174
]. By highlighting these
interdependent mechanisms, the present review affirms the need for comprehensive man-
agement approaches that address not only psychological distress but also modifiable health
behaviors [
170
]. Tailored interventions that incorporate nutritional counseling, physical
activity regimens, and sleep hygiene may thus hold therapeutic promise, mitigating the
dual burden of metabolic and mental health complications [175,176]. Advancing this inte-
grative 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 depression [
170
]. Notably, adopting healthier diets characterized by
nutrient-dense foods, minimized refined sugars, and balanced macronutrient intake ap-
pears to diminish systemic inflammation and improve metabolic regulation [
177
]. When
combined with regular physical activity, such dietary patterns may enhance neuroplasticity
through increased neurotrophic factor release, supporting neuronal resilience [
178
]. 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 [
165
,
179
,
180
]. Al-
though these findings remain preliminary, they collectively suggest that targeted lifestyle
programs can serve as essential components of comprehensive treatment plans [
181
]. More-
Biomedicines 2025,13, 1129 11 of 35
over, recent randomized controlled trials affirm that multifaceted approaches integrating
nutritional counseling, behavioral interventions, and exercise regimens yield meaningful
improvements in depressive symptoms and metabolic risk profiles [
182
]. This perspective
highlights the need to broaden therapeutic frameworks beyond pharmacological paradigms
to address the complex interplay among diet, behavior, and psychological well-being in
depression [183].
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 [
161
]. By perpetuating neurobiological stress, this spi-
ral intensifies symptom severity and increases metabolic risk, reinforcing suboptimal
eating patterns [
161
]. 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 inflammation, and restoring
metabolic homeostasis [
170
]. Although rigorous trials remain necessary to pinpoint opti-
mal protocols, strategic nutritional interventions hold considerable promise for curtailing
the depressive spiral and advancing patient-centered treatment paradigms in MDD [184].
6. Rethinking Depression Care: Drugs and Natural Options
As our understanding of MDD deepens, so too does the landscape of its treatment—
now evolving beyond traditional pharmacotherapy toward more integrative, personalized
care [
185
]. While established medications like SSRIs and SNRIs remain central, their side-
effect profiles and limitations prompt a reexamination of what comprehensive care can
look like [
186
]. Intriguingly, nature itself may offer untapped solutions [
187
]. From time-
honored botanicals to novel phytochemicals, natural compounds are gaining recognition as
adjunctive or alternative treatments with promising efficacy and improved tolerability [
188
].
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 treatment models [
189
,
190
]. These teams typically include psychiatrists—
who oversee diagnosis, medication management, and complex case coordination—and
clinical psychologists or psychotherapists, who deliver evidence-based therapies such as
CBT, IPT, and mindfulness-based interventions [
191
,
192
]. Nutritionists or dietitians also
play a key role by addressing nutritional deficiencies and promoting anti-inflammatory
dietary patterns that support mitochondrial and mental health [
191
,
193
]. Exercise phys-
iologists or physical therapists prescribe tailored physical activity regimens to reduce
depressive symptoms and improve neurobiological function [
191
,
192
]. Primary care physi-
cians manage medical comorbidities that often worsen mood disorders, while pharmacists
ensure medication safety and adherence [
194
]. Complementary and integrative health
practitioners may introduce acupuncture, yoga, or nutraceutical support to reduce ox-
idative stress [
195
]. 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 [
196
]. This interdisciplinary approach is especially effective
in treatment-resistant or complex cases, offering a comprehensive strategy that integrates
biological, psychological, and social dimensions of depression [197–199].
Among pharmacological options for MDD, selective serotonin reuptake inhibitors
(SSRIs) remain the preferred first-line treatment due to their efficacy and relative tol-
erability. However, alternative classes such as serotonin–norepinephrine reuptake in-
hibitors (SNRIs), TCAs, monoamine oxidase inhibitors (MAOIs), and N-methyl-D-aspartate
(NMDA) antagonists provide additional therapeutic pathways, especially in treatment-
Biomedicines 2025,13, 1129 12 of 35
resistant cases [
10
,
200
–
202
]. Despite their benefits, these agents are associated with a range
of adverse effects [
203
]. SSRIs can cause gastrointestinal disturbances, insomnia, sexual
dysfunction, and in some cases, QTc prolongation—particularly with citalopram [
204
].
SNRIs like venlafaxine and duloxetine may induce hypertension, hepatotoxicity, and with-
drawal symptoms [
205
]. TCAs carry anticholinergic burdens (e.g., dry mouth, constipation)
and significant cardiovascular risks, including arrhythmias [
206
]. MAOIs, though effec-
tive, are limited by dietary restrictions and the risk of hypertensive crises or serotonin
syndrome [
207
]. Atypical antidepressants such as bupropion and mirtazapine offer varied
mechanisms but introduce risks like insomnia, weight gain, or seizure potential [
208
].
Novel agents, including NMDA antagonists like esketamine, present dissociative and car-
diovascular side effects [
209
]. Given these diverse profiles, careful, individualized treatment
planning is essential [
208
,
210
–
213
]. 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 [214,215].
These safety concerns have prompted increasing interest in alternative and comple-
mentary strategies that can enhance efficacy while reducing adverse effects [
216
]. Herbal
medicines are gaining recognition as potential adjuncts in the treatment of MDD [
217
].
These natural compounds may exert neuroprotective, anti-inflammatory, and mood-
regulating effects while offering better tolerability and fewer side effects compared to
standard medications [
218
–
220
]. By improving safety profiles and supporting long-term
adherence, herbal therapies may help address some of the limitations associated with
conventional pharmacological approaches [
221
]. Their integration into clinical practice
could also support a more holistic and individualized model of care [
222
]. As research
continues to explore these compounds’ mechanisms and clinical potential, combining
pharmacological and natural 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 [
223
]. Rich in bioactive compounds,
plants offer a diverse array of phytochemicals capable of modulating the same neurobiolog-
ical pathways targeted by conventional antidepressants—often with fewer side effects [
224
].
From polyphenols and flavonoids to carotenoids and alkaloids, these natural agents show
potential to combat oxidative stress, inflammation, and neurodegeneration [
225
]. 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, as bioactive compounds naturally derived from plants, have attracted
increasing interest for their ability to modulate key neurobiological pathways involved in
MDD [
37
,
226
]. 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 activity and reducing neuronal apoptosis [
74
,
227
].
Within this class, flavonoids such as luteolin effectively scavenge free radicals and sup-
press neuroinflammation [
227
–
229
], while carotenoids offer similar antidepressant benefits
through antioxidant and anti-inflammatory mechanisms [
230
–
233
]. 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 [
234
–
236
]. Additional polyphenols—including quercetin, EGCG, fisetin, apigenin,
and baicalein—further reinforce these effects by modulating inflammatory signaling, reduc-
Biomedicines 2025,13, 1129 13 of 35
ing oxidative stress, and promoting mitochondrial function [
237
–
240
]. 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,Mitrag-
yna speciosa,Astragalus membranaceus, and species within the Acorus genus have shown
antidepressant-like effects primarily through their anti-inflammatory and antioxidant prop-
erties [
32
,
34
,
241
–
243
]. These effects are echoed in other plant-derived compounds that act
on convergent molecular pathways [
130
]. Withanolides from Withania somnifera modu-
late the HPA axis, reduce pro-inflammatory cytokines like IL-6 and TNF-
α
, and elevate
BDNF levels, enhancing stress resilience [
244
]. Hericenones and erinacines from Hericium
erinaceus stimulate nerve growth factor synthesis, reduce oxidative stress, and improve
monoaminergic balance [
245
]. Ginsenosides from Panax ginseng and bacopasides from
Bacopa monnieri both boost mitochondrial efficiency, suppress neuroinflammation, and
promote neuroplasticity [
130
,
246
]. Other promising agents include honokiol from Magnolia
officinalis, paeoniflorin from Paeonia lactiflora, and berberine from Berberis species, all of
which influence oxidative, inflammatory, and neurotransmitter systems [
247
–
249
]. Rhyn-
chophylline and salidroside further contribute to this phytochemical network by protecting
neurons and regulating mood circuits [
250
]. Collectively, these compounds offer diverse
mechanisms for mitigating the multifaceted pathways underlying mood disorders by re-
ducing inflammation, alleviating oxidative stress, fine-tuning neurotransmitter balance,
and fostering neuroplasticity, thereby highlighting their integrative therapeutic potential.
Although plant-based interventions often exhibit fewer side effects than conventional
antidepressants, their clinical application still requires deeper investigation to refine optimal
dosing, clarify underlying mechanisms, and ensure long-term safety [
251
,
252
]. Nonetheless,
mounting evidence supports the potential of phytotherapeutics as effective, integrative
strategies for addressing the complex and multifactorial nature of MDD [
1
]. By targeting
neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurotransmitter
imbalances, these compounds offer a multi-pronged approach to mood regulation [
253
].
Their ability to enhance neurotrophic factors such as BDNF further strengthens their
therapeutic value [254]. As the field of psychoneuropharmacology evolves, incorporating
plant-derived compounds into treatment frameworks may improve outcomes for patients
who are unresponsive or intolerant to traditional therapies [
255
]. Collectively, these findings
highlight the critical need for continued clinical research on phytomedicines in mood
disorder management [
256
]. Figure 2illustrates select phytochemicals and their modulatory
effects on brain metabolism and neural function, underscoring their relevance as natural
allies in depression care.
Biomedicines 2025,13, 1129 14 of 35
Biomedicines 2025, 13, x FOR PEER REVIEW 14 of 37
Figure 2. Phytochemicals and the role in brain health and reduction in depression. HPA: hypotha-
lamic–pituitary–adrenal; BDNF: brain-derived neurotrophic factor; a: hypericin; b: coumarin; c: eu-
calyptol; d: resveratrol; e: curcumin; f: gallic acid; g: epicatechin. ↑: increase; ↓: decrease.
8. From Curcumin to Cocoa: Plant-Based Mood Solutions
The following interventional studies reveal a promising though heterogeneous body
of evidence 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 admin-
istered in monotherapy or adjunctive formats. Although sample sizes, duration, and de-
sign quality varied, most studies used validated depression scales and biochemical end-
points, supporting a neurobiological rationale for clinical translation.
In a well-structured randomized controlled trial, Soltani et al. [25] evaluated the im-
pact of nanocurcumin supplementation in individuals with coronary slow flow phenom-
enon (CSFP). The intervention led to improvements in depressive symptoms, physical and
Figure 2. Phytochemicals and the role in brain health and reduction in depression. HPA: hypothalamic–
pituitary–adrenal; BDNF: brain-derived neurotrophic factor; a: hypericin; b: coumarin; c: eucalyptol; d:
resveratrol; e: curcumin; f: gallic acid; g: epicatechin. ↑: increase; ↓: decrease.
8. From Curcumin to Cocoa: Plant-Based Mood Solutions
The following interventional studies reveal a promising though heterogeneous body
of evidence 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 adminis-
tered 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 psy-
chological health-related quality of life, and cardiometabolic parameters, with biochemical
assays confirming anti-inflammatory and antioxidant effects [
257
]. In another study exam-
Biomedicines 2025,13, 1129 15 of 35
ining quercetin effects in patients who have experienced myocardial infarction, the authors
did failed to not find significant antidepressant effects [258].
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 individuals with multiple sclerosis following polyphenol-rich interventions.
However, its narrow population limits generalizability to broader MDD cohorts [
259
]. 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, indicating neuromodula-
tory 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 tubero-
sum 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 confound-
ing 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 de-
pressive symptoms. Although standardized cognitive assessments were used, low group
sizes and a lack of blinding limited interpretive strength and COVID-19-related disrup-
tions likely impacted outcome validity. 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. [
260
] investigated high versus low polyphenol diets in the PPhIT
trial, noting improved psychological well-being in the high-polyphenol group using stan-
dardized lifestyle and mood assessments. Park, Choi, and Lee [
260
] similarly conducted
a placebo-controlled flavonoid study using orange juice and observed improvements in
depression alongside increased serum serotonin, BDNF, and reduced CRP—though the
small sample again limits external validity.
Smetanka et al. [
260
] focused on the potential for pycnogenol to mitigate SSRI-induced
sexual dysfunction in patients taking escitalopram. However, the open-label design and
simultaneous pharmacologic interventions created confounding that weakens causal infer-
ence. In the curcumin trial by Kanchanatawan et al. [
40
], methodological strengths included
matched placebo capsules and double-blinding, although prior treatments continued dur-
ing 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—suggesting potential underpowering or scale insensitivity. In a postmenopausal
population, Terauchi et al. [
33
] demonstrated that grape seed proanthocyanidins reduced
depressive symptoms in a dose-dependent manner, using validated questionnaires. How-
ever, 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) [
261
]. Hirose et al. [
262
] 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.
Biomedicines 2025,13, 1129 16 of 35
Cognitive-affective benefits of blueberry-derived flavonoids were tested in a crossover
design by Khalid et al. [
262
], involving both children and young adults. Stratified analysis
revealed reductions in depressogenic cognitive patterns two hours after consumption,
supporting the acute neuromodulatory potential of these compounds.
Lastly, Sathyapalan et al. [
262
] evaluated chocolate rich in cocoa liquor and polyphe-
nols 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 efficacy 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 reviewed studies underscore the emerging promise of phytocompounds
as adjunctive or standalone interventions for MDD (Table 1). While most trials reported
clinically meaningful 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. Nevertheless, several investiga-
tions reported inconclusive or modest effects, indicating the necessity of improved 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 rel-
evance. Future 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, geographic location, sample demographics, intervention type, control
conditions, outcome measures, and reported adverse events. The interventions include a range of
phytocompounds—such as curcumin, flavonoids, anthocyanins, and isoflavones—administered in
monotherapy or adjunctive formats. Outcomes were assessed via validated 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. [257] Iran 42 patients (CSFP)
aged 35–70
Nano-curcumin
80 mg/day, 12 weeks
Improved depression
and quality of life
Nausea, headache,
and diarrhea
Dehghani et al.
[258]Iran 76 individuals
aged 35–65
Quercetin
500 mg/day, 8 weeks
Marginal depression
improvement
Headache, joint
pain, and
abdominal
discomfort
Hajiluian et al.
[259]Iran
50 MS patients
with depression,
aged 18–55
Ellagic acid
180 mg/day,
12 weeks
Reduced inflammation
and depression None significant
Choi et al. [263]Republic of
Korea
40 young adults
aged 18–29 with
MDD
Flavonoid-rich
orange juice, 8 weeks
Significant
improvement in
depressive scores
None significant
Maeda-Yamamoto
et al. [264]Japan 15 older adults
aged 50–70
Anthocyanin-rich
potatoes, 8 weeks
Improved
psychological stress
response
None significant
Biomedicines 2025,13, 1129 17 of 35
Table 1. Cont.
Study [Ref.] Country Population Intervention Outcomes Side Effects
Parilli-Moser et al.
[265]U.K. 38 new mothers High-flavonoid diet,
2 weeks
Reduced anxiety and
improved social
relationships
None significant
Barfoot et al. [266] Spain 63 young
overweight adults
Roasted peanuts and
peanut butter,
6–7 months
Significant depression
reduction
Digestive
symptoms and
softer stools
Bourdel-
Marchasson et al.
[267]
Europe 125 elderly adults
aged ~70
Antioxidant-rich
diet, 2 months
Reduced depressive
symptoms None serious
Kontogianni et al.
[260]U.K.
99 mildly
hypertensive
adults aged 40–65
High vs. low
polyphenol diet,
8 weeks
Improved depressive
symptoms Not reported
Park et al. [268]Republic of
Korea
40 healthy adults
(20–30 years old)
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.
[269]Slovakia 67 adults with
MDD, aged 18–65
Pycnogenol with
escitalopram,
12 weeks
No additional benefit
compared to
escitalopram alone
None significant
Kanchanatawan
et al. [270]
Multinational
61 adults aged
18–63 with MDD
history
Curcumin
500–1500 mg/day,
12–16 weeks
Improved depression
scores (MADRS)
Dizziness, nausea,
insomnia, and
diarrhea
Terauchi et al.
[261]Italy 60 menopausal
women aged 50–55
Equol and
resveratrol, 12 weeks
Reduced depressive
symptoms (HAM-D) Mild diarrhea
Khalid et al. [271] U.K. Young adults and
children
Wild blueberry drink
(flavonoids), acute
administration
Improved positive
affect shortly after
consumption
None significant
Hirose et al. [262] Japan 87 menopausal
women aged 40–60
Isoflavone aglycones,
8 weeks
Improved anxiety and
modest depression
changes
None significant
Sathyapalan et al.
[272]U.K., Iran 30 obese adults Curcumin 1 g/day,
30 days
Reduced anxiety and
no significant
depression
improvement
None significant
Terauch et al. [273] Japan
91 menopausal
women
(40–60 years old)
GSPE (100 or
200 mg/day) vs.
placebo, 8 weeks
↓Anxiety
(dose-dependent); 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 and
calmness None
Clinical pilot [274] U.K. 10 adults High-polyphenol
chocolate, 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 factor; 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 proanthocyanidin
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 Rating 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: depolarization of the ventricles, consisting
of Q, R, and S waves; SQ: Shadow Queen; SRP: roasted peanuts in shell; WBB: wild blueberry drink.
Biomedicines 2025,13, 1129 18 of 35
9. Discussion
MDD remains a complex, multifaceted psychiatric condition that resists simple ex-
planations or treatments [
275
]. The primary goal of this review was to explore how
phytochemicals—naturally occurring plant-derived compounds—may offer a biologically
plausible and clinically relevant approach to modulating the intricate neurobiological dis-
ruptions observed in MDD [
1
]. Central to the disorder’s pathophysiology are sustained
neuroinflammation, oxidative stress, mitochondrial dysfunction, and metabolic distur-
bances, which interact to compromise neuronal integrity, synaptic plasticity, and emotional
regulation [276]. While monoaminergic deficits have long dominated depression theories,
current evidence indicates these downstream effects may be fueled by deeper cellular
and immune dysregulation [
277
]. Phytocompounds such as polyphenols, flavonoids, and
alkaloids appear to influence these upstream processes by attenuating pro-inflammatory cy-
tokines, scavenging ROS, restoring mitochondrial dynamics, and modulating neurotrophic
signaling [
136
]. In doing so, they challenge conventional paradigms and suggest a more
integrative neuropsychiatric model—one that views depression through the lens of sys-
temic inflammation and neuroenergetic compromise rather than solely neurotransmitter
depletion [278].
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 antidepressant-like effects across preclinical models
and emerging clinical studies. These benefits are mediated through a combination of
neuroprotective, anti-inflammatory, and antioxidant mechanisms. Notably, curcumin
has been shown to downregulate pro-inflammatory cytokines (e.g., IL-1
β
and 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 mitochondrial 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 [
279
]. One
of the most prominent mechanisms is the upregulation of BDNF, a key molecule in synaptic
plasticity, neurogenesis, and neuronal survival [226]. 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 [
280
]. Another
critical mechanism involves the inhibition of the NLRP3 inflammasome, a key driver of
neuroinflammation [
276
]. Polyphenols like quercetin and baicalein suppress this pathway,
leading to decreased release of pro-inflammatory cytokines such as IL-1
β
and IL-18 [
281
].
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 [
282
]. 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 [
283
]. Once in the CNS, they
can stabilize mitochondrial function, modulate calcium homeostasis, and maintain mem-
Biomedicines 2025,13, 1129 19 of 35
brane potential, all of which are disrupted in MDD [
284
]. 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 [
89
]. By targeting upstream cellular stressors
and restoring homeostatic balance across neuroimmune and neurometabolic pathways,
phytochemicals represent a compelling therapeutic modality that resonates with the cur-
rent shift toward systems-based approaches in psychiatric research. Complementing this
systems-level approach, recent insights into quinoline-based drug design suggest that
subtle structural modifications, such as halogenation or esterification, can meaningfully
modulate excitotoxicity and immunoactivity signaling relevant to depression pathophysi-
ology [285].
The incorporation of phytochemicals into clinical treatment strategies for MDD
presents several promising implications for practice [
1
]. Unlike conventional antidepres-
sants, which often carry a high burden of side effects—such as sexual dysfunction, weight
gain, insomnia, or gastrointestinal disturbances—phytochemicals typically exhibit favor-
able safety and tolerability profiles [
256
]. This reduced side-effect burden may significantly
enhance patient adherence, particularly among individuals who are medication-sensitive,
elderly, or managing comorbid conditions [
224
]. Furthermore, many phytocompounds,
such as curcumin, resveratrol, and quercetin, are available in standardized formulations
and have shown efficacy when used alongside standard antidepressant regimens, support-
ing their role as adjunctive therapies [
286
]. Their natural origin also makes them appealing
to patients seeking holistic or integrative approaches to mental health [
287
]. To maximize
the benefits of phytochemical interventions, multidisciplinary care teams—comprising
psychiatrists, psychologists, nutritionists, pharmacists, and exercise specialists—are essen-
tial [
288
]. 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 [
289
]. This integrative model not only broadens
therapeutic options but aligns with growing interest in personalized medicine, where
treatment is adapted to the individual’s unique physiological and lifestyle context [290].
Despite encouraging findings, several challenges and limitations temper the imme-
diate clinical translation of phytochemicals for depression [
252
]. A primary concern lies
in the methodological variability across studies [
256
]. Many preclinical and clinical trials
differ widely in terms of dosage, treatment duration, and formulation, making it difficult
to establish standardized protocols [
1
]. Sample sizes are often small, with limited represen-
tation across age groups, genders, and ethnic backgrounds, reducing the generalizability of
results [
291
]. Moreover, key pharmacokinetic parameters—such as bioavailability, half-life,
and tissue distribution—remain poorly characterized for many phytochemicals [
292
]. This
complicates efforts to optimize dosage and timing for maximum therapeutic effect [
293
].
Additionally, the long-term safety of chronic phytochemical use is not well understood,
particularly when used in combination with conventional antidepressants, raising con-
cerns about potential herb–drug interactions [
294
]. These knowledge gaps highlight the
need for rigorously designed, large-scale randomized, controlled trials that incorporate
standardized extract preparations, dose-ranging studies, and biomarker-based outcome
measures [
295
]. Future research should also emphasize population diversity and assess
pharmacogenomic factors that may influence individual responses [
296
]. 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 rigor-
ously designed clinical trials and translational studies that bridge the gap between labora-
tory findings and real-world clinical application [
279
]. Large-scale, placebo-controlled trials
Biomedicines 2025,13, 1129 20 of 35
are essential to validate the antidepressant efficacy of individual phytochemicals, establish
optimal dosing strategies, and assess long-term safety [
297
]. In addition to studying single
compounds, future investigations should explore the therapeutic potential of phytochem-
ical combinations [
252
]. Many plant-derived compounds act on overlapping molecular
targets, and their synergistic effects on neuroinflammation, oxidative stress, and mitochon-
drial dysfunction may offer enhanced efficacy compared to isolated agents [
298
]. Combina-
torial approaches could mirror the polypharmacological nature of depression, targeting its
multifactorial pathophysiology more effectively [
225
]. Moreover, research should move to-
ward precision medicine models that account for individual differences in genetic makeup,
metabolic profiles, gut microbiota composition, and inflammatory status [
299
]. Stratifying
participants based on these biomarkers could identify responders and non-responders to
specific phytochemicals, allowing for more personalized treatment [
300
]. Integrating omics
technologies—such as metabolomics, transcriptomics, and pharmacogenomics—into trial
designs will enhance mechanistic understanding and treatment customization [
301
]. Finally,
future studies should include robust secondary endpoints that assess cognitive function,
quality of life, and functional recovery, not just symptom reduction [
199
]. 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 depression.
Effective management of MDD increasingly requires a multidisciplinary approach
that integrates biological, psychological, and lifestyle-based strategies [
302
]. Collaborative
care teams—comprising psychiatrists, psychologists, nutritionists, pharmacists, and ex-
ercise specialists—are well positioned to deliver comprehensive, personalized treatment
plans [
303
]. Phytochemical supplementation can be particularly valuable when embed-
ded within this broader therapeutic framework [
304
]. Nutritionists can guide dietary
modifications that reinforce the anti-inflammatory and antioxidant actions of phytocom-
pounds, while exercise specialists can prescribe physical activity regimens that synergize
with phytochemicals to enhance mitochondrial health and neuroplasticity [
305
]. Psy-
chologists can provide cognitive–behavioral or mindfulness-based therapies that further
modulate stress-related pathways implicated in MDD [
306
]. The 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 [
307
]. For ex-
ample, interventions that pair dietary polyphenols with structured aerobic exercise and
therapy have shown additive effects on depressive symptom reduction and cognitive func-
tion [
308
]. This integrated model not only reflects the multifactorial nature of depression
but also offers a pragmatic pathway to improve treatment adherence, reduce polyphar-
macy, and promote long-term mental wellness [
309
]. Phytochemicals, when coordinated
with other interventions, may serve as powerful components of such a multidimensional
care strategy.
This review illuminates the multifaceted nature of MDD and the potential utility of
phytocompounds in its management. Recent evidence reveals that MDD involves not
only monoaminergic dysregulation but also neuroinflammatory processes, oxidative stress,
and mitochondrial dysfunction, implicating diverse pathophysiological pathways [
223
].
By evaluating interventional studies centered on phytochemicals—including polyphe-
nols, flavonoids, and alkaloids—this review highlights their potential neuroprotective,
anti-inflammatory, and antioxidant properties [
22
]. These effects align with emerging
translational research suggesting that multi-targeted strategies may offer enhanced thera-
peutic outcomes in complex mood disorders [
79
,
310
]. Nevertheless, the heterogeneity of
study designs, phytocompound formulations, and patient populations underscores the
Biomedicines 2025,13, 1129 21 of 35
need for more robust trials with standardized protocols [
311
–
313
]. 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 investigation. Taken together, these insights reaffirm the value of
phytochemicals as complementary or alternative 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.
10. Conclusions
Emerging data suggest that specific plant-derived compounds can influence the neuro–
immune interface and mitochondrial health in major depressive disorder, yet these sig-
nals remain preliminary. Wide variation in extract standardization, dosing protocols,
study designs, and participant profiles hampers direct comparison, and most trials enroll
modest, geographically limited samples. To translate early promise into clinical prac-
tice, large phase-III studies with rigorous pharmacokinetic assessment, active compara-
tors, and extended safety follow-up are essential. Nonetheless, the literature reviewed
here highlights the distinctive neuroprotective, anti-inflammatory, and antioxidant capac-
ities of
phytochemicals—attributes
that align well with the complex biology of depres-
sion, extending therapeutic thinking beyond monoamine modulation alone. Although
several investigations report meaningful symptom relief with minimal adverse effects,
methodological
shortcomings—small
cohorts, heterogeneous interventions, and inconsis-
tent
endpoints—preclude
definitive guidance. Future research must emphasize harmo-
nized formulations, adequately powered populations, and mechanistic biomarkers to clarify
durability, optimal dosing, and synergy with standard antidepressants. Collectively, the
current evidence positions phytocompounds as promising adjuncts, warranting 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.; investiga-
tion, 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.V., C.M.G., E.d.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 have read and agreed to the published
version of the 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 Free, 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
Biomedicines 2025,13, 1129 22 of 35
mtDNA Mitochondrial deoxyribonucleic acid
NF-κB Nuclear factor kappa B
ROS Reactive oxygen species
SSRI Selective serotonin reuptake inhibitor
TCA Tricyclic antidepressant
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