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1. Anxiety and Your Patient
A holistic, integrative approach for the general
practitioner-
Copyright 9/11/2012

2. Epidemiology
 Journal Clinical Psychiatry- most
common psych disorder
 15.7 million in the US
 30% seek treatment
 Present to general practitioners more
than psychiatrist
Copyright 9/11/2012

3. What is Anxiety
 Persistent fear response without
identifiable specific trigger or
 Prolonged response
 Starts fight or flight response
 Anxiety increases risk of inflammatory
diseases
 More prone to mistakes, less
productive
Copyright 9/11/2012

4. Genetic?
 Studies show may be genetic
susceptibility with variants of retinoid-
related orphan receptor alpha (RORA)
gene to PTSD
 Gene primary function to protect brain
from stress
 Gene Variant of BDNF gene
Met66Met- smaller hippocampus on
imaging and higher response
amygdala to emotional stimuli with
Copyright 9/11/2012

5. Mediators- B.I.G
 Brain (neuroendocrine)
 Immune System- surveillance,
 Gut
 Vagus nerve 2 way communication
system between brain and gut
 All interact to form super information
highway
Copyright 9/11/2012

6. Brain-Theories and
Substances
 Trigger
 Arrives amygdala
 To Locus Cereleus
 Activation of sympathetic system
 Prefrontal lobe
 Response
Copyright 9/11/2012

7. Brain Connection- Pathway
 r
Trigger
Amygdala
Locus
Cereleus
NE
CRH
ACTH
Adrenal
Stimulation
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8. Theories and Substance
 Amygdala stores fear memories
 Used Pavlovian conditioned and
unconditioned stimulus
 Substances affect amygdala can
escalate or ameliorate anxiety
Copyright 9/11/2012

9. Brain Connection
 Locus Cereleus primary NE center in
brain
 LC can be affected by other NT
 LC connects to all parts of brain
including hypothalamus
 NE play role in HTN, behavioral
changes and modulates HPA axis
 Increased cytokines increase NE in
hypothalamus via LC neurons
Copyright 9/11/2012

10. Brain Connection
 Several factors seem to play a role
here
 NT such as GABA, Serotonin and
Norepinephrine and glutamate have
been assigned significant roles
 The HPA with CRF axis gets activated
as well
 Cytokines can form de novo in the
brain and trigger responses
Copyright 9/11/2012

11. Brain Connection
 The major neurotransmitters
implicated in the anxiety response
 GABA
 NE
 Serotonin
 Glutamate
Copyright 9/11/2012

12. Brain Connection
 Serotonin is known as inhibitory NT
 Derived from trytophan
 Majority found in gut (90%)
 Rest brain and platelets
 Foods that irritate gut can caused
excess release of serotonin leading to
diarrhea (goal is to expel substance
causing issue)
Copyright 9/11/2012

13. Copyright 9/11/2012

14. Brain Connection
 Serotonin depletion in prefrontal
cortex leads to anxiety symptoms
 Serotonin has 7 subtype receptors
 5HT1a- related to anxiety
 5HT3 in the chemoreceptor center
brain can be stimulated by excess
serotonin and cause nausea and
vomiting
Copyright 9/11/2012

15. Brain Connection
 GABA major inhibitory in the brain
 Also found in Gut
 Regulation of GABA system in
amygdala important part of anxiety
pathology
 Pathway conversion excitatory
Glutamate to GABA via enzyme
glutamate decarboxylase
Copyright 9/11/2012

16. Copyright 9/11/2012

17. Brain Connection- GABA
 3 types GABA receptors- A, B. C
 Deficiency in GABA receptors (A)- led
to hyper activation of HPA axis
 GABA-A (fast)– binding increase cl
conductance so hyperpolarize post
synaptic neurons to decrease
excitation
 GABA-B- inhibit Ca channels to
reduce NT release, and K channels to
decrease excitability Copyright 9/11/2012

18. Glutamate
 Excitatory NT (most abundant)
 Several studies indicate that
modulating glutamate receptors can
improve anxiety
 Mechanism not fully elucidated
 Glial cells responsible removal of
glutamate
 Dysfunction or reduction leads to
glutamate toxicity
Copyright 9/11/2012

19. Glutamate
 Thought to be mediated through
NDMA receptor
 Needs glutamate, glycine and voltage
for activation and opening channels
 Open- Calcium influx
 Excess calcium- neuronal injury
 Fine line because activation NDMA
needed for memory and learning
Copyright 9/11/2012

20. Norepinephrine
 Increases symptoms of anxiety
 When administered symptoms of
anxiety- HR, diaphoresis, etc.
 Controversy if NE from LC causative
Copyright 9/11/2012

21. Brain Connection-
Other substances
 CCK 4- provokes anxiety
 BDNF- responsible for health, growth
and plasticity of nerves (adaptability)
 BNDF protects neurons from
glutamate toxicity
 Oxytocin- role in social phobias
Copyright 9/11/2012

22. Brain Connection- BDNF
 Human study showed depressed
individuals with lower BDNF
 Those with lowest BDNF levels did not
respond as well to anti-depressant
treatment
 Several studies show BDNF facilitates
function of anti-depressant esp. SSRI
Copyright 9/11/2012

23. Immune Connection
 The immune system is thought to be
trigger
 Chronic GI inflammation increases
inflammatory cytokines and anxiety
behavior
 Immune system and neuroendocrine
share many receptor sites and ligands
 Cytokines (produced by immune system
and also by brain) can regulate stress
response in brain as well as endocrine
system and behavior Copyright 9/11/2012

24. Immune connection
 Immune system when triggered
produce cytokines
 Ex. IL-6, IL-1, IL-2, IFN-gamma, TNF,
 Peripheral cytokines can cross BBB
 Stimulate HPA axis as well as cause
brain (glial Cells) to produce de novo
cytokines
 Excess IL-6 act on neurons increase
anxiety and cognitive deficits
Copyright 9/11/2012

25. Immune Connection
 Cytokine can activate HPA axis
 Increase CRH
 CRH sensitize cells and facilitate
effect of cytokines like TNF
 TNF alpha injected in amygdala
facilitated ETOH withdrawal anxiety
 Inhibitor of CRH receptor decreased
magnitude of anxiety response
Copyright 9/11/2012

26. Immune Connection
 Interferon gamma stimulates enzyme
indoleamine2,3 dioxygenase (IDO).
This degrades Tryptophan
(responsible for serotonin formation)
to other inflammatory substances such
as Kynurenine
 17 B-estradiol could increases INF
gamma thereby potentially increasing
inflammation
Copyright 9/11/2012

27. Immune Connection
 Aging increases Cytokines such as
INF gamma, TNF alpha
 Dysregulates HPA feedback
mechanism thereby increasing cortisol
levels
 Cortisol affects metabolism of
tryptophan towards inflammatory
along with direct effect hippocampus
 Theorized one of reasons elderly more
prone to depression/anxietyCopyright 9/11/2012

28. Immune Connection
 Studies show that TCA like imipramine
and SSRI have anti-inflammatory
effect
 Decreases levels of IL-2, IL-1, TNF, IL-
6, INF gamma
 These substances have immediate
effect on NE and Serotonin but takes
longer for clinical benefits (about time
that it takes to have effect on
cytokines
Copyright 9/11/2012

29. Gut Connection
 Gut has over 100 million neurons
 90% visceral neurons have connection
with brain
 95% all serotonin found in gut
Copyright 9/11/2012

30. Gut Connection
 Studies showed that changing
bacterial flora in mice changed
behavior
 Colonized germ free mice with gut
flora from active or passive mice
would change behavior accordingly
 Mice treated with antibiotics- anxiety
reduction.
 Stopped antibiotics flora and anxiety
returned to baseline Copyright 9/11/2012

31. Gut Connection
 Changes seem to be associated with
change in BDNF (linked to anxiety and
depression)
 Stressor exposure changed bacterial
flora in gut (decrease genus
Bacteroides and increase Clostridium)
 Stressor also increased inflammatory
cytokines (IL-6, MCP-1) further
affected other bacterial flora
 IL-6 inflammatory cytokine
Copyright 9/11/2012

32. Gut Connection
 Evidence that Lactobacillus
Rhamnosus augments GABA function
in brain via vagus nerve from gut
(results lost with vagotomy)
 Also lowered corticosterone levels
Copyright 9/11/2012

33. Gut Connection
 Infectious colitis induces anxiety
Bifidobacterium longum NCC3001
improved anxiety (results lost with vagotomy)
 Bifidobacterium longum normalized
behavior and BDNF mRNA but did not
affect cytokine or kynurenine levels
 Enbrel- decreased cytokines and
improved anxiety but did not affect
BDNF
Copyright 9/11/2012

34. Gut Connection
 Since inflammation can directly affect
flora of gut and flora can affect
behavior
 Could anything such as food
sensitivities cause inflammation in gut
and thereby exacerbate anxiety
symptoms
 Personal food sensitivity such as
ALCAT may be an important adjunct
as testing looks at immune response
Copyright 9/11/2012

35. Gut Connection
 Study showed stress contributed to
development of food allergies by
increasing gut permeability therefore
increased uptake of food antigen
 Bacteria like H. Pylori has been shown
to do the same in gastric mucosa, also
increasing food sensitivity
 Activation of immune system and
cytokines
Copyright 9/11/2012

36. Gut Connection
 Food sensitivities trigger gut
permeability
 Part treatment remove triggers
 Heal gut
 Bifidobacterium Animalis Lactis LKM
512 found to help to keep tight
junction gut and decrease permeability
 Decreased inflammation in elderly
 Seems to suppress inflammatory
bacteria Copyright 9/11/2012

37. What to do?
 When and if possible identify trigger
 Gut symptoms- know can be variety of
things from food sensitivity, to
infectious or inflammatory trigger such
as IBD to emotional stress (remember
changes flora)
 ALCAT may be helpful
 Remove and or treat trigger
 Consider probiotics with
neuromodulatory effect
Copyright 9/11/2012

38. What to do
 Consider other substances to
decrease inflammatory cytokines while
treatment is on going (curcumin, fish
oil, and resveratrol, andrographis)-
?medical food
 Tea Tree Oil (inhalation)- decreases
TNF alpha, IL 1
 If over weight start weight loss
 Remember Adipocytes can generate
cytokines as well Copyright 9/11/2012

39. What to do
 German Chamomille- inhibited release
lipopolysaccharide which induce
macrophage prostaglandin E2 (LOX-2
inhibitor
 Maybe possess some anti-microbial
properties (gut dysbiosis)
 Contains Apigenin flavonoid- study
show mild sedative via inhibition
NDMA-R
Copyright 9/11/2012

40. What to do
 I have found neurotransmitter testing
helpful
 Even though no info on receptors, etc.
I find it helps me to chose
supplements or meds
 Check for easy nutrient deficiencies
B12, folate, red blood cell magnesium
(easier than loading test)
 Check cortisol/ACTH levels - helps in
choosing tx
Copyright 9/11/2012

41. What to do- herbal
 Valerian- blocks glutamate receptor
 Jujube (Ziziphysis Spinosa)- inhibits
glutamate receptor to decrease
excitability
 Kava- shown to improve anxiety
 Concern with liver issues due to
quality of Kava, parts used and
inappropriate dosage
 Passion Flower extract – thought to
have GABA agonist properties
Copyright 9/11/2012

42. What to do
 Tryptophan- just remember that
inflammation can turn a good AA bad
 Studies do not support St. Johns Wort
for anxiety
 Magnesium- modulates NDMA-R slow
influx calcium- protecting neurons
 Vitamin B12 studies show protects
neurons NDMA-R glutamate toxicity
Copyright 9/11/2012

43. What to do
 L-Theanine- studies suggests works
thru GABA- A receptors
 Other studies show affect on serotonin
and dopamine NT
 Personally noted that if dopamine on
NT test high, theanine may have
slightly anxiogenic affect
 Good news- neuroprotective by
decreasing formation glutamine to
glutamate
Copyright 9/11/2012

44. What to do- HPA Axis
 Lavender Essential oil stimulates PNS
to decrease excitability
 Lemon Balm- inhibitor of GABA
transaminase (enzyme clears GABA)
 Address HPA axis
 Stress management
 Cognitive therapy (enhanced with D-
cycloserine for specific phobias)
Copyright 9/11/2012

45. What to do-HPA
 Magnolia officianlis (honokiol and
magnolol)- decrease corticosterone,
increase 5HT in hippocampus,
antimicrobial, decrease TNF alpha
Copyright 9/11/2012

46. What to do
 If menopausal consider there may be
a hormonal component
 Changes in hormones such as
estrogen, progesterone and
testosterone can contribute to anxiety
symptoms
 I could correct other issues first to
optimize results
Copyright 9/11/2012

47. What to do- Hormones
 Several studies suggest estradiol can
be anxiolytic
 Estrogen increases the mRNA for
trytophan hydroxylase enzyme (rate
limiting step in production of serotonin
 Effects in dorsal raphe and seems to
occur binding ER beta
Copyright 9/11/2012

48. What to do- hormones
 Can increase proinflammatory
cytokines
 Avoid with autoimmunity
 ? One study suggest this effect may
be at least in part influenced by
presence of hydroxylated estrogens
(2,4,16) and cortisol
 Personal approach r/o autoimmunity,
correct inflammation if present before
this step Copyright 9/11/2012

49. What to do- Hormones
 Progesterone- anxiolytic or anxiogenic
 Several studies suggest that effect on
GABA receptors
 Conversion to allopregnanelone
Copyright 9/11/2012

50. What to do- Pharmacological
 SSRI, 5HT1a-R agonist- decrease
inflammation, increase serotonin (E.g.
Lexapro, Buspar)
 Also seem to modulate NDMA-R
 Benzodiazepene- GABA
 B-Blocker (Inderal)- performance
anxiety (stage fright, exams, etc.)
 Block sympathetic symptoms, also
acutely decrease endorphin levels
Copyright 9/11/2012

51. Some Concerns
 Prolonged use SSRI can lead to
osteoporosis
 Shown eventual decrease in serotonin
levels below baseline with chronic use
 Benzodiazepenes addictive potential
 Long term effect of beta blocker-
depression, memory loss etc.
Copyright 9/11/2012

52. What to Avoid
 Spirulina- increases, TNF alpha
 Echinaccea- can potentially increase
IL-6, TNF alpha
 ?? Honey- works by increasing TNF
alpha, IL 6, IL 1
 Remember cytokines can stimulate
HPA axis as well as activate amygdala
and LC =NE anxiety
 Caffeine blocks its receptors
adenosine that slows HR and calms-
Copyright 9/11/2012

53. THANK YOU
For more details visit
https://www.alcat.com
Copyright 9/11/2012