Low levels of SCFAs have been associated with depressive-like behavior, compared to high levels of SCFAs ( Figure 2 ) (15, 19, 71). SCFAs belong to the major gut bacteria metabolites and can offer relevant benefits in terms of depression relief, anti-inflammatory effects, neuroprotection, regulating T-cell induction, and a good BBB permeability balance (15, 16). This improvement of BBB integrity by butyrate (a SCFA) has been associated with the upregulation of tight junction protein (TJP) expression, which are proteins in the brain restricting substances to move freely between the brain and blood (71). Dysregulation of TJP is related to impaired BBB integrity, exposing the CNS to damaging substances. However, due to the MGBA being highly interconnected and SCFAs not being the only microbial metabolites, the causal link between SCFAs and the increase of the BBB remains uncertain. Moreover, reduction of SCFA-producing bacteria play an important role in dysbiosis, gut mucosal inflammation and loss of intestinal barrier integrity (leaky gut) (16).

Another important biomolecule involved in MGBA and MDD is LPS (21). Research suggests that LPS has the capability to trigger depressive-like behavior in animal models (72). LPS is a microbe-associated molecular pattern (MAMP) and a large constituent of gram-negative bacteria that binds to toll-like receptors (TLRs) located on immune cells (19, 73). MAMPs are microbial-derived products which can activate immune cells to promote the release of pro-inflammatory cytokines, which increases permeability of the intestinal barrier (‘leaky gut’) and the BBB, and influence CNS function and behavior (15). Additionally, when pro-inflammatory cytokines are able to cross the (damaged) BBB, they can interact with neurons which can lead to sickness behavior and MDD. The activation of TLRs can also activate the HPA axis, which may result in further increment of BBB permeability and gut-membrane-permeability, the latter associated with leaky gut (19, 45, 74).

A leaky gut can be the result of the gut epithelial barrier being damaged by dysbiosis and is displayed in Figure 2 as a dashed line (15, 47). The leaky gut has been associated with MDD through the immune system (60), and gut permeability markers are associated with patients with recent suicide attempts (42). Also stress in rodents might increase the leaky gut (74). However, direct mechanistic evidence between dysbiosis and a leaky gut is limited (75). What research does suggest, is that a leaky gut increases unregulated translocation of microbes over the lamina propria (thin layer of connective tissue, such as in the gastrointestinal tract). This can lead to, for instance, the infiltration of immune cells into the brain (71). It has been hypothesized that this infiltration can be pathogenic in the CNS because of the destructive properties of these cells.

Leaky regions in the BBB, called circumventricular organs, allow molecules and cytokines to travel to the brain, are related to systemic inflammation, and may cause altered brain function (76). Immune cells for instance produce cytokines like IL-17A, which further impair BBB integrity (displayed in Figure 2 as a dashed line) and contribute to neuroinflammation (77). This mechanism has been associated with CNS diseases such as multiple sclerosis and morbus Parkinson (78).

Moreover, a leaky gut allows LPS to activate even more TLRs inside and outside the gut. Because of increased BBB permeability and a leaky gut, LPS reaches systemic circulation and is therefore able to travel to the brain, where they can bind to TLR4 located on brain endothelial cells (cells which are part of the BBB), displayed at the top left of Figure 2 (79). Here, LPS can alter TJP expression, contributing to impaired BBB integrity, immune cell trafficking, and the release of more pro-inflammatory cytokines (71). Interestingly, TLR4 has been found to be upregulated in MDD patients (14). Moreover, when MDD patients were successfully treated, the TLR4 levels were found to be restored, suggesting their potential role in depression.

This example highlights how the immune system, the gut, BBB integrity and MDD are interrelated. However, there are many more complex interactions like these involved, but covering them each individually is outside the scope of this review (60, 64).

On top of the biomolecules described in the previous section, neurotransmitters (NTs) are thought to play an important role in the MGBA ( Figure 2 ). Gut microbiota are able to secrete multiple NTs (and precursors), neuropeptides and metabolites. The NTs that are released by different bacteria species are GABA, acetylcholine, serotonin, dopamine, and histamine (19, 20). Another study even suggests that various Lactobacillus spp. can synthesize all the above-mentioned NTs (32). From the gut bacteria, NT (precursors) can travel through the blood or the VN to the brain (80).

Synthesis of NTs and neuropeptides that regulate cognition and behavior is in turn partly modulated by SCFA (mainly butyric and propionic acid) (81, 82). They enhance tyrosine and tryptophan hydroxylase expression, which are involved in dopamine, noradrenaline, and serotonin synthesis (81, 82) and have neuroprotective properties ( Figure 2 ) (83).

Serotonin, dopamine, and norepinephrine are the monoamines that are mostly associated with MDD (7). All three are modulated by antidepressants such as SSRIs and noradrenaline and dopamine reuptake inhibitors. Serotonin is thought to be a crucial NT which is known as the primary regulator of mood and cognition (82, 84). Notably, 90%–95% of serotonin is compartmentalized in the gut, and serotonin production can be regulated by the GM (84). Another article mentions that patients with MDD generally have low circulating levels of tryptophan, possibly because low levels of plasma tryptophan are related to alterations in immune function (64, 76). As tryptophan goes predominantly through the kynurenine pathway, it is interesting that research showed that the kynurenine/tryptophan ratio was significantly higher in depressed individuals compared to healthy controls (59). Additionally, dopamine and noradrenaline are also NTs that have an influence on the CNS and are produced by microorganisms in the gut ( Figure 2 ). For instance, stress in mice showed increased levels of dopamine and noradrenaline in the gut (85).

However, there is a major controversy about the association between MDD, serotonin and tryptophan. A recent paper involving 17 studies (systematic reviews, meta-analyses and more) concluded there is no consistent support for an association between serotonin and depression (10). Also, the relationship between tryptophan and serotonin remains weak. The weak relationship between MDD, dopamine and norepinephrine has not been investigated as comprehensively, but because of the controversy around serotonin, careful interpretation is required (10). This does not necessarily mean the monoamines are not involved in the MGBA, but the interaction is more complex and the relevance for MDD seems to be far less than previously assumed. However, it is important to reiterate that the study by Moncrieff et al. (10) has faced significant critiques regarding its reliability, emphasizing the complexity of serotonin’s role in MDD.

Another NT associated with microbiota influencing MDD is nitric oxide (NO) ( Figure 2 ). The gastrointestinal tract is rich in sources of NO and the GM is known to be involved in oxidative stress (81). Nanomolar concentrations of NO seem to have a neuroprotective effect, but excessive NO production can be neurotoxic – associated with neuroinflammation, cellular damage, axon degradation, and neurodegenerative disorders including MDD. Excess production of NO may lead to the generation of reactive oxygen species and reactive nitrogen species, both causing oxidative stress. This can lead to cellular and DNA damage. Depressed patients show a significant increase in oxidative stress (47, 81). This may have to do with the fact that overproduction of reactive oxygen species characterizes activation of the inflammatory pathway. Also, research shows that endogenous antioxidants can be decreased in MDD patients (81, 86). This is in line with research that showed that depletion of the GM might also affect the function of antioxidants (87).

Alterations in brain-derived neurotrophic factor (BDNF) modulation are also a risk factor of MDD in which microbiota can play a role ( Figure 2 ) (18). BDNF is a neurotrophin and growth factor that has neuroprotective effects, and plays an essential role in the survival of neurons (64). It is widely expressed throughout the CNS and especially active in the hippocampus (30, 64). Decreased levels of BDNF in the hippocampus are associated with depression and are often seen as comorbidity in IBS and other inflammatory-bowel diseases (84). Furthermore, various treatments for depression, such as antidepressants, show an increase of BDNF expression in the brain (64). BDNF has also been used as a marker for antidepressant effects (70).

It is important to stress that bacteria can be considered beneficial or non-beneficial, as indicated in Figure 2 . For example, some bacteria species can promote cytokine production (54) and increase anxiety (64), while other bacteria can reduce anxiety-like behavior (4, 17, 43). In line with these results, some studies found an effect of probiotics on the HPA axis (88), while others did not (89). Also, antibiotics can exert both positive effects and negative effects on the GM and MDD (69, 87).

Taking the information of section 4 and 5, we suggest that MDD is not a brain-only phenomenon, but a gut-brain interaction phenomenon. Genetics and neurobiology certainly play a role, but are not the sole cause. The HPA axis and immune system are part of the interconnected MGBA, and dysregulation of the HPA axis, a pro-inflammatory state and dysbiosis contribute to the development of MDD. Additionally, the bidirectional connections seen in Figure 2 regarding the HPA axis and GM, cytokines and the GM, cytokines and microglia and so forth highlight the overall bidirectional character of the MGBA. We believe that to treat depression more effectively, the MGBA is a crucial part to focus on and cannot be ignored.

Approximately 60–65% of MDD is explained by external factors such as adverse life events (5, 6). This is likely in large part the result of (chronic) stressors, as high levels of cortisol could potentially function as a predictive indicator of the risk of developing MDD (7). The source of stress could be in the past (e.g., early-life stress, childhood maltreatment or trauma) or it could be more recent (e.g., managing current life events and SDs) ( Figure 3 ). On a psychological level, stressors can lead to avoiding, reducing, or predicting behavior towards a certain stressor (e.g., avoiding social interactions). From a biological perspective, stressors increase the level of cortisol of the individual, disrupting the HPA axis. Moreover, slightly higher cortisol levels in MDD patients have been found compared to controls (32, 34). Interestingly, MDD also increased cortisol levels in response to stressful stimuli. This fits the model as van der Gronde et al. (5) postulated: ‘depression is the result of a failure of coping mechanisms to control the stressors and a differential dysregulation in the stress system’.

According to a meta-analysis from 2019, people who went through early-life stress had higher odds of developing MDD prior to reaching the age of 18 years old compared to those who did not have a history of early-life stress (94) ( Figure 3 ). They also found that the type of early-life stress plays a role in juvenile mental health. Poverty, illness/injury, and natural disasters were not associated with MDD, while emotional abuse and death of a family member were more strongly related to depression. Other than MDD, adverse childhood experiences are associated with significantly higher odds of anxiety, internalizing disorder, and suicidality in more extreme cases (95). Another large part of early-life stress in children and adolescents is negative behaviors of their parents (7). These negative behaviors could include hostile behavior and lower engagement. Additionally, depressed parents may also increase their children’s risk for developing depression.

Depression among children and adolescents is in turn associated with poor school attendance like absenteeism and truancy (96). These school performances may then again contribute to the downward depression spiral ( Figure 3 ). Research trying to find potential underlying mechanisms demonstrate that resilience can partly protect against detrimental effects of child maltreatment (97). From a biomolecular perspective, research found altered HPA stress responses and lower levels of glucocorticoid receptor mRNA and other epigenetic differences in the hippocampus of humans who experienced childhood trauma (98).

SDs are also essentially external sources of (chronic) stressors and can be associated with MDD (90) ( Figure 3 ). SDs include economic security, social protection, recent positive events (e.g., holidays), equality and neighborhood safety (7). Generally, because SDs differ to such a large extent between individuals, it is challenging to determine whether MDD is a cause or consequence of SDs and rule out confounding factors.

A report by the world health organization (WHO) described that in every age and phase of life, challenges such as poverty, violence, inequality, and environmental deprivation pose a threat to mental health (99). Additionally, a recent comprehensive review demonstrates that depression is associated with failure to complete secondary school, unemployment, work disability, lower income-earnings and household income (90). Vice versa, employment has been shown to lower the likelihood of depression, potentially possibly by enhanced autonomy, socioeconomic status, and personal growth opportunities. Interestingly, however, better SD conditions do not mean beneficial effects only by definition, as another paper found that higher parental education correlates with increased prevalence of alcohol and drug usage during early adulthood (100).

From a biomolecular viewpoint, earlier work reported that lower socioeconomic status during adolescence was linked to epigenetics (101). Increased methylation, a chemical modification in DNA, of the serotonin transporter gene predicted heightened reactivity of threats of the amygdala, a brain region involved with processing fear. This amplified amygdala reactivity in turn moderated the connection between a positive family history of depression and the later development of depressive symptoms. If reproduced, this prospective pathway could serve as an innovative target biomarker for intervening and preventing mental health issues in individuals at high risk.

Counseling interventions, which provide guidance and support to enhance health and well-being, play an important role in the social environment of individuals with depression. This can be done by family or friends, or a professional such as a general practitioner (GP). Since friends and family typically do not monitor depression scores systematically, limited data are available on this aspect. What research does suggest is that adding cognitive behavioral counseling to standard depression treatments provided by GPs over six months is more effective in reducing depression symptoms and improving quality of life than usual care alone (102). Outside the GP, there is evidence that counseling provided by minimally trained community counselors effectively alleviated depression and anxiety levels (103).

Stressors are part of life, and healthy individuals naturally experience them (5). However, (mild) stressors may become a problem when they accumulate, become too much, and individuals fail to cope with high amounts of stress ( Figure 3 ). This effect of chronic mild stressors accumulating and eventually contributing to the development of depression was also observed in rats (104).

Although the number of stressors matter, the ability of people to cope with these stressors is important as well ( Figure 3 ). Resilience means the capacity to sustain or reclaim one’s psychological well-being in the midst of challenges (i.e., risk or threat) (7, 93). Research shows that it is evident that resilience is strongly related to mental health (93). This might be explained by the fact that people who are more vulnerable for stress (e.g., suffering from autism spectrum disorder) may develop MDD from mild stressors, while less vulnerable individuals may only experience MDD when exposed to severe stressors (5, 7). Research demonstrates that the level of resilience can vary from one person to another (93). This may differ between individuals based on genetics (105), but resilience is a multisystemic dynamic process that can develop through an individual’s life in which early-life stress can also have an effect (93). Additionally, a genome-wide association study demonstrated a strong positive genetic correlation between neuroticism (personal trait to react with negative emotions when confronted with threat, frustration, or loss) and MDD (106, 107) ( Figure 3 ).

As mentioned earlier, MDD patients often share comorbid conditions along with their depression (5). A recent article mentions that approximately 75% of MDD patients will satisfy the criteria for at least one additional psychiatric disorder (22). This includes physical comorbidities such as cardiovascular disease, obesity and type 2 diabetes mellitus as well as mental disorders like anxiety, substance use disorder, psychosis, and autism spectrum disorder (5, 7) ( Figure 3 ). Also, specific diseases like COVID-19 can be related to depression (108).

A recent comprehensive systematic review concluded that MDD was identified as a risk factor for both the development and exacerbation of various comorbidities (38). They assessed the association of MDD with about 36 comorbidities distributed over several groups including cancer, CNS, cardiovascular, metabolic diseases, autoimmune, musculoskeletal/pain, gastrointestinal, respiratory and substance use disorders. Based on the findings, autoimmune diseases and cancer were the least associated with MDD, while cardiovascular and metabolic conditions showed the strongest correlation (38). The study indicated that depression was more likely to increase the risk of developing comorbidities than existing comorbidities influencing MDD, except for substance use disorders. Interestingly, they discussed that a significant number of MDD-associated comorbidities are related to dysfunction of the HPA axis and the immune system, which supports our findings in sections 4 and 5. Moreover, numerous research studies acknowledge that, beyond biological mechanisms, the connection between depression and cardiovascular diseases could be influenced by diet and lifestyle factors (38).

Related to the MGBA, epidemiological data indicates that there is a positive correlation between obesity and an increased risk of developing mood disorders such as MDD (56, 109). As mentioned in section 5, a systematic review and meta-analysis of longitudinal studies found that depressed individuals have a 58% increased risk of developing obesity and that people with obesity were found to have a 55% increased risk of experiencing depression as time progressed (56).

Research shows that individuals suffering from MDD exhibit decreased levels of physical activity and that these inactive people are at a higher risk of developing depression (110) ( Figure 3 ). Aerobic exercise has even demonstrated comparable effectiveness to antidepressants, such as SSRIs like sertraline. The potential underlying mechanisms of exercise attenuating depression could be the stimulation of BDNF, enhanced sleep, the relief of stress, attenuated inflammation, increased activity in the prefrontal cortex and social factors like enhanced self-esteem and social interactions that help against loneliness (110).

However, while some meta-analyses support the potential antidepressant effect of exercise on MDD (112), other meta-analyses did not find significant effects (113). Nevertheless, another article states that exercise should be viewed as a supplementary component to complement other treatments for depression (8). Furthermore, exercise is associated with benefits to broader human health aside from depression, such as preventing and managing cardiovascular disease and obesity (114, 115). Together with the fact that exercise is a low-threshold intervention, exercise could be a favorable activity for people in general.

Choices in diet can have a potential effect on the spiraling mechanism of MDD and might be related to the high prevalence of MDD in Western, urbanized countries (116) ( Figure 3 ). A recent systematic review concluded that evidence suggests that a higher diet quality is related to an attenuated risk for the onset of MDD-related symptoms (117). However, another systematic review observed conflicting levels of evidence for different kinds of diets and depression (118). The fact that defining ‘a healthy diet’ is rather variable may contribute to these observed inconsistencies. Extreme diets may affect the risk of depression more severely. For example, individuals who consumed above half a liter of soft drinks every day had about 60% increased risk of having depression and depression-related symptoms compared to individuals not consuming soft drinks (119).

Research suggests that the GM plays an important role in linking diet and depression (120, 121). The ‘Western diet’ consists of highly processed foods that contain high amounts of fat and added dietary sugars (16, 47, 54). High sugar consumption is related to microbiota dysfunction, lower production of SCFAs, a pro-inflammatory state, a leaky gut and oxidative stress (47, 54). A high-fat diet for an extended period is recognized for its ability to induce chronic, systemic inflammation, increments of cytokines, and disrupt BBB integrity (44, 54). Furthermore, whereas high levels of non-digestible fibers promote the growth of beneficial bacteria (21), a lack of dietary fibers may be associated with higher depression scores (59).

On top of diet, exposure to pollutants such as glyphosate, the most widely used herbicide globally, can play a role in the gut-brain axis and be a risk factor for depression (122). Glyphosate has been associated with increased mRNA expression levels of TNF and IL-6 (123, 124). This is particularly significant given that over half of the species in the central human gut microbiota are estimated to be sensitive to glyphosate (125). Related to pro-inflammatory cytokines, both microplastics and air pollutants have been associated with increased levels of TNF and IL-6 (126, 127) as well as depression (128, 129). Furthermore, heavy metals (e.g., lead and mercury) have been linked to dysbiosis and oxidative stress, which disrupts intestinal barrier permeability of the GM (130, 131). This is notable, as heavy metals have also been linked to depression (132).

For the last two decades, research already indicated the relationship between depression, and alcohol and drugs of abuse (133, 134) ( Figure 3 ). Substance abuse can accompany depression as patients may seek to find a temporary escape to their depressed mood. However, alcohol and drugs of abuse only worsen depression in the long run due to their adverse effects (135). As alcohol and drugs have abuse potential, patients can become dependent on these substances.

A recent comprehensive systematic review containing meta-analyses found a fivefold risk between depression and cannabis dependence and a threefold risk between depression and substance use disorder (136). They even found a pooled odds ratio based on three studies of 11.3 for dysthymia (persistent depressive disorder) with drug dependence compared to no dependence. An older article described that about one-third of depressed patients also have a substance use disorder (134). Smoking is also related to depression, and cessation of smoking seems to improve psychological well-being as well (112). These results strongly support the idea that there is a consistent increased risk for comorbidity between depression and substance-related disorders.

Gut-brain interactions underlying this idea include the association between increased intestinal barrier permeability and substance abuse, particularly alcohol use disorder (137–139). Research showed that alcohol consumption is related to dysbiosis in both rodents (140) and humans (141), and that alcohol-dependent individuals show elevated levels of oxidative stress, TNF, LPS, IL-6, and systemic inflammation (137, 138). Also opioids, nicotine, and cannabis, have all been linked to changes in gut microbiota composition, highlighting its potential role in substance abuse (137).

Research suggests that sleep disturbances occur in 80-90% of depressed patients (7, 142). Indeed, a meta-analysis concluded that improving sleep was associated with significant medium sized effects on improving mental health (Hedges’ g = -0.53) and depression (Hedges’ g = -0.63) (143) ( Figure 3 ). A possible contributing factor is the increase of usage of mobile phones. There is solid evidence that excessive mobile phone use, which is frequently reported, is correlated with the increased mental disorders such as depression, and poor sleep quality (144). This could be part of a lifestyle intervention to alleviate the symptoms of depression. Moreover, research shows that exercise interventions significantly improve sleep (145). On the contrary, sleep deprivation as a treatment has been associated with the improvement of depressive symptoms in certain subgroups of patients as well (146). However, this effect diminished after two weeks, was not superior compared to antidepressants, and the meta-analysis was based solely on post-treatment assessment. Nevertheless, sleep is an important factor to take into account in the spiraling mechanism ( Figure 3 ).

A possible promising application of our spiraling risk factor model including the MGBA is early diagnosis ( Figure 3 ). Currently, MDD is diagnosed mainly based on the DSM-5-TR (American Psychiatric Association) and ICD-11 (WHO). Both assess depression based on behavior-related symptoms, in contrast to disorders such as cancer and diabetes, where diagnostic approaches have shifted towards genomic and other more objective tests (7). Although these-symptom based diagnosing methods are pragmatic, a subjective component remains present, as practitioners may assess MDD differently based on their own background, experience and culture. Moreover, details in the DSM and ICD change when a new version becomes available. It would be more objective to measure depression using biomarkers instead of behavioral symptoms, if validated biomarkers were available. Research might progress on this, considering high levels of cortisol and IL-6 may predict depression onset (7). IL-6 may be extra interesting, as gut permeability markers correlated significantly with IL-6 levels in depressed patients (42).

A current alternative diagnostic system that has made a start in this area is the Research Domain Criteria (RDoC) project by the National Institute of Mental Health early 2009. The aim of RDoC is to ‘develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures.’ (147). In this approach, neurodevelopment, environmental effects, cognition processes, and certain brain circuits are involved in the framework. However, critics have raised concerns about the uncertain validity of RDoC, and it seems there has not been much invested in the development of biomarkers yet (148).

Therefore, we believe it is worth investing in the research of biomarkers for MDD. A recent systematic review and meta-analysis concluded only cortisol may be a possible predictor for MDD, but high-quality and prospective studies are needed to underpin this hypothesis (149). Another paper concluded that changes in cortisol response variability is more associated with the development of MDD than absolute baseline levels for females (150). Thus, the predictive effect of cortisol may also be dependent on patient characteristics and subtypes of MDD, which research should take into account. Some research with immunometabolic markers, brain imaging and omics (i.e., genomics, metabolomics) has already commenced in this area (7).

For optimal results for moving patients up the MDD spiral, various treatment approaches should be considered ( Figure 3 ). The current first levels of care for MDD are related to psychotherapies (7). Cognitive behavioral therapy (CBT) is the most validated and robust method, but other variants like supportive therapy and psycho-education are used as well (8). A newer development called digital therapeutics combines treatments like CBT with software-based (internet/mobile apps) technologies (151).

With mild-to-moderate MDD, psychotherapy is combined with a wide variety of pharmacological treatments including anxiolytics (5, 7). Conventional antidepressants are monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), but due to a more favorable benefit-risk ratio, they were mostly replaced by selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for MDD (8). Interestingly, SSRIs might be associated with reducing anxiety and inflammation as well, highlighting the interconnected nature of the disease (152, 153). Besides the use of other monoamine reuptake inhibitors (e.g., selective norepinephrine reuptake inhibitors), anxiolytics (e.g., lorazepam), and novel antidepressant agents (e.g., bupropion, mirtazapine, ketamine and psychedelics), SSRIs remain the gold standard for pharmacological treatment of MDD (5, 8, 154).

For severe and treatment-resistant depression, somatic treatments such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are used (7). The current most effective approach for treating resistant forms of depression involves a combination of pharmacotherapy, psychotherapy, and somatic therapies (8).

Besides established treatments, there are experimental MDD treatment options directly related to the MGBA. These include FMT and the use of prebiotics and probiotics (45), but there are limitations as well (155). While the probiotic Lactobacillus rhamnosus showed reduced stress behavior in mice, no significant effects related to stress-related measures, inflammation and cognitive performances were found in humans (156). Additionally, we do not believe that these ‘mono treatments’ are viable standalone treatments, as MDD is a heterogeneous disorder with a wide variety of psychological symptoms and environmental risk factors that extend beyond the MGBA (5) ( Figure 3 ). MGBA-related treatments like FMT, prebiotics and probiotics may help correct the balance to some extent, but treating MDD effectively is likely to require multimodal treatment approaches including psychotherapy, pharmacotherapy and lifestyle interventions.

In addition to the prescribed treatments used to alleviate symptoms of depression, it is possible that an individual experiences effects of other treatments (recent or in the past) used for comorbid diseases. Discussing them all is outside the scope of this review, but we will cover some relevant examples.

Research shows that some patients treated with antibiotics show depressive complaints (87) ( Figure 3 ). The link between antibiotics and MDD may be the result of antibiotics affecting not only pathogenic bacteria, but also commensal, protective bacteria. In addition, antibiotics can generate peripheral inflammatory factors which can cross the BBB or activate the HPA axis, increasing stress hormone levels. Contrary to this, other studies showed that antibiotics can also provide therapeutic benefits such as reducing neuroinflammation and depression-like behavior (69, 87, 157). The exact impact of antibiotics on MDD is likely to be complex and requires further study.

Immunotherapies to treat cancer, autoimmune diseases and allergies have been associated with MDD (158) ( Figure 3 ). For instance, depression is the most common side effect observed in individuals undergoing extended treatment of the pro-inflammatory compound INF-α. Conversely, anti-inflammatory TNF antagonists like infliximab have the potential to alleviate depressive symptoms in individuals with inflammatory disorders, such as Crohn’s disease and ankylosing spondylitis (159). This shows the impact of the immune system on MDD, and could lead to the development of therapeutic options.

An advantage of lifestyle interventions is that they are easily accessible and non-invasive for patients. This makes them accessible to combine with other treatment strategies if patients are willing to adhere to them. For example, research on dietary coaching demonstrated reduced depressive symptoms in patients with depression and improved prevention of MDD in healthy individuals (160). Moreover, although not all results are significant by itself, adding exercise is unlikely to be harmful and might help rebalance the spiral of MDD (110) ( Figure 3 ). When someone abuses drugs, addiction facilities could be considered. As poor sleep is commonly found in many depressed patients, interventions to improve sleep patterns by a professional may help (142). Together, these separate interventions combined (involved with the brain, the gut and stressors) may move an individual significantly up in the spiral ( Figure 3 ). Moreover, as limited access to treatment in low-income countries is a big problem, lifestyle interventions may be relatively affordable to implement compared to conventional treatments of MDD.

As lifestyle interventions alone are not likely to be sufficient as a standalone treatments, other aspects of the spiraling risk factor model need to be considered ( Figure 3 ). Moreover, not all lifestyle interventions (exercise for example) provide consistent results (7, 113). This might have to do with the fact that patients often struggle with adherence to lifestyle interventions such as diet, exercise, or drug abuse reduction, limiting the results (161). Therefore, addressing the other factors in our spiraling risk factor model remains valuable.

Better than diagnosing and treating MDD is preventing the development of MDD. What becomes clear from Figure 3 is that patients can move (slowly) from a healthy to a depressed state. If practitioners can intervene earlier or even prevent the initiation of the spiral altogether, it might be more efficient than treating patients where the interaction between multiple risk factors are ongoing ( Figure 3 ). Prevention of MDD can be divided into three types: universal prevention (addressing the entire population), selective prevention (addressing high-risk individuals such as individuals who have experienced trauma recently) and indicated prevention (addressing individuals with subthreshold symptoms) (90).

Universal prevention is a society-level problem, as 85% of MDD patients have no access to treatment in low-income countries (7). Moreover, decreasing poverty and violence would help against MDD through several pathways in Figure 3 (e.g., stable sociocultural environment, rarer adverse life events), but solutions for this are beyond the scope of this review. Selective prevention may be achieved by screening patients at high risk for MDD (e.g., soldiers returning from war, or those who experienced childhood trauma), or a school setting. Research of prevention in school settings involving behavioral and cognitive programs provided small overall effects (162, 163). This preventive effort allows for early intervention on pathways such as coping mechanisms or in more extreme cases (pharmacological) treatments ( Figure 3 ). Indicated prevention has the potential to prevent patients who have some symptoms, but not enough to be diagnosed with MDD, from developing further symptoms. Lifestyle interventions (e.g., exercise and healthy diet) and evaluating the mental and physical condition (e.g., stressors and comorbidities) described in earlier sections might be more successful in an early stage and prevent further disease burden, inhibiting the downward spiral ( Figure 3 ).

In addition to new early diagnostic and treatment approaches, multimodal prevention interventions should focus on exhaustion and sources of stress (5). Using a combination of psychotherapeutic treatment modalities could prevent the onset of MDD by improving the pace of learning new coping behaviors, exerting a synergistic impact on the developmental perspective, and breaking the downward spiral of stress and exhaustion. This might also help for other related mental disorders where exhaustion and stress are central, such as autism spectrum disorder.