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Why Stress Causes Depression and How To Stop It

Why Stress Causes Depression and How To Stop It

Stress and depression

Stressed out? Who isn’t nowadays.

Stress is becoming an increasingly large part of our lives. As our societies become more developed and increasingly fast paced, its hard not to feel stressed out in attempts to keep up. But Its not just that type of stress thats a potential issue. Its many types which could stem from relationships, beliefs, food, the environement and how you generally perceive and interact with the world around you.

Although you could argue most of us have it pretty good nowadays in terms of our basic needs being met, thats certainly not reflected in the prevalence of mental health conditions.

Mental health problems are a growing public health concern, now more than ever. Globally. Just to throw a few statistics your way to really illuminate the magnitude of the issue;

As of august 2017, anxiety disorders were the most common mental illness in the US – 18.1 % of population, 18 yrs and older.  (*).

Major depressive disorder – 16.1 million americans ages 15 – 44. (*).

Since 2015, 19% of UK adults surveyed said they had been diagnosed with depression, and a further 6% for anxiety (*).

Thats to say that nearly a fifth of the US population has an anxiety disorder, and a fifth of the UK population for has some form of depression.

So whats contributing to the increased prevalence of these conditions within our societies? One of the key players is stress. No shit, right? Many of us know stress doesn’t support a healthy and sustainable existence, but the degree to which stress influences these outcomes can be quite astounding.


How stress works: a basic overview

‘Stress’ believe it or not is actually a survival mechanism, which is quite ironic because its serving the exact opposite purpose in modern environments. When we perceive a situation to be dangerous, that lights up an autonomic response to escape that threat. What stresses me out is not necessarily going to stress you out as we may see the world through different lenses in everyday scenarios. However, im fairly sure many of us will react in a similar way if we were about to be attacked by a predatory animal.

The problem is that modern environments don’t allow us the luxury of outrunning a predator. Modern stressors aren’t so easily escaped due to their emotional or mental nature.

When we pick up on a stressor, information is filtered through the prefrontal cortex in the brain and sent to the limbic system to be ‘interpreted’. The limbic system is comprised of the amygdala, hippocampus and hypothalamus, which allows us to store and experience memory, emotion and fear.

This is where stress differs between you and I. Different fears, memories and emotional processing determines how each of us react to the information coming in from the pre-frontal cortex. Hence, different perceptions of, and reactions to stimuli which may or may not produce stress.

Stress can also be of a physical nature, such as with exercise and exertion. In addition, the environment is full of stressors such as extreme climactic conditions which your body attempts to maintain equilibrium amongst. There’s also toxicity which is more a product of modern environments, and is becoming an increasing problem.

See mechanisms for a deep dive into how stress works


Causes of stress

Causes of stress

Stress can be either good (eustress) or bad (distress), depending on the stressor, how frequently it is applied and the cumulative effect of multiple stressors over a prolonged or short amount of time. Exercise is an example of eustress because it is hormetic – we get stronger as a result. But, do too much and it can become deleterious to your health.

Because stress can take so many forms its easy to accumulate and contribute to whats known as your allostatic load. That famous metaphor of the camel and the final straw that broke his back – that sums allostatic load up. There’s only so much you can take at given points in time, and an allostatic load that is too heavy can end up being the final straw. 

Here’s a few cloaks stress (distress) can mask itself under:

Food sensitivities

Say what? Yeah, you heard me – food sensitivities. Reactions to food proteins such as gluten, casein, and proteins in soy, eggs and peanuts for example provoke IgG mediated immune responses, largely in cases of leaky gut. As a result, the immune system arouses the sympathetic nervous system to increase mediators of the stress response – adrenaline, noradrenaline and cortisol. See inflammation & microbiome mechanisms. 


Dietary choices as a whole, regardless of being well tolerated can be highly inflammatory. High glycemic foods coupled with a high fat diet particularly so. Processed, refined and fried foods are big culprits as well, in addition to oxidised vegetable oils.

Again, through inflammatory mediation, the sympathetic nervous system can be activated. Blood sugar regulation is a big culprit here because wild swings can both induce inflammatory processes and cortisol secretion.


Sleep Debts

Lack of sleep is a serious stressor, and exerts its effects directly on the sympathetic nervous system and the HPA axis. Since the hypothalamus is home to your master circadian clock, it also mediates the output of catecholamines and glucocorticoids like cortisol in response to light/dark cycles and circadian rhythms.

Therefore, acute and chronic sleep debts can have your stress response humming away, which may manifest as changes in mood overtime.

Sleep Deprivation and Circadian Disruption: Stress, Allostasis, and Allostatic Load

Severe & prolonged caloric restriction 

In attempts to maintain blood sugar > 5mmol/L, increases in circulating cortisol ensure sufficient glucose is liberated from muscle tissue and the liver. In this way, the heart and brain still have the fuel they need to function.

The sympathetic nervous system is chemically sensitised to changes in blood sugar concentration, and will therefore instruct the hypothalamus to release mediators of the stress response (adrenaline and cortisol) to release glucose into circulation.

Adverse Experiences

These could also be called traumatic experiences, and exist on a spectrum anywhere from jarring childhood memories to experiences on the battlefield (PTSD). As I mentioned earlier, memories fears and life experiences are stored in the limbic system, and determine the highly individual realities we all experience. Therefore, triggers, reflections and reminders of such events whether conscious or not, fire the stress response into action.

Stressful experiences substantially increase risk of developing major depression (*)

Beliefs, Perceptions & Psychological stress

These are deeply routed into our identities, and rarely do we get the chance to dig into the subconscious mind where they lay. These collectively form part of who we are and our traits, such as perfectionism – stemming from a need to be good enough, for fear of rejection. Whether you have grown to be consciously aware of your beliefs and perceptions about yourself and the world or not, triggers that challenge them may induce a response via the hypothalamus regardless. 

Social and socioeconomic status, loss of job and loved ones are also psychological stressors implicated in depression (*)


As you’ve probably picked up on by now, the sympathetic nervous system is a central component of the stress response. Moderate to high intensity aerobic and anaerobic activity directly stimulates the sympathetic nervous system, initiating the catecholamine cascade, which in the case of exercise co-ordinates various physiological responses to exercise.

However, prolonged, overly voluminous and chronic overexercise may overstretch your sympathetic nervous system – think of an elastic band stretched beyond its rebound capacity. This is whats famously known as overtraining. 

Prevent overtraining by tracking your HRV


An inflammatory response is closely tied with the stress response, and can both initiate HPA activity and be produced as a result of it. In fact, there is an entire field dedicated to the study of this phenomena – psychoneuroimmunology.

As with diet and food sensitivities, environmental and chemical sensitivities equally can arouse immune system activation. In addition, your individual detoxification capacity, environmental exposure and toxic load all influence your exposure to potentially triggering immune activation.

Inflammation is at the root of producing depressive symptoms.

Inflammatory cytokines are the mediators of depression. Adrenalin and in some cortisol can be triggers for these messengers, and allow cytokines like interleukin-1β (IL-1β) and 6 (IL-6) to instruct inflammatory processes by communicating with various immune cells, such as macrophages in the brain.

The effects of neuroinflammation are thought to play a significant role in the stress / depression relationship, and is known as the cytokine hypothesis of depression.

This meta analysis found Inflammation to be significantly correlated with subtypes of depression, such as atypical depression (*). This type of depression is also highly correlated with metabolic dysregulation.

Infections are also inflammatory. Long standing, chronic infections exhibit a low grade inflammatory response which can produce secondary depression as a result (*).

How stress causes depression: key mechanisms and pathways

Mechanisms of depression

George M. Slavich and Michael R. Irwin. From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction Theory of Depression. 2014

  1. Inputs from environmental stimuli. In this illustration the example is social stressor specific and pinpoints the mechanism of inflammation.
  2. The HPA Axis
  3. Sympathetic nervous system
  4. Efferent (responsive) arm of the parasympathetic nervous system
  5. Immune cell (relevant to glucocorticoid resistance)
  6. Infiltration of inflammatory cytokines through a leaky BBB
  7. Refers to sensory (afferent) arm of parasympathetic nervous system

The HPA Axis

The Hypothalamic Pituitary Adrenal (HPA) axis is the highway in which messages are sent from the brain throughout the body and fed back accordingly. Via a cascade of hormonal communication, corticotropin releasing hormone (CRH) and adrenocorticotropin (ACTH) act on the adrenal cortex to produce a stress hormone called cortisol. Cortisol is also known as a glucocorticoid.

Your hypothalamus is quite the instigator; Its a small gland, but damn does it have some firepower. After the limbic system has established how it wants to react to a situation (based on your fears, emotions or physical and environmental stimuli) it instructs the hypothalamus to communicate neuroendocrine (hormonal) messengers throughout the body, starting with CRH.

Whilst cortisol and CRH are incredibly important hormones for maintaining homeostasis, persistent stress can provoke dysregulation which can be pathological. Receptors for both cortisol and CRH are widely distributed throughout the body, and given their vast physiological influence throughout the body, changes in circulating levels can seriously mess with immune function, HPA feedback, metabolism and many other structural and functional systems.

Prolonged stress is a well established pathology for cognitive and mood disorders, mediated via elevated glucocorticoids (*) and subsequent HPA dysregulation. HPA hyperactivity is found in patients with melancholic depression (*), and in subtypes of major depression (*).

Overexpression of CRH has also been shown to induce HPA axis dysregulation in rats (*), and elevated levels of CRH have been repeatedly observed in humans with major depression (*).

Finally, a cross sectional study found both hypercortisolism and hypocortisolism (very high and low cortisol) to be associated with depression (*), which indicates a two way street by which HPA dysregulation can drive depression.

The Autonomic Nervous System


Sympathetic activity is the branch of the ANS that initiates another medium of chemical stress. 

CRH also instructs the adrenal medulla to secrete catecholamines – adrenaline and noradrenaline, which do the bidding of the stress response throughout the sympathetic nervous system.

Where the HPA axis secretions like cortisol allows the body to respond to stress long term, catecholamines act more acutely, in the short term.

As I’ve briefly mentioned earlier, inflammation plays a central role in producing symptoms of depression. Well ladies and gentlemen, you have the sympathetic nervous system to thank for that (for the most part). It does this by regulating pro-inflammatory cytokine release via noradrenaline signalling in organ systems and bodily tissues (*). Noradrenaline signalling increases those devils IL-6, TNF-a and IL-1, producing systemic inflammation (*).

Interestingly, different depression subtypes are associated with opposing autonomic and neuroendocrine profiles (*). In other words, both very low and very high levels of catecholamines and hormones may produce depression.

Parasympathetic (vagal)

One of the hallmarks of stress is sympathetic dominance, which is also further perturbed by a relative lack of parasympathetic activity. No bueño, because the parasympathetic branch of the autonomic nervous system is responsible for relaxation and rest responses, which are essential for digestion, sex drive, sleep and general well being.

Autonomic imbalance, that is an increase in SNS activity and decrease in PNS activity is a hallmark of major depression (*), (*).

One of the principal nerves within the PNS is the vagus nerve. This does the majority of signalling throughout the PNS, and can have significant anti-depressant effects when stimulated. It is able to regulate mood by increasing the availability of noradrenaline and serotonin in areas of the brain such as the limbic system and prefrontal cortex (*), (*)

Electric shock treatment of the vagus nerve is a novel treatment approach for depression, but is effective in 22-37% of cases after a 12 month treatment (*). This reveals yet another pathway which can account for some forms of depression. I am curious what resolving the root cause of vagal inactivity (aka stress) might do for depressive symptoms as opposed to just stimulating it artificially.

The vagus nerve is also a sensor, and can respond to the presence of inflammatory messengers, IL-1β, IL-6, TNF-α released due to SNS activity. This is where overactive SNS activity can mess with PNS activity, as vagus nerve relays the presence of inflammatory cytokines to the brain, causing further disturbances in mood.

HPA activity and glucocorticoid resistance

Typically glucocorticoids like cortisol keep inflammation at bay. That is however when cortisol and HPA activity stay within ‘normal’ ranges.

In hypercortisolism, which is ~ 50% of depression cases, the body attempts to ‘water down’ the effects of chronic and elevated secretions of cortisol. Immune cells become less sensitive to its action, and may underexpress glucocorticoid receptors, limiting the binding opportunities for cortisol to exert sufficient anti-inflammatory action (*).

Therefore HPA hyperactivity may actually induce increases in inflammation rather than the typical anti-inflammatory actions (*). This is one of the ways by which inflammation is exacerbated and goes on to disturb neuotransmitter signalling in the brain.

Glucocorticoid receptors can also become resistant to cortisol feedback along the HPA axis.

Cortisol usually inhibits its own secretion through negative feedback, but decreased receptor sensitivity prevents that feedback to limit CRH and ACTH secretion. The result is an HPA axis that is unable to get the message to cool off, and therefore becomes hyperactive (*). This is known as glucocorticoid resistance.

HPA overactivity is one of the most consistent findings in cases of depression (*), and HPA abnormalities may exist in up to 65% of depressed individuals (*).

Glucocorticoid resistance and is a familiar bodily defence mechanism. This is also how insulin resistance occurs in diabetes, but with insulin instead of cortisol.

Neurotransmitter dysregulation

Neurotransmitter imbalance

If the HPA axis is the highway of stress, then you’ll bet there are a few by roads that fork off of it. For example, the GABAergic system can provide additional regulation to the HPA axis and the glucocorticoid cascade (CRH > ACTH > Cortisol > Stress (HPA activation)):

ALLO and THDOC are steroid derived neuropeptides which are produced in response to stress (ACTH). They are made from cholesterol, and are synthesised in the adrenal cortex and the brain (*). When in the brain, they facilitate the binding of GABA to its receptor, as potent allosteric modulators of GABAAR’s (*). This enhances GABA’s regulatory capacity of the HPA axis, reducing stress and anxiety.

ACTH > Cholesterol > progesterone > ALLO-THDOC > allosteric action on GABA receptors (altered transmission) regulates HPA axis (inhibitory action).

Since neurosteroids are synthesised in response to ACTH, chronic HPA activity may actually reduce their synthesis (*). Consequently, diminished ALLO and THDOC concentrations in the brain are unable to potentiate the binding action of GABA to GABAAR. This may reduce inhibitory influence of GABA on HPA axis activity through reduced GABAergic transmission.

GABA concentrations are found to be lower in depressed patents (*), possibly due to the reduction in GABAergic transmission from chronic stress.

In addition to reductions in GABA, relative increases in glutamate are seen in depressed subjects. The influence of these neurotransmitter systems is significant since they both outnumber all other neurotransmitter systems in the brain (*). Glutamate acts as an excitatory neurotransmitter, as opposed to GABA which is inhibitory, whose combined actions modulate cognitions and mood. Alterations in these systems may further disrupt excitatory to inhibitory neurotransmitter ratios (*).

Glutamate excess may be a result of chronic exposure to glucocorticoids from HPA activity; stress exposure increases glutamate release, alters expression of glutamate receptors, alters clearing of glutamate from the synapse and disrupts glutamine/glutamate cycling (*).

We cant talk about neurotransmitters without mentioning the famous monoamine theory of depression. Thats right, I’m talking about serotonin.

It may come as no surprise that there is an association between HPA activity and serotonin signalling. Rats treated with glucocorticoids showed changes in 5-HT (serotonin) circuitry (*). Additionally, in clinical and animal studies hypercortisolemia is associated with decreased 5HT1A receptor activity, which results in serotonergic dysfunction (*).

A meta analysis of observational studies also found reduced 5HT1A receptor binding was associated with the development of depression, and alterations in serotonergic transmission in specific brain regions (*).

Its also worth reiterating that although high levels of cortisol seems to be a key mediator in these developmental changes, low levels also produce depressive symptoms. This reveals a complex matrix of interaction between the HPA axis, glucocorticoid receptor activity and feedback mechanisms.

Finally, a study in individuals with a polymorphism (SLC6A4) 5-HTTLPR (serotonin transport) found an association with stress and HPA activity, which may increase the susceptibility to developing depression (*).

Disruption of the Gut Microbiota

The microbiome – gut – brain axis is a two way highway, which allows gut microbes to communicate with the brain and vice versa. Both the brain and microbiome are incredibly sensitive to changes that occur with each other, and constitute a highly intelligent feedback system.

As you probably know by now, the sympathetic nervous system and HPA axis are the central mediators of the stress response. These are also the highways which connect the gut and brain, carrying the messages. So, chronic sympathetic and HPA signalling isn’t great news for your microbiota, and excessive CRH signalling can upset the delicate balance amongst the microbial community.

CRH is the hormone which initiates the stress response via both the HPA axis, releasing glucocorticoids and the SNS releasing catecholamines – the chemical manifestation of stress.

Chronic stress has been shown to alter the composition of the microbiota in mice (*), and has even been shown to reduce levels of the bacterial strain lactobacillus (*).  Disruption of the gut microbiome is an increasingly acknowledged developmental abnormality implicated in many conditions, and is known as dysbiosis.

Human studies have shown intestinal dysbiosis in cases of depression. A recent case control study revealed that the microbiota of depressed patients was less diverse and had a relative abundance of alterations compared to healthy controls (*). Another CC also found reduced levels of Bifidobacterium in patients with major depressive disorder, as well as decreased lactobacillus (*).

Depletion of bacterial strains such as these is significant because of the role they play in both regulating inflammation and producing neurotransmitters.

Lactobacilli and bifidobacteria are both key bacterial strains for producing short chain fatty acids as a result of carbohydrate fermentation (mainly fibre like inulin, pectins, B glucans and resistant starch). SCFA are the metabolites of this fermentation process, and they do some quite incredible things:

SCFA regulate the synthesis of gut derived 5-HT (serotonin). 95% of serotonin is produced by gut cells, some of which can influence autonomic nervous system activity and produce changes in psychiatric status (*).

SCFA are also able to produce dopamine (*), GABA (*) and acetycholine (*), all of which are neurotransmitters whose activity mediate symptoms of depression.

SCFA have immunomodulatory function (*), and can change circulating levels of anti and pro-inflammatory cytokines which can directly affect brain function. IL-6, TNF-a and CRP are all pro-inflamamtory cytokines that appear consistently in depression (*). Inflammatory cytokines have a profound influence on both the monoaminergic systems – dopamine, serotonin and acetylcholine, and the glutamate system (*), which accounts for a lot but not all symptoms of depression.

SCFA also regulate blood brain barrier integrity (*) which may also influence the permeability to pathogens and cytokines which could further disrupt mood.

In addition to gut microbes, the integrity of the intestinal lining is also an issue with excessive stress. Again, CRH (stress) regulates gut permeability and can cause tight junctions to open, making the gut leaky (*). This is an issue, as this allows pathogenic bacteria and their metabolites (lipopolysaccharide – LPS) to initiate inflammation via activation of Toll like receptors – TLR2, TLR4 (*), exacerbating barrier dysfunction. Its possible that this inflammatory loop contributes to the further dysrgulation of HPA , SNS signalling and neurotransmission altering mood.

Both alterations in gut microbiota and intestinal permeability (leaky gut) have been found in various types of depression (*) (*).

The kynuerenine pathway

This pathway is a way in which cortisol, adrenaline and inflammatory cytokines could all bring about depression. Additionally, both serotonergic and glutaminergic neurotransmission can be affected, which may account for alterations in mood.

We can see how the kyneurinine pathway is being expressed by examining metabolites of tryptophans precursor – serotonin. Theres thought to be an association between high amounts of kynurenine metabolites and depressive symptoms.

Typically tryptophan is available for serotonin and kynurenic acid (KynA) synthesis. KynA is thought to be neuroprotective, and is reported to be reduced in depression (*).

But, under inflammatory conditions tryptophan can be shunted down the famous kynuerenine pathway. Inflammatory cytokines shift Tryptophan metabolism towards Quiniloic acid. QA activates the NMDA Glutamate receptor, and could produce excitotoxicity causing neuronal damage and lead to the development of depression (*). This funnelling of TRP to QA reduces KyNA, which is thought to serve as the neuroprotective branch of the kynurenine pathway.

Serotonin and depression

Sleep disturbance and kynurenine metabolism in depression. Hyong Jin Choa Jonathan Savitzbc Robert Dantzerd T. Kent Teaguee Wayne C. Drevetsf Michael R.Irwina. 2017.

By assessing Quinolinate and Kynurenate with a urinary organic acids test, this may help inform the activity of Tryptophan metabolism. Consequently this may indicate the presence of pro-inflammatory cytokines.

Robust evidence (*) supports association between depressive symptoms and production of neurotoxic kynurenine metabolites to be mediated by inflammatory cytokines. Cytokine induced activation of IDO and KMO shuttles tryptophan down the kyneurinine pathway.

By shifting tryptophan down the kyneurinine pathway, cytokines may also impair 5-HT (serotonergic neurotransmission) by way of using up tryptophan (*).

The kynurenine pathway can be activated by elevated Glucocorticoids, Adrenaline and Inflammatory Cytokines (induced by Adrenaline).

Its helpful to measure HPA activity, Cortisol metabolism (production and clearance), which could be driving the kynurenine pathway. In addition Sympathetic nervous system activity (SAM) is worth looking at, which is the rationale for measuring Vanilmandelate – a metabolite of adrenaline. 

Vanilmandelate measurements help asses adrenaline signalling and potential inflammaton. Low VMA may indicate decreased AD + NAD – adrenal insufficiency – depression, inability to deal with stress, fatigue.

Overview of the kyurenine pathway:

How stress causes depression

Katherine O’ Farrella Andrew Harkinab. Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders. 2017

Ash shown above:

  1. Conversion of Tryptophan to Kynurenine is induced by enzymes TDO, IDO.
  2. Stress induced release of Glucocorticoids (namely Cortisol) induces the activity of TDO
  3. IDO induced in response to stress through adrenaline – β adrenergic stimulation of immune cells – producing inflammatory cytokines IL-1β, IL-6 and interferon (IFN)-γ.
  4. Tryptophan crosses BBB and can be shunted towards metabolites which have reactive oxidative properties.
  5. Quinolinic acid at microglia can bind Glutamate NMDA receptor and produce exito/neurotoxicity > depressive symptoms.

Thyroid status

Characteristics of depression in relation to thyroid status typically show high T4 levels, low T3, elevated rT3 and a blunted TSH response to TRH (*). Although, not all cases of depression may necessarily be associated with some or all of these features. For example; the prevalence of depression in hypothyroidism is said to be close to 50%, and 28% for hyperthyroidism (*), which indicates complex dynamics around thyroid function and mood alterations.

Nevertheless, since the HPA axis is closely intertwined with the thyroid (HPAT axis), some of these changes could be attributed to chronically elevated output of cortisol.

Cortisol increases t4 via activation of TRH producing neurones in the hypothalamus, stimulating the HPT axis, which has been associated with depression (*). This may also account for the reduced response TSH has to TRH, as an adaptation to deal with levels of TRH that are too high (*).

Additionally, cortisol inhibits the activity of deiodinase (D2), an enzyme that converts t4 to t3 in the brain. Consequently, t4 is converted to rt3 by deiodinase 3 (D3), which further inhibits the activity of D2 (*). This is another pathogenic factor in depression.

Changes in signalling throughout the HPT axis, such as TRH, TSH and deiodinase activity (high rt3 low t3) eventually influence the amount of available T3. This is significant because its T3 that actually exerts the most biological activity. This is why we want conversion from t4 and to rt3 to be well regulated to produce T3 within optimal ranges, which will then go on to act on target tissues throughout the body.

Changes in serotonin neurotransmission are positively correlated to T3 concentrations (*), which has been shown in rats to be mediated through changes in the sensitivity of 5HT1A receptors, and subsequent increases in serotonergic transmission (*).

Therefore, changes in the activity of deiodinase enzymes are a big deal; they indirectly influence brain serotonin via the amount of T3 available (*). This may be how cortisol throws a serious spanner in the works, through altering deiodinase activity.

However, serotonin can also inhibit TRH, and reduced levels of serotonin in the brain may increase TRH causing downstream changes to thyroid function (*). This is yet another example of the non-linear fashion by which these systems can interact with each other, almost in a loop / feedback mechanism.

In a similar way, T3 can alter adrenergic neurotransmission by increasing the sensitivity of adrenergic receptors (*). Noradrenaline, like serotonin is a monamine neurotransmitter and acts through the adrenergic system. The activity of these neurotransmitters are famously implicated in depression, understood as the monamine theory of depression. Therefore, its interesting to note the effects of T3 on B-adrenergic receptors, given that T3 has demonstrated anti-depressant effects.

In another complex loop, noradrenaline availability is also necessary for conversion of T4 into T3 in the brain (*), as well as for the stimulation of TRH from the hypothalamus (*) to initiate production of thyroid hormones (T3), and therefore sensitise adrenergic receptors.

This demonstrates the need to address not just the thyroid and its influence on cognition, but other influences on brain function and subsequent effects on thyroid function, such as the other mechanisms outlined.

Endocannabinoid signalling

The endocannabinoid system closely regulates mood in part through its interaction with the HPA axis. Stress (HPA activity) can actually change endocannabinoid signalling by decreasing levels of anandamide (AEA) and increasing 2-arachidonylglycerol (2-AG) across brain regions including the amygdala and hippocampus (*).

AEA is significantly lowered in chronic stress by an up regulation in FAAH, the enzyme responsible for its degradation. This comes in response to increasing CRH from the hypothalamus in response to the feedback of elevated cortisol (*).

AEA is actually known as the bliss chemical, and binds to the CB1 receptor to bring about these effects. Relatively low brain levels are implicated in depression, which is no surprise given the influence of CB1 in modulating mood (*).

CB1 receptors are expressed on many different neurotransmitter systems including serotonergic (*), adrenergic, glutaminergic (*), GABAergic (*), and dopaminergic (*) neurones. Its also well known that activation of CB1 produces significant elevations in mood

Chronic stress, mediated through cortisol (corticosterone) results in a reduction in CNR1 expression and loss in CB1 receptors (*). Interestingly, CB1 receptor density has been found to be decreased in the anterior cingulate cortex of patents with depression compared to controls (*)

So, together both low AEA and less CB1 to bind affect neurotransmission and mood.

Endocannabinoids and depression

Keith A. Sharkey and John W. Wiley. The role of the endocannabinoid system in the brain-gut axis. 2016.

How to treat stress related depression

One thing that I hope has become clearer as you soldier through this article is that depression can have many different forms and mechanisms. Its for this reason that well targeted and cumulative interventions may prove beneficial over single and generalised approaches. What works for you may not work for someone else, and you may benefit from a highly unique combination of interventions.

Cognitive Behavioural Therapy

CBT is a way of re-shuffling perceptions, beliefs and attitudes within the limbic system. Through changing reactions to, and perceptions of stress, CBT may reduce the physiological response to stress from psychological inputs.

This meta-analysis of 115 studies found CBT in depressed adults to be just as effective as other forms of psychotherapy. When combined with other treatments, CBT was significantly more effective than pharmacotherapy alone (*)


This is still quite a ‘woo woo’ concept for some people as there is no real tangible evidence that it will do anything for them until they practice it. However, the shift in psychology and physiology can be profound from locking into meditative states.

This review examined the mechanisms by which meditation works its magic, and suggested a decrease in the stress response through synchronisation of heartbeat and breathing (*). This is known as cardiorespiratory synchronisation, and can be achieved through a state of mindfulness inducing a ‘mind-body’ response. The relevance to depression here is that these changes are brought about through the hypothalamus and autonomic nervous system; a pathway which we know (see mechanisms) could be at work. 

An intervention trial studied the effects of a mindfulness based practice on autonomic nervous system activity in 18 participants. The study found a significantly improved sympathetic – vagal tone after 8 weeks, which was measured by heart rate variability (more on HRV here) (*).

This meta-analysis of 9 RCT’s found mindfulness based practices (MBP) to be effective in reducing depression in cancer patients (*). Most of the therapies were 8 weeks in duration, and benefits lasted up to 12 weeks after the start of intervention, which supports that notion that MBP’s need to be ongoing for lasting results.

FYI, the type of MBP differed between studies so benefits may not be ubiquitous for all MBP’s alike.

Yoga/Qi Gong/Tai Chi

These practices are unique in the way that they provide a way in which to unify the body and mind through movement, breathing and focused attention.

Yoga is probably the most famous of these mind~body practices, and the majority of yoga subtypes tend to be slightly more vigorous than Tai Chi and Qi gong. The way in which yoga exerts its benefits is highly relevant to both stress and depression, through the regulation of neuroendocrine pathways such as the HPA axis and autonomic nervous system.

A meta-analysis of 5 RCT’s found yoga to be an effective intervention for depressive disorders (*). Additionally, the benefits were in part attributed to normalisation of autonomic nervous system function (lower SNS higher PNS activity – see mechanisms).

A prospective study on 24 mentally stressed women found significant reductions in salivary cortisol after 3 months of lenegar yoga practice (*). Another study found significant reductions in the catecholamines adrenaline and noradrenaline following 3 weeks of yogic exercises (*).

These studies indicate that yoga may be an effective means of reducing the stress response through HPA hyperactivity, and SNS dominance (see mechanisms).

Qi gong, but not tai chi was found to reduce the severity of depressive symptoms in a meta-analysis of 6 RCT’s (*). However, the authors noted the quality of studies was questionable.

Nevertheless, other studies have shown Tai chi to have a beneficial impact on autonomic nervous system balance and vagal tone (*), (*)

A meta analysis of 26 RCT’s found mind body practices including yoga, Qi gong and Tai chi to be beneficial for reducing pro-inflammatory signalling. It was suggested that an improved quality of life is mediated through mechanisms such as HPA control, autonomic function (*).

Yoga, Qi gong and tai chi for depression

Julienne E. Bower, Ph.D. and Michael R. Irwin, M.D. Mind-body therapies and control of inflammatory biology: A descriptive review. 2015.

Probiotics and prebiotics

These are particularly relevant to the gut microbiome mechanism, where stress ends up depleting neurotransmitter producing, immune regulating and gut barrier modulating bacteria.

The good news is that with some strategic nutrition and supplementation, you may be able to offset some of the consequences the stress response has on the microbiome.

Stress induced changes to the HPA axis and autonomic nervous system show sensitivity to probiotic intervention (*) and supplementation of Bifidobacterium may prevent the onset of depression from stress in humans (*).

This systematic review suggested probiotic supplementation may improve symptoms of major depression by increasing serotonin availability, and reducing inflammatory markers (*). These benefits are mostly associated with strains of Lactobacillus and Bifidobacterium. Although further research is needed with regards to mental health outcomes of probiotics, these findings are promising.

Prebiotics nurture beneficial bacteria like Lactobacillus and Bifidobacterium to support their growth (*). Consequently these bacteria are better equipt to regulate the environment in the gut via metabolites of prebiotic fermentation – short chain fatty acids (SCFA). 

Although evidence in humans is sparse due to the fairly recent discovery of prebiotics for mental health; this link has been shown in animals. Mice who were treated with two prebiotics – fructooligosacchardies (FOS) and galactooligosaccarides (GOS) showed significant reductions in corticosterone (cortisol in humans) (*). In addition, the mice also showed changes in their behaviour – reduced anxiety and depression scores.

Garlic, onions, bananas, jerusalem artichokes, asparagus and oats are great sources of fructooligosaccharides and inulin. Beans like kidney, lima and lentils are a great source of galactooligosaccharides.

Anti-inflammatory agents

As outlined under the causes of stress and in the mechanisms, inflammation is one of the root causes in producing depressive symptoms. As inflammation is triggered by the stress response, and in response to environmental stressors, any effort to reduce the impact of inflammation may help curb the manifestation of stress into depression.

There are many herbs, compounds, nutrients, supplements and foods with anti-inflammatory properties. Here, I’m just going to outline a few which are particularly efficacious.

Cannabis is a well known anti-inflammatory, and has shown to be effective in reducing symptoms of depression in up to 90% of patients (*). Cannabinoids also reduce excessive HPA axis activity following stress, which may also account for anti-depressant effects (*).

Turmeric shows to be a promising anti-inflammatory, anti-depressant, neuroprotective in animal models (*). An RCT found Curcumin to have partially beneficial anti-depressant effects in patients with major depression, which were obvious from week 4-8 of intervention. Effects were attributed to the anti-inflammatory and regulatory capacity of Curcumin on the HPA axis (*).

Ginger is a well known anti-inflammatory, and targets inflammation at the source (COX-2 Inhibitor) and NF-Kb (master switch of inflammation) (*). Dehydrozingerone (phenolic compound in ginger) showed potent anti-depressant activity in mice, which was attributed to changes in serotonergic and noradrenergic neurotransmitter systems (*). This may be, in part a result of a reduced inflammatory response.

An RCT found Cacao polyphenols to enhance positive mood states after 30 days of drinking a dark chocolate drink (*). CP’s reduce pro-inflamamtory mediators – leukotrienes and nitric oxide, measured in vivo 2 hours after eating polyphenol rice cacao products (*).

Blueberry flavinoids acutely improve mood in young adults (*), possibly due to anti-inflammatory, and antioxidant capacity. Blueberries demonstrated these qualities by inhibiting NF-κB and inflammatory cytokines TNF-α and IL-6 (*).

Green tea polyphenols had anti-depressant effects in a mouse model of depression, possibly through inhibition of the HPA axis (*), in which the anti-inflammatory properties of GTP may play a role. Epigallocatechin 3-gallate (EGCG), a catechin in green tea is a potent antioxidant and regulates signal transduction pathways (*).

Omega-3 fish oils are effective for improving depressive symptoms, which a meta analysis found in patients with major depression (*). They also address inflammation at the root (COX inhibitors), reducing expression of inflammatory cytokines (*).

Neutropic factors

There are specific compounds which can stimulate the growth of new neurones in the brain, particularly the hippocampus. Such growth is called neurogenesis, which is positively correlated with improvements in mood and depression. Exercise and learning new skills also stimulate these compounds, as well as various compounds in plants.

Cannabinoids induce hippocampal neurogenesis in rats and produce anti-depressant effects (*). Endocannabinoids may play a role in phases of neurogenesis, and using cannabinoid specific targets may be a good approach for mood disorders (*).

Sulfurofane from broccoli epigenetically stimulates neuronal BDNF (*), and has been shown to produce anti-depressant effects in mice (*). Sulfurophane has neuroprotective action via stimulation of BDNF in vitro (*).

Ashwagandha reverses the loss of neurones and synaptic loss, and has well established antidepressant properties, is anti-inflammatory and regulates HPA axis activity (*). Many of these benefits can be attributed to the adaptogenic properties of this herb.

The active compound madecassoside in Gotu kola increases the expression of BDNF and showed neuroprotective activity in the brain of rats (*). This meta analysis of 6 RCT’s found improvements in mood due to greater alertness after 1 hour of dosing Gotu Kola (*).

Rhodiola rosea is an adaptogenic herb which not only has anti-inflammatory properties, but also regulates HPA axis activity, and increases expression of BNDF in the hippocampus of rats (*). A clinical trial found a Rhodiola extract to produce anti-depressant effects in patients with mild to moderate depression after 6 weeks of supplementation (*).

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