Diet as a Lifestyle Factor and its effect on neurobiology and Major Depressive Disorder in Youth.

By Lisa Cutforth

Author Note: Major Depressive Disorder (MDD or Major Depression) is a clinical diagnosable mental illness. While the focus of this paper is MDD, research that referredgenerally to depression or depressive symptoms was also included. In the context of this paper diet factors were deemed relevant to include that worsen or improve depression ordepressive symptoms because it is likely they would impact MDD prevention, disease progression or treatment outcomes for the patient.

Abstract:

Major Depressive Disorder (MDD) represents a significant mental health challenge in youth populations, with profound implications for neurodevelopment and long-term outcomes. This literature review examines the complex relationship between diet as a lifestyle factor and its impact on youth neurobiology in the context of MDD. The review synthesizes current evidence on neurobiological mechanisms underlying youth depression, explores the unique vulnerabilities of the adolescent brain, and evaluates how dietary patterns influence these neurobiological processes. Evidence consistently demonstrates that the adolescent brain's heightened plasticity creates both vulnerability to environmental impacts and opportunity for intervention. Diet emerges as a modifiable lifestyle factor that can significantly impact neurotransmitter synthesis, inflammation, and brain structure and function. Mediterranean dietary patterns show protective effects against depressive symptoms, while Western dietary patterns increase risk largely because of nutrient deficiencies and inflammatory factors. The review concludes that diet represents an important and relevant lifestyle factor that can positively and negatively impact MDD in youth.  It can be used as an intervention for prevention and integrated into comprehensive treatment approaches to improve symptoms and outcomes of youth depression.

Introduction:

Major Depressive Disorder (MDD) is a complex and prevalent mental illness, affecting 20% of teens currently according to NIMH, (2021). The rate of depression increases from childhood through to adolescence, and into adulthood (Mullen 2018, NIMH, 2021). Shoreyand colleagues (2021) proposed more than a third of adolescents (aged 10-19) globally are at risk of developing major depression, though diagnosis is difficult in children and often missed.

MDD is defined and diagnosed through a cluster of specific and persisting symptoms outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5TR). While DSM-5TR criteria are similar across ages, symptom presentation may differ, irritability may be present instead of low mood, and failure to gain expected weight in children is more relevant than weight loss or change (Mullen, 2018).Symptoms are often overlooked as young children show somatic or behavioural symptoms, with low verbalisation of feelings, and troubled teenagers missed because of stereotypes. Gathering data from multiple sources (e.g. parents and teachers) is valuable. (Mullen, 2018).

Prevention, early diagnosis and treatment of major depression in adolescents is important because MDD can have significant effects when onset is in childhood or adolescence (Mullen2018, Zielinska et al 2022).  It is the leading cause of disability, impacts academicperformance, and social and interpersonal skills (at a time when relationships are a crucialpart of development), and it increases the risk of re-occurrence of depression and substance use disorders later in life. Most concerning though is that it increases the risk of death by suicide, the second major cause of death in young people aged between 12 and 17 (Redlich et al 2017, Mullen 2018, Remes et al 2021, Vargras-Medrano, 2020, Zielinska et al 2022). As many as 8% of adolescents diagnosed with MDD die by suicide as young adults (Mullen 2018).

Developmentally adolescents are sensitive to MDD because of their unique neurobiology and heightened plasticity (Vargras-Medrano 2020). Brain plasticity makes them vulnerable to the negative impacts from the environment and their biology but equally this neuroplasticity supports the case for early intervention. Of the various hypotheses attempting to explain MDD, the biopsychosocial model offers a useful holistic framework to explore the complex relationship between biological, psychological and social impacts contributing to MDD. (Egger et al., 2017, Remes et al 2021, Sherff et al., 2024) The neurobiology of MDD is complex, particularly when considered in the context of neuroplasticity in adolescents, and there is no single hypothesis that can account for this complexity. The major theories of depression discussed in works by Filatova and colleagues (2021) and Cui and colleagues(2024) include: monoamine hypothesis (relating to reduced neurotransmitter levels); the stress-induced depression hypothesis (relating to Hypothalamic-Pituitary-Adrenal axis dysregulation); the inflammation/cytokine hypothesis (relating to inflammatory markers); the neurotrophic hypothesis (relating to Brain-Derived-Neurotrophic-Factor (BDNF) and other genetic/epigenetic or metabolomic hypotheses of which the methionine-homocysteine (along with MTHFR) is of interest. Filatova and colleagues (2021) explored some of the common mechanisms and relationships between them that contribute to the development and manifestation of the disorder.  For the context of this review, the monoamine hypothesis; the inflammation/cytokine hypothesis and the methionine-homocysteine metabolic pathway will be considered because they can be impacted by nutrition status.

This review will consider the impact of diet as a lifestyle factor that can either positively or negatively affect youth neurobiology and MDD.

Neurobiological underpinnings of MDD in youth:

Developmental stages: adolescent neuroplasticity and MDD vulnerability

Adolescence is a sensitive period of neuroplasticity marked by both opportunity and vulnerability, largely due to the heterochronous development of brain regions. (Sisk, 2023) According to Perry’s (2006) neurosequential model, brain structures develop hierarchically, with basic survival systems forming first. Sensitive periods are characterised as time frames of heightened adaptability or vulnerability as developmental systems interact with environmental input (Murphy et al., 2022). This stage features increased adaptability to environmental input but also heightened risk due to the imbalance between a rapidly developing limbic system (heightened amygdala activity) and a slower-maturing prefrontal cortex (Powers & Casey, 2015). Greater emotional sensitivity with impaired regulation ability elevates the risk for psychopathology, including depression and suicide (Mullen, 2018; Akil & Nestler, 2023). Additionally during this time, brain development shifts from generating new neural connections to synaptic pruning and organisation of grey matter (Sisk, 2021).These processes shape both typical and atypical developmental trajectories and intersect with the peak emergence of mental illness (Powers & Casey, 2015; Sisk, 2023; Mullen, 2018; Akil & Nestler, 2023). While plasticity enables learning, such as language acquisition, adverse experiences (e.g., trauma) during sensitive periods can disrupt development and lead to long-term psychological vulnerabilities. (Murphy et al., 2022)

Cognitively, adolescence brings the emergence of metacognition, awareness of their own thoughts and how others perceive them. (McNeely & Blanchard, 2009) This is a period of self-exploration and social learning, yet impulsivity and risk-taking, especially in peer contexts are common due to an underdeveloped prefrontal cortex and a reward-sensitive brain. The adolescent brain is particularly reward-sensitive with greater ventral striatum (part of the reward-processing network) activation in response to rewards during adolescence (Del-Giacco et al, 2021). Luking and colleagues (2016) found in adolescents with depression, reduced activity in the ventral striatum during reward anticipation and receipt may predict both the onset and severity of depressive symptoms (Luking et al 2016).  

Structural and functional brain changes in MDD:

Structural and functional MRI has significantly advanced our understanding of the neurological basis of MDD (Cui et al., 2024; Redlich et al., 2017; Li et al., 2021; Miller et al., 2015, Wise et al, 2014). Major depression is associated with numerous structural and functional differences in neural systems involved in emotion processing and mood regulation. Consistently structural and functional changes were observed in the limbic and prefrontal cortical regions in adults with MDD, this included increased amygdala response to negative stimuli and reduced hippocampal volume with increased functional activity, and both decreased volume and functional activity in the striatum (Wise et al 2014, Redlich et al 2017). Neuroimaging research suggests that abnormalities also occur in a number offunctionally interconnected areas: cortical (prefrontal cortex) and subcortical (thalamus and ventral striatum).  These areas are implicated in the processing of novel information whereas limbic regions eg. the hippocampus and amygdala are involved in emotion and mood modulation. The PFC is important in top down emotion control over limbic regions.  In depression, abnormalities in these functional networks have been demonstrated.  These functional and structural changes in mood regulation systems may inform the neurobiological basis to explain symptoms (Wise et al, 2014).  

However, Redlich and colleagues (2017) noting adult findings could not be generalised to adolescents conducted further research. Redlich and colleagues (2017) found similar patternsin adolescent samples: elevated amygdala response to negative stimuli (but decreased response to positive stimuli) and reduced hippocampal volume, suggesting amygdala hyperactivity as a state marker and hippocampal atrophy as a potential indicator of early-onset depression. Redlich et al. (2018) further linked heightened limbic reactivity to disease severity. Hippocampal volume reduction is a widely reported biomarker, even in children (Murphy et al., 2022). Sisk (2023) found that both depressed adolescents and those at risk exhibit hippocampal volume loss, supported by Li et al. (2021), especially with onset before age 21. The hippocampus, crucial for mood and stress regulation, may underlie MDD-related dysfunction when atrophied. Li et al. (2021) also reported thinning in the hippocampus and basolateral amygdala in adolescents with recurrent MDD.

Hansen and colleagues (2015) also found reduced volume and activity of the striatum in adolescents.  They linked blunted ventral striatum (VS) development, often associated with emotional neglect, to future depressive symptoms. Luking and colleagues (2016) support ventral striatum hypoactivity during reward anticipation and receipt in adolescents predicts MDD onset and severity. In MDD, reduced dopamine (neurotransmitter released from VS)signaling contributes to diminished motivation and pleasure. This region, sensitive to early adversity, may drive motivational deficits and anhedonia, (a treatment resistant depressive symptom associated with apathy and loss of pleasure). Luking et al (2016) argued that heterogeneity of MDD has shifted research toward specific symptom constructs.  It is likely the relationships are multifactorial and more complex than simple constructs.

The traditional monoamine theory suggests deficiencies in monoamine neurotransmitters such as serotonin, dopamine and norepinephrine may be an underlying cause of clinical depression.  (Cui et al 2023).  Reduced levels of serotonin, dopamine, and norepinephrine are observed in depressed individuals and may also contribute to suicide risk (Zielinska et al 2023, Vargas-Medrano et al, 2020). Reduced volume and serotonergic dysfunction in the prefrontal and anterior cingulate cortices (regions involved in emotion regulation and decision-making) was observed in adolescents with depressive disorders who had attempted suicide. Synthesis and release of the neurotransmitters is dependant on multiple factors, including changes in plasma composition, which can be influenced by the presence or absence of nutrients in the diet. In addition, dietary modifications can affect nutrient intake (essential amino acids, essential fatty acids, vitamin, and mineral intake), which can impact cognitive functioning by regulating inflammatory processes (think cytokine/inflammatory hypothesis) and influence molecular systems and cellular processes in the body. Optimising the supply of nutrients in the diet, which are essential for proper brain function should be emphasised for depressive disorders. (Zielinkska et al, 2023)

Lifestyle factors and MDD

Adolescence is a transitional phase during which young people increasingly make independent decisions about their lifestyle choices. There is a growing body of research documented in literature by Marx et al (2023), Kunugi (2023), Ortego et al (2022) and Abbott et al (2020) to recommend certain lifestyle factors like exercise, nutrition and diet, time in nature, positive relationships, adequate sleep, stress management and religious or spiritual practices as health promoting. Conversely lifestyle risk factors tend to include alcohol and illicit drug use, smoking, being too sedentary, insufficient sleep duration and eating behaviours resulting in deficiencies or obesity according to literature by Velten et al (2018), Loewen et al (2019), and Yang (2025).

Therapeutic lifestyle changes are often underutilised, despite considerable evidence of their effectiveness, which can sometimes be comparable to psychotherapy or pharmacotherapy(Walsh 2011, Marx et al, 2022).  According to Zielinska and colleagues (2022) modifiable lifestyle factors like nutrition are still underacknowledged and underutilised. The number of studies in adolescent populations supporting the importance of lifestyle factors has increasedhowever according Zielinska et al (2022) longitudinal and clinical studies are still lacking.  

Adolescence marks a transition to more influence over food choices and establishing dietary habits that carry through into adulthood (Khanna et al, 2019; Zielinska et al, 2022; Yang 2025). Adolescents' increased sensation seeking, decreased impulse control and peer influence can all influence diet choices. Being wired to seek reward may meaning opting for excess junk food because it is highly reinforcing by design. Frequent stimulation of the reward system could result in enduring brain adaptations. The prefrontal cortex plays a role in eating behaviour. The PFC is typically underdeveloped in the teen years. Lower activity in PFC is also characteristic of MDD. The impact of this can be two-fold in children. It can affect appetite and decision making and affect nutrition status and weight as a consequence.Another consideration is the impact of depressive symptoms, (fatigue, apathy and anhedonia) on diet choices. Depressed adolescents may opt for easy processed convenience foods or hedonic options like sugary or carbohydrate-rich foods, replacing healthy foods in the diet, especially when under the influence of their peers.

The role of diet in Youth MDD

Diet is a modifiable lifestyle factor that can affect neurobiology and mental health (Ortego et al, 2022; Zielinska et al, 2022; Adan et al, 2019). The brain’s composition, structure, and function depend on access to essential nutrients including amino acids, essential fatty acids, and key vitamins and minerals. A current report by Zielinska et al (2022) shared important literature indicating the Mediterranean diet (MD) pattern (to have the most evidence) to reduce risk and symptoms of depression, whereas eating a Western-style diet can increase the risk and severity of depression in adolescents. The MD is rich in plant foods such as vegetables, fruits, whole grains, legumes, and nuts, seeds, fish and olive oil as the main, with low to moderate intake of dairy products and eggs, and meat and very low processed foods intake (include refined carbs, sweets) (Zielinska et al., 2022). Conversely the Western diet (WD) is based on highly processed foods and is characterized by high consumption of processed and red meat, refined carbohydrates (cakes, sweets) and fried foods, dairy products, and a low intake of vegetables, fruits, whole grains, and legumes (Zielinska et al., 2022).

There have been multiple studies, systematic reviews and meta-analyses done to support the relationship between nutrition and depression specifically, though they were not all focused on adolescents (Adan et al, 2019). Adan and colleagues (2019) referenced a systematic review by Lassale et al (2018) combining a total of 20 longitudinal and 21 cross sectional studies that provided compelling evidence that a Mediterranean diet is protective against depression. Khanna et al (2019) conducted a systematic review of 56 studies that considered the nutritional aspects of depression on adolescents. Healthy foods like those featuring in a Mediterranean diet were inversely associated with the risk of depression and may improve depressive symptoms.  However there are limitations in these studies, it is hard to double blind a study involving food, and nutrition and diet are notoriously difficult to accurately assess and account for, studies often rely on individual reporting or different types of dietary assessments.  A study by Korczak et al (2021) sought to examine the association between diet and depression, addressing inconsistency by using four dietary measures previously studied in children and adolescents. This was the first of its kind to examine the association of dietary behaviours with MDD in a clinical population of children, across diagnostic categories, and across dietary assessment instruments. They concluded children with MDD consume fewer healthy foods than children without MDD, with little variation by dietary measure supporting the protective role of a healthy diet (Korczak et al., 2021).

There is strong evidence that patients with MDD are malnourished or at risk of malnutrition, which may influence the complex expression of depression symptomology (Ortego et al., 2022). Deficiencies in key nutrients such as amino acids (especially tryptophan), omega-3 polyunsaturated fatty acids, vitamins B and D, and minerals like magnesium, iron, and zinccan impair brain structure and function and contribute to depressive symptoms (see Appendix item 2). Nutrients including tryptophan, vitamin B6, B12, folate, phenylalanine, tyrosine, histidine, choline, and glutamic acid are vital for synthesizing neurotransmitters such as serotonin, dopamine, and norepinephrine (Kris-Etherton et al., 2021). Liwinski and Lang (2023) also link folate deficiency with increased depression risk, more severe symptoms, longer episodes, and higher relapse rates. Zwolinska and colleagues (2021) emphasize the methionine-homocysteine pathway, essential for methylation, the process by which neurotransmitters are synthesized. This pathway depends on folate and vitamin B12; deficiencies hinder neurotransmitter production, supporting the monoamine hypothesis of depression. Reduced levels of neurotransmitters may underlie depressive pathology

As well as deficiencies diet may play a role in inflammation. Unhealthy diets like the WDbeen associated with increased markers of an inflammatory state, whereas the MD has been reported to reduce inflammation. There is a direct relationship between increased pro-inflammatory markers, unhealthy diets and depressive symptoms among children and adolescents (Korczak et al., 2021). Ortego et al (2022) advocate the Mediterranean diet maymodulate various pathophysiological mechanisms of MDD which as well as reducing inflammation include other important things like limiting the impact of oxidative stress; enhancing mitochondrial function (which has an effect on energy levels); and optimising neurotransmitter synthesis and break down (by providing amino acids and important nutrient catalysts which can impact mood and motivation) among other factors. (It’s important to note that excess nutrients can contribute to malnutrition or imbalances, not just deficiencies, particularly problematic for mental health are high levels of serum copper or iron overload, and excess omega-6 can have an inflammatory effect (Walsh, 2011).

A wholefood diet is more than just the sum of its parts, for example Ortego (2022) explained the synergistic effect a diet abundant in seafood (like the MD).  Sardines contain healthy fats (polyunsaturated fatty acids like omega-3) and fat soluble vitamins (like vitamin D).According to Chettry and colleagues, both reduced white matter integrity and lower levels ofomega-3 PUFAs are seen in people with MDD. Kohler and colleagues (2016) explainingomega-3 fatty acids are protective against depressive symptoms because of their anti-inflammatory properties, as well as their role in maintaining structural integrity of white and grey matter (as part of lipid membranes and myelin sheath). (Myelin is a fatty substance that insulates nerve fibres to improve nerve signalling in the brain.)  Low serum vitamin D levels appear to be inversely related to clinical depression (Ortego, 2022). Vitamin D has a role in underlying biological mechanisms (like immune and gut microbiota modulation, serotonin synthesis and circadian rhythms and BDNF production).

The MD diet is also rich in dietary fibre from fruit and vegetables, and this seems to exert critical actions in the gut microbiota, leading to the production of short-chain fatty acids (SCFAs), and may lower inflammation by modifying both the pH and the permeability of the gut. This has been positively associated with a reduction in depressive symptoms (Ortega, 2022).

Research gaps and future directions

Despite the growing body of evidence linking diet to mental health and MDD, there are still significant gaps in knowledge and data, particularly in relation to depression in young people (Ortego et al., 2022; Shorey et al., 2022; Zwolinska et al., 2021; Marx et al., 2023). Nutrition is a challenging research area and many studies have been largely observational, and many positive results seem to gained from long term adherence (Ortego et al., 2022). There is generally a lack of research consolidate worldwide prevalence of depression amongst adolescence and compare datasets (Shorey et al., 2021). This is a clear need for more longitudinal and intervention studies specifically focused on adolescents to better understand the relationship between diet, neurobiology, and the occurrence, progression and prognosis of major depression in this cohort.

Future research should also aim to integrate various biomarkers, including neuroimaging data, inflammatory markers, alongside nutrients status to provide a more comprehensive picture of the mechanisms at play (Korczak et al., 2021). The development of youth-specific dietary interventions and public health programs is another important area for future work. Finally interdisciplinary research approaches that bring together experts from psychiatry, nutrition and neuroscience will be crucial for advancing the understanding in this field.

Conclusion:

The evidence presented in this review highlights the significant and complex relationship between diet, neurobiology and Major Depressive Disorder in youth. Diet is not merely a peripheral factor but a key modifiable lifestyle element that can act as both a risk and a protective factor for mental health. The mechanistic pathways through which diet exerts its influence are multifaceted, involving the synthesis of neurotransmitters, the modulation of inflammation and oxidative stress, effects on neuroplasticity and brain structure, and interactions with genetic and epigenetic factors. Also relevant is the significance of creating healthy eating behaviours and habits while young and in this unique developmental period, due to the increased plasticity and response to environment and maximising protective benefits and minimising harm.

An increasing number of studies have demonstrated that the occurrence and recurrence of MDD can be prevented or diminished by means of improving lifestyle factors like diet (Cui et al., 2024). Given the profound and lasting impact of adolescent onset MDD, the importance of early intervention cannot be overstated. The adolescent brain, with its heightened plasticity, presents a critical window of opportunity for intervention to have meaningful and enduring impact. Diet represents a promising, accessible and empowering strategy that can be used as an adjunctive or even a primary preventative measure for youth depression, and also an important treatment aid. By adopting a more integrated, biopsychosocial approach that acknowledges the crucial role of nutrition, more effective and personalised strategies for promoting mental health in young people can be achieved.

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Appendix:

Item 1: Diagnostic and Symptom Criteria Example for MDD in Youth:

DSM–5 criteria for diagnosing depression in the pediatric population:

• The presence of at least 5 of the following items in the same 2-week period with having a change in the level of function. At least 1 of the items is either a depressed mood or loss of interest or pleasure. It is important to note that other medical conditions can not explain symptoms.

o Depressed or irritable mood most of the day, almost every day, as demonstrated by either subjective report, for example, the patient feels sad, empty, or hopeless, or observation made by others, for example, the patient appears sad. 

o A significant decrease in interest or pleasure in activities most of the day, nearly every day as indicated by self-reporting or observation

o Failure to make expected weight gain or remarkable weight loss when not dieting or a remarkable weight gain, or decrease or increase in daily appetite

o Lack of sleep or excessive sleeping almost every day

o Psychomotor unrest or retardation almost every day (observable by others, not merely subjective feelings of restlessness).

o Lack of energy nearly every day

o Feelings of worthlessness or inappropriate guilt (possibly delusional) nearly every day (not merely self-reported or guilt for being sick)

o Decrease capacity to think or concentrate or indecisiveness, almost every day (either by self-report or as observed by others)

o Repeated thoughts of death (not just fear of dying), recurrent suicidal ideation without specific plans; suicide attempt; or a definite plan to commit suicide

• The illness causes clinically remarkable distress or impairment in social, occupational, or other important areas of functioning.

• The episode is not due to the physiological effects of a substance or another medical condition

• The occurrence of the major depressive episode cannot be explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders

•  Had no manic or hypomanic episodes

Item 2: Table Nutrient and diet impact on MDD summary of literature conclusions:

Nutrient

Conclusions

Proteins

Higher total protein consumption as well as that specifically derived from milk and dairy products may lower depressive symptom risk.  (however no benefit from protein intake from animal sources).  A beneficial effect of a higher supply of tryptophan (precursor to serotonin) in the diet was shown to decrease risk of depression.  Consider Methionine and Homocysteine impact, and gene impact.

Carbohydrates

Greater exposure to added sugars, low quality carbs and low dietary fibre intake has been shown to correlate with a higher risk of depression.  

Fats/PUFA

A beneficial effect of increased omega 3 fatty acid intake to prevent depressive symptoms in various group.  (Variable data on whether EPA or DHA)

B vitamins

Low dietary or serum levels of B1, B6, B9, B12 have been associated with a higher prevalence of depressive symptoms. Consider Methionine and Homocysteine impact, and gene impact.

Vitamin D

Depressed patients have significantly lower serum vitamin D levels.  Approximately 80% of depressed patients do not get enough vitamin D daily.

Mineral components

Dietary deficiencies in magnesium, zinc, selenium, copper and manganese have been associated with greater likelihood of depression.  Both excess and deficiency of copper and iron may affect the risk of depression.

Iron and zinc deficiency

1