Advanced nutrition for the brain series: stress, the HPA-axis and neuroinflammation. Targeted nutritional interventions for successful treatment of mental health conditions. Inflammation is a major contributing factor to chronic modern illness and is driven, in part, by chronic stress and HPA-axis over stimulation. Mental health conditions, in particular clinical depression, are increasingly linked with neuroinflammation. As such, anti-inflammatory interventions are known to result in significant clinical benefits. During this webinar Dr Bailey will discuss the biological mechanisms linking stress, chronic inflammation and mood disorders, together with a review of the current evidence for a targeted, anti-inflammatory nutrition approach to treatment. Nina will also clarify why some of the recent trials have failed to report benefits and how to optimise your anti-inflammatory interventions to treat clients with anxiety, depression, schizophrenia and PTSD.

1. Nina Bailey
BSc (Hons) MSc PhD ANutr
Stress, the HPA-axis and neuroinflammation

2. Acute stressors occur rapidly and
have an obvious onset and
offset; chronic stressors are
ongoing and may not have a clear
endpoint
Brief, predictable stressors are
generally beneficial in terms of
enhancing cognition, emotion
and neurobiological systems such
as the immune system
Chronic, sustained stressors are
considered to be the most
deleterious, contributing to
immune and endocrine
dysfunction, altered mood, and
several neurobiological and
psychological diseases

3.  Many physical illnesses are associated with behavioural changes - such as
decreased appetite, weight loss, fatigue, sleep disturbances, impaired cognitive
abilities and depressed mood
• These symptoms appear to result from immune activation and are mediated
by inflammatory cytokines (i.e. IL-1, IL-6 and TNF-α) and named ‘sickness
behaviour’
 Similar symptoms (to sickness behaviour) can be induced artificially by the
administration of bacterial endotoxin and IFN-α (given therapeutically for
hepatitis C)
• These IFN-α -induced symptoms can be successfully treated with SSRI
antidepressants, suggesting that the production of inflammatory cytokines
may also underpin the development of depressive illness

4. An excessive level of cortisol is neurotoxic, especially for hippocampal neurones
which play a predominant role in memory and learning
Patients with Cushing's disease (exposed to excessive release of cortisol over long
periods) present with reductions in hippocampal volume that correlate to deficits in
cognitive function and memory (Andela et al. 2013)
Depression, anxiety and cognitive dysfunction, decreased libido, disrupted sleep are
also common in patients with Cushing's disease
In a 1997 study - 66% of Cushing’s patients exhibited psychopathology, consisting
mainly of atypical and major depression as well as anxiety disorder and increased
suicide risk
After three months following treatment (surgery) for hypercortisolemia, this
dropped significantly to 54% and further decreased to 24% after 12months
Starkman 2013; Dorn et al. 1997

5. Elevated cortisol levels and decreased hippocampal volume
The neurotoxic effects of cortisol on the hippocampus may depend on at
least three factors:
the developmental stage of the structure (the hippocampus glucocorticoid
receptors density may change throughout development)
the level and sustainability of cortisol released
the severity and/or duration of the stressful event/s
Bremner 1999

6. Psychological stress
Psychological stressors fall into different categories, depending on the
individual's age during stress exposure, severity and chronicity of the
stressor, and the subjectively perceived threat:
 Altered mother-infant interaction (i.e. foster care)
 Chronic abuse (physical and mental)
 Life-threatening situation (rape, combat situation, natural disaster)
 Chronic stressors in adult life (such as loss, financial issues, etc)

7. Early life stress
 Stress early in life may induce a vulnerability to stress later in life, resulting in
an increased risk for anxiety, depression and post traumatic stress disorder
(PTSD)
 In the pathogenesis of PTSD, fear memory becomes excessively consolidated
and extinction learning doesn’t progress with high comorbidity between
PTSD and depression
 Childhood physical abuse predisposes for PTSD development of anxiety
disorders and depression in adulthood and influences its clinical course and
predicts a poorer treatment outcome
 Women with a history of childhood abuse are more than twice as likely to
develop depression as non-abused women
Juruena et al. 2015

8. Changes in brain structure in mood disorders
 Dysregulation of the HPA-axis/elevated cortisol is strongly implicated in the
pathology of major depressive disorder and are also key features in
neurodegenerative disease
 MRI scans and post mortem studies show that depression is related to changes
in regions of the brain relating to mood (i.e. the temporal lobes, medulla and
hippocampus)
Levels of neurotrophins such as Brain-Derived Neurotrophic Factor (BDNF)
involved in neuronal survival and synaptic plasticity, are lower in patients with
major depression, bi-polar depression and animal models of depression
Du & Pang 2015

9. Cortisol and long-chain omega-3 fatty acids
Studies have found a modulating effect of HPA-axis
activity on long-chain fatty acid metabolism
Cortisol influences mobilisation, oxidation and
synthesis of fatty acids
For example, cortisol inhibits Δ5- and Δ6-desaturase-
activity enzymes responsible for unsaturation of fatty
acid chains
High cortisol concentrations are therefore associated
with a decrease in omega-3 EPA and DHA
concentrations
Mocking 2013
DHA
EPA
ETA
SDA
ALA
Δ -6 desaturase
Elongase/desaturase
Δ -5 desaturase
Elongase

10. Bosma-den Boer et al. 2012

11. RBC membrane content of AA versus circulating TNF-α and IL-6
concentrations in healthy adults
Flock et al. 2014

12. Primary structural function &
anti-inflammatory docosanoid
production
Anti-inflammatory eicosanoid
production
REDUCED INFLAMMATION
DHAEPA
Pro-inflammatory eicosanoid
production
INFLAMMATION
AA
AA to EPA ratio
direct antagonism
The relationship between the omega-3 index and the AA to EPA ratio
Omega-3 index

13. There is now an extensive body of data showing that depression is
associated with both a chronic low-grade inflammatory response and
activation of cell-mediated immunity
High AA and low EPA increases the inflammatory ‘potential’
Meta-analyses of 14 studies comparing PUFA levels between
depressive and control subjects
 omega-3 levels significantly lower in depressed subjects
compared to controls
 Differences in the levels of omega-3 were more pronounced for
individuals with severe depression
Low omega-3 index and a high AA to EPA ratio are associated with
the severity of depression
Conklin et al. 2007; Lin et al. 2010

14. Elevated cytokines are associated with depression
Meta-analysis (18 studies) found significantly increased levels of IL-1β,
IL-6, and TNF-α in post mortem brain samples of suicide victims compared
with brain samples of healthy control individuals who did not die by
suicide
Levels of IL-1β and IL-6 were robustly associated with suicidality
 Higher levels of the systemic inflammatory marker IL-6 in childhood (9
years) are associated with and increased risk of developing depression
and psychosis in young adulthood (18 years)
Black et al. 2014; Khandaker et al. 2014

15. Cytokine-induced depression
 Intravenous administration of IFN-α for seven days in healthy males
– Volunteers became feverish, fatigued and lacked appetite before
becoming socially withdrawn, slow to answer questions, losing
interest in their surroundings, sleeping most of the day
(Rohatiner et al. 1983)
IFN-α affects HPA-axis activity
– Increased cortisol brought about by IFN-α administration
significantly correlates with depression and fatigue
(Raison et al. 2010)

16. Serotonin
TDO
IDO
IFN-γ, TNF-α,
IL-1, IL-6
Kynurenine
Quinolinic acid
NMDA agonist
3-Hydroxykynurenine
+
+
+
KMO
5-HTP
Neuronal damage Depression
Kynurenic acid
NMDA antagonist
NMDA receptor
Tryptophan
Cortisol
IDO
Sleep disturbance
IFN-γ, TNF-α,
IL-1, IL-6
+

17. Omega-3 modulates neurotrophins
High omega-3 intake is associated with higher levels of BDNF and is
associated with increased/greater grey matter volume (hippocampus &
amygdala) in healthy individuals (Conklin et al. 2007; Ferreira et al. 2014)
Omega-3 deprivation [animal model] decreases frontal cortex omega-3
content and reduces frontal cortex BDNF expression (Rao et al. 2007)
A potential role of omega-3 in brain trauma

18. Production of
inflammatory cytokines
and catecholamines
Increased activity of
HPA-axis
Increased secretion of
cortisol
Decreased dendritic branching
atrophy/death of neurones
Normal growth and
survival of dendritic
neurones
STRESS
Low omega-3 intake
Reduced omega-3 metabolism
(via ∆ 5 & ∆ 6, desaturase)

19. 5-HIAA/serotonin ratio
After exerting its action in the
postsynaptic neuron, serotonin is
transported back to presynaptic
neuron by specific transporters (SERT)
The serotonin is incorporated again
into vesicles and metabolised to form
5HIAA
When SERT activity is increased, more
serotonin is metabolised to 5HIAA
Therefore, the 5HIAA/serotonin ratio
would be higher

20. Serotonin recycling and degradation
 The depletion of tryptophan and subsequent decrease in serotonin production is a
well-established feature of mood disorders pathophysiology (Oxenkrug 2010)
 SERT activity is increased by certain pro-inflammatory cytokines, thus reducing
overall serotonin activity (Jazayeri et al.,2010; Song et al. 2007)
Rats fed omega-3-free diets were associated with greater RBC membrane AA
composition and increased plasma IL-6, TNF-α and CRP compared to controls
 Both AA levels and AA to EPA ratio are positively correlated with plasma IL-6,
TNF-α, and CRP levels
 The 5-HIAA/5-HT ratio is significantly greater in frontal cortex,
hypothalamus, and ventral striatum of omega-3 deficient rats relative to
controls
(McNamara et al., 2010)

21. • Increased HPA-axis activity
• Increased cortisol production
• Increased IDO/TMO/KMO activity
• The kynurenine (KYN)/tryptophan ratio
• Increased SERT activity/low serotonin
• Decreased neurotrophins
• Decreased neurogenesis
• Increased hippocampal atrophy
• Decreased delta-6 desaturase activity
• Increased COX-2, PLA2 & PGE2 activity
Neuroinflammation in mood disorders
High AA to EPA ratio
Low omega-3 status
Cytokines
Cortisol

22.  2012 meta-analysis of 10 studies (including 2,280 subjects)
- EPA and total n-3 PUFAs were decreased in patients with
dementia
- levels of EPA, but not DHA or other PUFAs, were significantly
lower in patients with pre-dementia syndrome
- EPA may act as a disease-state marker AND a risk factor for
cognitive impairment (Lin et al. 2012)
 EPA intake is more advantageous than DHA in reducing "brain effort"
relative to cognitive performance (in young adults) (Bauer et al. 2014)
22
Omega-3 and dementia risk

23. Omega-3 increases blood flow to the brain supplying oxygen and fuel delivery, are
essential for neurotransmitter production and function, memory, learning, cognition, and
brain and neurone cell structure
Benefits restricted to those with sub-optimal omega-3 intake!!

24. Increased interest in the use of omega-3 in military settings to
reduce/prevent PTSD and suicide rates
Low EPA and a high AA to EPA ratio is associated with the severity of
the PTSD symptoms in Croatian war veterans (Kalinić et al. 2014)
Subjects with PTSD had significantly higher pro-inflammatory scores
(IL-1b, IL-6, TNF-α, INF-γ and CRP) compared to combat-exposed
subjects without PTSD (Lindqvist et al. 2014)

25. PTSD in severely injured patients
Significant numbers of accident–injured individuals worldwide who are
admitted to intensive care units develop PTSD
1 in 4 patients will develop full-blown or partial PTSD
Hippocampus is crucial for converting short-term memory into long-term
In the pathogenesis of PTSD, fear memory becomes excessively
consolidated and extinction learning doesn’t progress with high comorbidity
between PTSD and depression
Promoting adult neurogenesis by omega-3 supplementation early in the
post trauma period might facilitate the clearance of fear memory from the
hippocampus and consequently minimise PTSD symptoms

26. DHA for the prevention of PTSD in severely injured patients
110 accident-injured patients
3-month daily dose of 1,470mg DHA and 147mg EPA
Primary outcome was total score on the Clinical-Administered PTSD
Scale
Secondary outcome included PTSD diagnosis (full-blown or partial)
Specific effect of DHA on BDNF levels
(Matsuoka et al. 2015a; Matsuoka et al. 2015b)

27. DHA for the prevention of PTSD in severely injured patients
 No significant differences in CAPS total score at 3-months (DHA
10.78 vs Placebo 9.22)
 11.1% of the DHA group and 5.5% of the placebo group
developed PTSD
 RBC omega-3 DHA and EPA in the DHA group significantly
elevated compared to the placebo group (p <0.01)
Changes in BDNF levels at week 12 were inversely associated with
depression severity but with no specific effect of DHA on either BDNF
level
(Matsuoka et al. 2015a; Matsuoka et al. 2015b)

28. DHA group Placebo
Baseline 3-months Baseline 3-months
AA to EPA ratio 10.0 6.5 9.3 8.8
Omega-3 index 7.63 10.58 7.78 8.00
AA 12.33 10.9 11.94 11.58
EPA 1.23 1.64 1.29 1.32
DHA 6.40 8.94 6.29 6.68
Matsuoka et al. 2015a

29.  RBC membrane fatty acid composition was determined in first-
episode bipolar manic or mixed (n=40) and healthy (n=40) subjects
 At baseline bipolar subjects exhibited significantly lower RBC DHA
levels compared with healthy subjects
 EPA , DPA and AA were not different
McNamara et al. 2015
First-episode bipolar disorder is associated with erythrocyte
membrane docosahexaenoic acid deficits

30. Bipolar Healthy controls
AA to EPA ratio 65.9 58.9
Omega-3 index 3.1 3.9
AA 17.5 17.6
EPA 0.28 0.33
DHA 3.1 3.6
McNamara et al. 2015
First-episode bipolar disorder is associated with erythrocyte
membrane docosahexaenoic acid deficits

31. Fatty acid intervention is dependent on
• Omega-3 status
• EPA vs DHA requirements
• AA to EPA ratio ( inflammation)

32. Omega-3 intervention studies meta-analysis findings
•2009 meta-analysis (28 studies) clarified ‘EPA but not DHA to be responsible for
the efficacy of omega-3 long-chain polyunsaturated fatty acid supplementation in
depression (Martins 2009)
•Only those supplements containing EPA ≥ 60% of total EPA + DHA, in a dose
range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against
primary depression (15 studies) (Sublette et al. 2011)
•It is the EPA in excess of DHA within a supplement that exerts therapeutic effects
(Sublette et al. 2011)
•Meta-analysis of 8 RCTs (high EPA to DHA ration in 7 of the 8) indicate a
beneficial effect of omega-3 monotherapy on depressed mood in women
compared with placebo (Yang et al. 2015)

33. Hamilton Depression Rating Scale (HDRS) total scores after a 12 week
treatment with 1g daily DHA, docosahexaenoic acid or EPA,
eicosapentaenoic acid. *p<0.001.
1g pure EPA more effective
than 1g DHA in treating
depressive symptoms
(Mozaffari-Khosravi et al. 2012)
Pure EPA vs pure DHA in the treatment of clinical depression

34. The effect of EPA supplements in combination with fluoxetine
• Sixty outpatients with a diagnosis of major depressive disorder based on
DSM-IV criteria and a score >or=15 in the 17-item Hamilton Depression Rating
Scale (HDRS) were randomly allocated to receive daily either 1g EPA or 20 mg
fluoxetine, or their combination for 8 weeks
– Response rates (>or=50% decrease in baseline HDRS) were 50%, 56%
and 81% in the fluoxetine, EPA and combination groups, respectively
(Jazayeri et al. 2008)
– EPA alone or in combination with fluoxetine, as well as fluoxetine alone
decreased serum cortisol after 8 weeks
(Jazayeri et al. 2008; Jazayeri et al. 2010)

35. Why is EPA so effective in managing the symptoms of
depression?
EPA to DHA ratio of oils may affect the anti-inflammatory ‘potential’ and
there is evidence to suggest that EPA may be more effective than DHA in
reducing levels of the inflammatory cytokines TNF-a, IL-6 and IL-1β
(Bhattacharya et al. 2007)
Oils with a high ratio of EPA to DHA appear to be more effective in
treating depression and may explain some of the neutral findings reported
in some studies

36. Improves symptoms in
treatment-resistant
depression
Bypasses delta-6
desaturase
Reduces activation of
PLA2 and the release of
AA and PGE2
Reduces hippocampal
atrophy
Normalisation of
BDNF levels
Improved cell survival via
increased neurotrophin
receptor expression
Decreased pro-
inflammatory cytokine
production
Lowers cortisol levels
EPA
Increased production of pro
resolving mediators & anti-
inflammatory eicosanoids

37. In patients with hepatitis C treated with IFN-α up to 45% will
develop depression
IFN-α treatment in hepatitis C patients was associated with an
increase in depressive symptoms and serum kynurenine
concentrations and a decrease in serum concentrations of tryptophan
and serotonin
Low omega-3 and high AA to omega-3 ratio predicts depression
induced by IFN-α treatment
Bonaccorso et al. 2002; Lotrich et al. 2013

38. A 2-week intervention with EPA, DHA or placebo followed by 24 weeks of
IFN-α treatment (n=52)
Compared with placebo, the incident rates of IFN-α-induced depression
were significantly lower in EPA-treated but not in DHA-treated patients
(10% and 28%, respectively, versus 30% for placebo, p = .037)
Both EPA and DHA significantly delayed the onset of IFN-induced
depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for
placebo, p = .002)
EPA treatment increased both EPA and DHA erythrocyte levels, but DHA
only increased DHA erythrocyte levels
Su et al. 2014

39. EPA’s effects: high vs low inflammatory markers
 155 subjects diagnosed with major depressive disorder (as defined by
the Hamilton Depression Rating Scale - HAM-D-17) ≥ 15 were
randomised to 8-weeks of a double-blind treatment with EPA (1060mg)
or DHA (900mg) or placebo
 Outcomes were determined using mixed model repeated measures
analysis for ‘high’ and ‘low’ inflammation groups based on individual or
combined biomarkers
(IL-1ra, IL-6, CRP, leptin and adiponectin)
Rapaport 2015

40. EPA’s effects: high vs low inflammatory markers
 Although overall group differences were negligible, subjects with any
‘high’ inflammation responded more to EPA than placebo or DHA and
less to DHA than placebo
 Subjects identified as being high on any of the five biomarkers were
more likely to respond to EPA than to placebo with DHA and the EPA
placebo separation increasing with increasing numbers of markers of
high inflammation
 EPA supplements are more likely to be ‘effective’ where there is pre-
existing inflammation
Rapaport 2015

41. Biomarkers for personalising omega-3 fatty acid dosing
Omega-3 index
an early cardiovascular risk indicator
Omega-6 to omega-3 ratio
an established marker of long-term health and chronic illness
AA to EPA ratio
a measure of ’silent’ or chronic inflammation
A personalised plan aims to achieve:
an omega-3 index of more than 8%
an omega-6 to omega-3 ratio of between 3 and 4
an AA to EPA ratio of between 1.5 and 3

42. ‘RESTORE’
pure EPA
‘MAINTAIN’
EPA, DHA and GLA
Minimum 3-6 months
 AA to EPA ratio
 Inflammatory regulation
 Symptoms of inflammatory illness
 Optimum brain, cell, heart, immune
and CNS function
 Optimum wellbeing
 Omega-3 index
 AA to EPA ratio
 Long-term general and cellular health
 Heart, brain and eye health
 Reduce risk of chronic illness and help
protect against inflammatory disease
Therapeutic role of Pharmepa®
RESTORE & MAINTAIN™

43. • Increased HPA-axis activity
• Increased cortisol production
• Increased IDO/TMO/KMO activity
• The kynurenine (KYN)/tryptophan ratio
• Increased SERT activity/low serotonin
• Decreased neurotrophins
• Decreased neurogenesis
• Increased hippocampal atrophy
• Decreased delta-6 desaturase activity
• Increased COX-2, PLA2 & PGE2 activity
Neuroinflammation in mood disorders
High AA to EPA ratio
Low omega-3 status
Cytokines
Cortisol

44.  SAMe – metabolism of neurotransmitters
serotonin, melatonin and dopamine
 cysteine and glutathione – vital for antioxidant
protection and detoxification processes
 DNA – cell cycle, genetic replication, growth
and development
 carnitine, choline and CoQ10 – energy
metabolism and mitochondrial function
 myelin proteins – nerve transmission and CNS
communication
A healthy methylation cycle – necessary for the production of:

46. Highly bioavailable (‘body-ready’) micronutrient
actives
Formulated at proven dosages for enhanced efficacy
Strong benefits supported with strong health claims
Offers benefits for cardiovascular health, brain
function and mood balance
Synergistic benefits alongside the Igennus clinical
omega-3 range
Small, easy-to-swallow tablets optimised for split-
dosing
Split-dosing overcomes bioavailability issues related
to vitamin B12 intake and maintains optimal blood
levels of key B-vitamins
Suitable for vegetarians & vegans
Suitable for adults and children aged 7+
Nutritional information Per dose % RI*
Vitamin C (ascorbic acid) 160 mg 200
Vitamin B3 (niacin) 48 mg 300
Vitamin B5 (pantothenic acid) 36 mg 600
Vitamin B1 (thiamine ) 20 mg 1818
Vitamin B6 (pyridoxal-5-phosphate) 20 mg 1429
Vitamin B2 (riboflavin-5-phosphate 14 mg 1000
Vitamin B12 (methylcobalamin) 900 µg 36000
Folate ([6S]-5-methyltetrahydrofolate) 400 µg 200
Vitamin B7 (biotin) 300 µg 600
Super B-Complex

47. Igennus MindCare® is the first comprehensive range of targeted brain
nutrition supplements based on four identified consumer need-states.
EPA & DHA +
vitamins E & D
EPA & DHA +
vitamins E & D
EPA & DHA +
vitamins E & D
EPA & DHA +
vitamins E & D
Magnesium glycinate,
L-Theanine &
micronutrients
Acetyl-l-Carnitine,
L-Theanine, taurine,
caffeine &
micronutrients
5-HTP, Magnesium
glycinate &
micronutrients
N-Acetyl L-Cysteine,
alpha-lipoic acid,
resveratrol &
micronutrients

48. Education Technical
Sophie Tully
Nutrition Education Manager
sophiet@igennus.com
Dr Nina Bailey
Head of Nutrition
ninab@igennus.com

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