Anxiety and depression: The hidden link

Anxiety and depression are common conditions in modern times. With events such as the current Covid-19 crisis exacerbating stress, anxiety and depression in many people due to the worry, uncertainty, isolation and social distancing. Therefore, it is a crucial time to focus on mental health and support cognitive wellness.

Anxiety and depression are considered separate conditions however, they are not mutually exclusive with stress and anxiety considered a major trigger for the onset of depression. Comorbid depression and anxiety disorders occur in up to 25% of general practice patients. About 85% of patients with depression have significant anxiety, and 90% of patients with anxiety disorder have depression.1 This blog looks at the differences (and similarities) between the two considered mechanisms which trigger onset and highlights interventions to help support mood and cognitive and mental health.

Skip to Key Takeaways

What is anxiety?

Anxiety is a normal reaction to stress and can be beneficial in some situations. It can alert us to dangers and help us prepare and pay attention. Anxiety disorders differ from normal feelings of nervousness or anxiousness and involve excessive fear or anxiety, they are the most common form of mental health disorders, affecting nearly 30% of adults in their lifetime.

What is depression?

Depression is among the most common and costly of all psychiatric disorders. Nearly one in four women and one in six men experience depression during their lifetime, and up to 65% of individuals have recurrent episodes of the disorder. The WHO characterises depression by; persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities.  It can also disturb sleep, appetite and concentration.

Anxiety, grief and fear are all normal emotions which are designed to help us protect ourselves, so in what circumstances do these normal emotions lead to anxiety disorders and/or depression?

Theories of pathogenesis2

Most contemporary theories for depression concur that stress can initiate cognitive and possibly biological processes that increase the risk of the disorder. Major stressful life events are one of the best predictors of the onset of depression. Indeed, certain life events, such as those involving social rejection, confer a 21.6% increase in risk for onset of major depressive disorder.2 However although these theories are generally well accepted little has been investigated about the physiological processes that are influenced by stress and that, in concert with cognitive and affective processes, may lead to depression.

Research now has demonstrated that stressful events or ongoing psychological stress increases inflammatory components of the immune system, leading to increases in long term chronic inflammation. This is thought to be a major driver of depression. Increases in inflammation can in turn elicit profound changes in behaviour, which include the initiation of anxiety and depressive symptoms such as sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioural withdrawal.

In particular social stressors involving conflict, threat, isolation, and rejection have been shown to increase inflammatory markers including IL-6, TNFα and CRP.

A common method of inducing stress in humans is by the Trier Social Stress Test (TSST). Participants in this paradigm are asked to prepare and give an impromptu speech and to perform difficult mental arithmetic in front of a nonresponsive, socially rejecting panel of raters. It was found that:

  • Stress-related appraisals and reactions appear to modulate inflammation responding to acute social stress
  • Individuals who report experiencing more fear to the TSST have been found to exhibit greater increases in the proinflammatory marker
  • A third study reported that a public speaking tasks (similar to the TSST) induced feelings of anxiety, depression, and anger; greater increases in anxiety and anger were, in turn, independently related to greater increases in circulating IL-6 (an inflammatory marker)
  • Greater difficulty in maintaining a positive cognitive–affective state during the TSST was associated with greater increases in circulating IL-1β and that increases in circulating IL-1β in turn predicted increases in depressive symptoms over the following year.

One thing that has become clear over the last few years is that individuals can be exposed to the same type of stressful life events which can trigger high levels of inflammation in some but less in others. People who have an increased inflammatory response are then more likely to develop anxiety disorders and depression. The main factor that determines the initiation of inflammation is the perception of stress. People who perceive stress as helpful or do not consider the same situation as a negative stressful event have a reduced inflammatory response in comparison to those who feel the event is negatively stressful. In one study, perceived stress was inversely related to self‐esteem and positively associated with work‐related stress and depression, respectively.3 Therefore, interventions which aid a healthy perception of stress are useful preventative factors… more on these later.

How does inflammation trigger anxiety and depression?

The inflammasome

Inflammasomes are multi protein complexes which are initiated during some inflammatory responses. Their role is then to cause the maturation of the enzyme caspase-1 and activate the pro-inflamamtory cytokines (IL)-1β and IL-1 which are involved in neuroimmunomodulation, neuroinflammation and neurodegeneration. The inflammasome is hypothesized to be a key mediator of the response to physiological and psychological stressors, and its dysregulation may be implicated in major depressive disorder.

Studies found that genetic deficiency of caspase-1 decreased depressive- and anxiety-like behaviours, and conversely increased locomotor activity and skills. Caspase-1 deficiency also prevented the exacerbation of depressive-like behaviours following chronic stress. Additionally, pharmacological caspase-1 antagonism with minocycline ameliorated stress-induced depressive-like behaviour in wild-type mice. This suggests that inflammasome and hence caspase-1 activation plays a major role in the development of anxiety and depressive disorders.

Inflammation certainly plays a role in the pathogenesis of anxiety and depressive disorders directly by neuroinflammation and degeneration. However, this is not the only mechanism by which inflammation, particularly via caspase-1 activation has an influence on mood disorders. It has been shown that when caase-1 is inhibited gut microbiota changes are observed including increase in relative abundance of Akkermansia spp. and Blautia spp., which are compatible with beneficial effects of attenuated inflammation.4

Inflammation and the gut

Inflammation also influences mood disorders by inducing changes to the gut microbiome. These changes that occur are complex and not yet fully understood. But depression is consistent with specific alterations to the gut flora. More than 70% of the microbiome comes from the two most prominent phyla Firmicutes and Bacteroides, while Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia are present in reduced numbers. For instance, patients diagnosed with major depression disorder (MDD) have a different faecal microbiome composition compared to healthy controls: MDD patients showed increased Bacteroidetes, Protobacteria, and Actinobacteria, and less Firmicutes. Further, among genus these patients showed increased Enterobacteriaceae and Allistipes, and less Faecalibacterium, the last of which inversely correlated with the severity of the depression.

Similar effects are seen in anxiety disorders where faecal microbiota of patients suffering from generalised anxiety disorder (GAD) showed a much lower prevalence of five genera: Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricicoccus, and Sutterella. It is thought these may be relevant to mental health due to their documented production of short‐chain fatty acid (SCFA) compounds. SCFAs are essential for supporting the integrity of the digestive lining as well as the blood brain barrier and stimulation of the vagus nerve (nerve connecting gut with the brain), which could be a mechanism by which these changes elicit effects on mood and anxiety.

Additionally, psychological stress as well as alterations to bacterial diversity can increase intestinal permeability and allow bacterial liposaccharides (known as endotoxins) to enter blood circulation when an immune response is initiated. This peripheral inflammation can spread to the central nervous system (CNS) in various ways and thus affect mental health by promoting neurotoxins and hindering neurotransmitters.5,6

There has been demonstrated to be a strong correlation between IBS and depressive disorders, further cementing the relationship between inflammation, digestive function and cognitive health. It is worth mentioning that 90% of our feel-good neurotransmitter, serotonin, is made in the gut; further cementing this association. Research suggests that self-reported anxiety and depression provide a twofold risk for IBS onset. IBS is associated with the same risk factors as depression including genetic factors, food sensitivity or allergies and infections as well as increased inflamamtory markers (IL)-6 and IL-10. As mentioned, this inflammation alters gut microbes and the permeability of the gut mucosa. Therefore, there are multiple associations of disruption to neurotransmitter production (via microflora), increased gastrointestinal permeability leading to further inflammation, increased permeability of blood brain barrier (and therefore neuroinflammation) as well as activation of the HPA axis (therefore increased stress hormones).7

Vicious Cycle

There is a cycle which occurs that can be difficult to break where stress in itself can trigger anxiety and lead to inflammation (which in itself causes neurodegeneration and neuroinflammation), which disrupts the microbiome and affects neurotransmitter production, as well as signalling to the brain via the vagus nerve and additionally increases gastro-intestinal permeability which increases inflammation and can disrupt the blood brain barrier leading to further neuroinflammation. In tune all of these factors can then affect physiological stress which is increased by inflammation and gastrointestinal disturbances but also neuroinflammation may disrupt the way in which we perceive stress and therefore is a vicious cycle.

Although depressive and anxiety disorders manifest in different ways and may involve dysregulation of different neurotransmitters the pathogenesis is very similar in most anxiety and depressive disorders. It is important to realise that many medications for depression have been demonstrated to increase anxiety at least in the short term (and conversely anxiolytics can predispose to depression as they “depress” the CNS). So, it is useful to identify this as it is likely that different neurotransmitters are involved but also as these two are strongly related, they should not be treated exclusively and balance is key.

It should be noted that treatment for one can trigger the other i.e. anxiolytics are central nervous system depressants so if overdone can directly lead to depression and conversely anti-depressants (especially SSRI’s that also inhibit reuptake of noradrenaline) can predispose to or cause anxiety.8,9

Covid-19

In the prevailing world of the coronavirus pandemic many people who do not normally experience depression and anxiety are suddenly experiencing both. This is due to many factors including increased concerns about personal health and finances, the stressful impact of social isolation and worry about the impact on the planet. This is exacerbated by the media, which is permanently reporting on effects of Covid-19, which is no longer via TV news bulletins but constantly alerting via social media on phones and computers, which enhances the overwhelming feeling of stress and being out of control. This will also have a significant effect on perceived stress.

Perceiving Stress

As mentioned above a large factor affecting the way in which stress trigger inflammation is the way we perceive stress. This is easier said than done, who has ever been told not to worry, don’t stress or relax? Does this ever help?

However interventions which help to change our mindset can be very useful in the way in which we perceive stress.

Meditation/mindfulness – this is one of the best ways to reduce tension and anxiety and support a healthy mind. However when we are busy it is one of the things that tends to get pushed to the back of the queue and people forget to do it or are just not interested. Mindfulness-based stress reduction has small positive effects on depression, anxiety and psychological distress.

Mindfulness doesn’t have to take much time, you can just do simple breathing exercises, there are many different ways to do this but a simple one is 4-4-8. This is where you breathe in for the count of four, hold for four and breathe out for eight, doing this for a minute each day has been shown to reduce the symptoms of anxiety.

You can also use an app for directed meditation or mindfulness if you want to explore this further. There are many apps available, some popular ones are Calm and Headspace.

Exercise – exercise is important for both mental and emotional wellbeing as it can increase feel good endorphins as well as improving resistance to stress.

Be Grateful– gratitude journals have been shown to help improve measures of stress and depression. One study showed that people asked to journal five things they were grateful for that had occurred in the past week were 25% happier than those who didn’t or journaled negative emotions.

Acts of kindness – one thing which has been strongly shown to improve our mood and wellbeing are acts of kindness. Practicing kindness also has a profound effect our own mental & physiological health, helping us to become happier and compassionate towards others. Being kind to others has been known to help boost our own immune system, slow down aging, elevate our self-esteem and improve blood pressure.

In many cases further medical help can be required such as psychotherapy and cognitive behavioural therapy.

Nutritional interventions

Nutritional interventions to be considered should include method to reduce inflammation, support the microbiome and support gastrointestinal integrity. Therefore, the health of the gut always should be considered for anyone who is experiencing depression:

Consider supporting a healthy bowel flora by:

  • Take a live bacteria supplement – administration of probiotics and prebiotics has been shown to diminish the stress response during difficult tasks, improve the integrity of the intestinal barrier, and decrease inflammation. There is considerable evidence suggesting that these improvements among other effects may contribute to decreased anxiety‐ and depression‐like behaviours in murines
  • Consuming fermented foods such as kefir, kombucha, sauerkraut and miso
  • Consuming prebiotic (fuel for gut bacteria) foods and polyphenols from chicory, olives, baked apples and Jerusalem artichoke

Research has shown that nutrients important for repair and integrity of the digestive lining include:

  • Vitamin A
  • Vitamin D3
  • L-Glutamine
  • Zinc

Additionally, reducing inflammation should be considered:

Reduce inflammation by:

  • Optimising gut health
  • Reducing omega 6 fatty acids from meat, dairy and vegetable oils
  • Increasing omega 3 fatty acids from oily fish, chia and flax seeds and dark leafy green vegetables
  • Using anti-inflammatory foods such as turmeric (curcumin) and ginger
  • Increasing vitamin E containing foods such as avocado
  • Increasing Vit C-rich foods

General interventions

If you want to improve mood it is always important to consider:

  • Foods which contain tryptophan e.g. walnuts, turkey, oats, bananas
  • B6 and magnesium which convert 5HTP to serotonin
  • Gut health, suspect leaky gut and / or dysbiosis and consider a probiotic
  • Inflammation consider an anti-inflammatory diet as well as anti-inflammatory nutrients such as Omega 3 fats (as EPA), curcumin and ginger
  • Support anti-oxidant status and reduce oxidative stress
  • Is there a need for additional vitamin D3, zinc and methylation support (eg methylfolate and methylcobalamin)

Key Takeaways

  • Anxiety and depression are different conditions but are not mutually exclusive and often concur with each other
  • Stressful life events and ongoing physiological stress have been shown to increase inflammation and hence disrupt gastro-intestinal function (via disruption to microbiome and increased permeability of gastro-intestinal tract). These dysfunctions are associated with anxiety disorders and depression
  • The way in which stress is perceived has a greater effect on inflammation than the stress itself (if stress is viewed as negative this increase inflammation), therefore interventions to alter stress perception including meditation and mindfulness should be considered
  • Nutritional interventions include supporting anti-inflamamtory pathways, a healthy microbiome and integrity of the gastro-intestinal tract

If you have questions regarding the topics that have been raised, or any other health matters, please do contact me (Amanda) by phone or email at any time.

amanda@cytoplan.co.uk
01684 310099

Amanda Williams and the Cytoplan Editorial Team


References

  1. Tiller JW (2013) ‘Depression and anxiety’, Med J Aust, 99(S6) S28-S31.
  2. Slavich GM, Irwin MR (2014) ‘From stress to inflammation and major depressive disorder: a social signal transduction theory of depression’, Psychol Bull, 140(3) pp774-815.
  3. Lee JS, Joo E, Choi KS (2012) ‘Perceived Stress and Self‐esteem Mediate the Effects of Work‐related Stress on Depression’, Stress nad Health, 29(1) pp75-81
  4. Wong ML, Inserra A, Lewis MD, et al (2016) ‘Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition’, Mol Psychiatry, 21(6) pp797-805.
  5. Jason M. Peirce K (2019) ‘The role of inflammation and the gut microbiome in depression and anxiety’, Journal of Neuroscience Research, 97(10) pp1223-1241
  6. Jacobson, N. C., & Newman, M. G. (2017) ‘Anxiety and depression as bidirectional risk factors for one another: A meta-analysis of longitudinal studies’, Psychological Bulletin, 143(11) pp1155–1200
  7. Sibelli A, Chalder T, Everitt H, Workman P, Windgassen S, Moss-Morris R (2016) ‘A systematic review with meta-analysis of the role of anxiety and depression in irritable bowel syndrome onset’, Psychol Med, 46(15) pp3065-3080.
  8. https://www.sciencedaily.com/releases/2016/08/160824135045.htm
  9. https://www.addictioncenter.com/drugs/drug-classifications/central-nervous-system-depressants/

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6 thoughts on “Anxiety and depression: The hidden link

  1. I currently take Citralopram and Atomoxitine daily, I was really hoping to hear about a supplement as I really want to stop but still waiting for supplement that can help me.

    1. Hi Neil – Many supplements appropriate for mood and stress are contraindicated with citalopram. We cannot attach supplements to our blogs as this would be making a health claim about products, which we are unable to do due to legislation, especially with regards to anxiety. I would recommend completing a health questionnaire HERE, which can provide you with more targeted advice to support you with this. Thanks, Helen

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