1. INFLAMMATION
AND DEPRESSION:
WHEN THE DOMAIN OF PAIN IS THE BRAIN
MARTHA STARK, MD
Faculty, Harvard Medical School
MarthaStarkMD @ HMS.Harvard.edu
Friday, September 22, 2017
1

2. GOALS AND OBJECTIVES
PROVIDE AN EXPLANATION AS TO WHY
ACUTE STRESS CAN “OPTIMIZE” BUT
CHRONIC STRESS WILL “TRAUMATIZE”
EXPLAIN THE CONCEPT OF LIMBIC KINDLING
AND ITS RELEVANCE TO DEPRESSION
ELABORATE UPON THE RELATIONSHIP BETWEEN
STRESS – INDUCED NEUROENDOCRINE AND
STRESS – INDUCED NEUROIMMUNE DYSREGULATION
ON THE ONE HAND AND DEPRESSION ON THE OTHER
SPEAK TO THE RELATIONSHIP BETWEEN
CHRONICALLY ELEVATED ANTI – INFLAMMATORY
CORTISOL AND CHRONICALLY ELEVATED
PRO – INFLAMMATORY CYTOKINE LEVELS ON THE ONE
HAND AND CHRONIC INFLAMMATION ON THE OTHER
2

3. PREVIEW
THE STRESS RESPONSE ~ GENERAL ADAPTATION SYNDROME
ACUTE AND CHRONIC STRESS ~ BIPHASIC DOSE – RESPONSE
WALTER B CANNON ~ HANS SELYE
UPSTREAM APPROACH ~ FERRETING OUT UNDERLYING CAUSES
ANTECEDENT PRIMING (“SENSITIZING”) FACTORS
LIMBIC KINDLING ~ HYPERSENSITIVITY TO STRESS
REVERSIBLE EPIGENETIC MODIFICATIONS
LIFESTYLE CHOICES ~ ENVIRONMENTAL EXPOSURES
HOMEOSTASIS ~ ALLOSTASIS
THE GROUND REGULATION SYSTEM ~ THE WISDOM OF THE BODY
REGULATORY CAPACITY ~ DYSREGULATION
ACTIVATED NEUROENDOCRINE SYSTEM
UPREGULATED HYPOTHALAMIC – PITUITARY – ADRENAL “STRESS” AXIS
ANTI – INFLAMMATORY CORTISOL
DESENSITIZED CORTISOL RECEPTORS
ACTIVATED NEUROIMMUNE SYSTEM
UPREGULATED MACROPHAGES (IN THE BODY) AND MICROGLIA (IN THE BRAIN)
PRO – INFLAMMATORY CYTOKINES
INFLAMMATION IN BODY AND BRAIN ~ DEPRESSION
INFLAMMATORY BIOMARKERS
NATURAL (NEUROPROTECTIVE) ANTI – INFLAMMATORIES
3

4. CHRONIC INFLAMMATION
PERIPHERALLY AND CENTRALLY
REDNESS, HEAT, SWELLING, AND PAIN
SILENT ENEMY
INVISIBLE WOUND
4

5. “MELANCHOLIA BEHAVES
LIKE AN OPEN WOUND”
MOURNING AND MELANCHOLIA (FREUD 1917)
COMPLEX INTERCONNECTEDNESS BETWEEN
A DYSREGULATED STATE OF MIND
AND A DYSREGULATED IMMUNE SYSTEM
INDEED
WHETHER AS CAUSE, CORRELATE, OR CONSEQUENCE
CHRONIC INFLAMMATION IS IMPLICATED
IN DEPRESSION ABOUT ONE THIRD OF THE TIME
SO ALWAYS AT LEAST CONSIDER
NATURAL ANTI – INFLAMMATORIES
FOR YOUR DEPRESSED PATIENTS
5

6. 6
… epidemiological and clinical studies show a role for
inflammation as a risk factor for major depression …
(Muller 2014)

7. 7
… accumulating evidence suggests that immune
dysregulation plays an important role in the
pathophysiology of depression …
(Su 2015)

8. 8
… increased levels of circulating
pro-inflammatory cytokines and concomitant
activation of brain-resident microglia
can lead to depressive symptoms …
(Wohleb et al. 2016)

9. “DEPRESSION: AN INFLAMMATORY ILLNESS?”
(KRISHNADAS AND CAVANAGH 2012)
“FINDINGS FROM PRECLINICAL AND CLINICAL
STUDIES SUGGEST THAT DEPRESSION IS
ASSOCIATED WITH INFLAMMATORY PROCESSES”
AS EVIDENCE, THEY CITE THREE OBSERVATIONS:
ONE THIRD OF THOSE WITH DEPRESSION SHOW
ELEVATED PERIPHERAL INFLAMMATORY BIOMARKERS,
EVEN IN THE ABSENCE OF A MEDICAL ILLNESS
INFLAMMATORY ILLNESSES ARE ASSOCIATED
WITH GREATER RATES OF DEPRESSION
PATIENTS TREATED WITH CYTOKINES ARE AT
GREATER RISK FOR DEVELOPING DEPRESSION
AND THEY CONCLUDE ...
9

10. 10
… while it is unlikely that depression is a primary
inflammatory disorder, there is now evidence to
suggest that inflammation may play a subtle role
in the pathophysiology of depression …
(Krishnadas and Cavanagh 2012)

11. 11
… a link between chronic inflammation and
dementia, at least in some patients with
recurrent and chronic depression …
(Leonard 2017)

12. THE CHRONIC LOW – GRADE INFLAMMATION
ASSOCIATED WITH CHRONIC DEPRESSION
IS NOW THOUGHT TO BE A PREDISPOSING FACTOR
FOR DEMENTIA IN LATER LIFE
IN PART BECAUSE OF IMMUNE – MEDIATED ACCELERATED DEGRADATION
OF TRYPTOPHAN BY AN UPREGULATED KYNURENINE PATHWAY
MORE SPECIFICALLY
STRESS – INDUCED PRO – INFLAMMATORY CYTOKINES ACTIVATE THE
TRYPTOPHAN – DEGRADING ENZYME INDOLEAMINE 2,3 – DIOXYGENASE (IDO)
WHICH SHUNTS TRYPTOPHAN DOWN THE KYNURENINE PATHWAY
SUCH THAT LESS TRYPTOPHAN IS THEN AVAILABLE TO BE
SHUNTED DOWN THE PATHWAY THAT SYNTHESIZES SEROTONIN
(THE “HAPPY” NEUROTRANSMITTER / HORMONE IN THE BODY)
THE NET RESULT OF WHICH WILL BE NOT ONLY
DECREASED PRODUCTION OF SEROTONIN FROM TRYPTOPHAN
BUT ALSO
INCREASED PRODUCTION OF NEUROTOXIC EXCITOTOXINS
FROM KYNURENINE
LIKE QUINOLINIC ACID – A POTENT NMDA (GLUTAMATE) RECEPTOR AGONIST
12

13. 13
indoleamine
2,3-dioxygenase (IDO) (5-HTP)
5-hydroxytryptamine
(5-HT)
N-methyl-D-aspartate
(glutamate) receptor
neurotoxic
(NMDA receptor agonist)
neurotoxic
(causes oxidative stress)
STRESS-INDUCED
NEUROINFLAMMATION
UPREGULATES THE
KYNURENINE PATHWAY
activated
pro-inflammatory
cytokines
NET RESULT OF THE DYSREGULATED KYNURENINE PATHWAY
EXCITOTOXICITY AND COGNITIVE IMPAIRMENT
(R Dantzer et al. 2008)
the most potent
one of which is
interferon gamma

14. CHRONIC DEPRESSION
AND CHRONIC NEUROINFLAMMATION
DYSREGULATED
KYNURENINE PATHWAY
A NEUROTOXIC SHIFT IN THE BALANCE
OF KYNURENINE METABOLITES
EXCITOTOXICITY
PROGRESSIVE
NEURODEGENERATION
DEMENTIA
14

15. BUT CHICKEN OR EGG?
DOES INFLAMMATION CAUSE DEPRESSION?
OR
DOES DEPRESSION CAUSE INFLAMMATION?
15

16. FIRST A DISCLAIMER
SURGEONS KNOW NOTHING
BUT DO EVERYTHING
NEUROLOGISTS KNOW EVERYTHING
BUT DO NOTHING
PSYCHIATRISTS KNOW NOTHING
AND DO NOTHING
PATHOLOGISTS KNOW EVERYTHING
AND DO EVERYTHING
BUT TOO LATE
16

17. WELL, I AM A PSYCHIATRIST 
IT HAS BEEN WRYLY SUGGESTED THAT PSYCHIATRY
WAS ONCE ALL ABOUT THE MIND
AND NOT AT ALL ABOUT THE BRAIN
BUT THAT PSYCHIATRY IS NOW ALL ABOUT THE BRAIN
AND NOT AT ALL ABOUT THE MIND
OUT OF RESPECT FOR THE INTIMATE INTERDEPENDENCE
OF MIND AND BRAIN AND IN DEFERENCE TO BOTH
MY PSYCHIATRIC AND MY NEUROSCIENCE COLLEAGUES,
I REFER TO THE “MENTAL COMPONENT” AS THE MindBrain
MY FAVORITE DESCRIPTION
OF PSYCHIATRY IS
“MEDICAL TREATMENT OF THE SOUL”
PARENTHETICALLY, A DISTINCTION SOMETIMES MADE
BETWEEN THE MIND AND THE BRAIN IS THAT
THE MIND INTERPRETS WHAT THE BRAIN PERCEIVES
17

18. THE VILLAINESS IN WHAT FOLLOWS WILL BE
DYSREGULATING STRESS
HERE DEFINED AS
ANYTHING THAT DISRUPTS HOMEOSTASIS
THE HEROINE WILL BE
RESTORATION OF HOMEOSTASIS
BY “LIGHTENING THE LOAD”
TO CORRECT FOR TOXICITIES
AND “REPLENISHING THE RESERVES”
TO CORRECT FOR DEFICIENCIES
ALL WITH AN EYE
TO “FACILITATING THE FLOW”
OF INFORMATION AND ENERGY
THROUGHOUT BODY AND BRAIN
SUCH THAT ENVIRONMENTAL STRESSORS CAN BE MORE
EFFECTIVELY PROCESSED, INTEGRATED, AND ADAPTED TO
AND HOMEOSTATIC BALANCE RESTORED
BY A NOW MORE RESILIENT SYSTEM 18

19. 19
“EVERY STRESS LEAVES
AN INDELIBLE SCAR,
AND THE ORGANISM
PAYS FOR ITS SURVIVAL
AFTER A STRESSFUL
SITUATION BY BECOMING
A LITTLE OLDER.”
HANS SELYE

20. “STRESS IS WHEN YOU
WAKE UP SCREAMING,
ONLY TO REALIZE
THAT YOU HAVEN’T
YET FALLEN ASLEEP”
ANONYMOUS
20

21. THE SPECIFIC REGULATORY ORGAN
SYSTEM(S) TARGETED BY STRESS
WILL BE THE RESULT OF
A “PROPRIETARY” COMBINATION OF
CONSTITUTIONAL ENDOWMENT
BIOCHEMICAL INDIVIDUALITY (WILLIAMS 1956)
LIFESTYLE AND ENVIRONMENTAL FACTORS
PSYCHOLOGICAL UNIQUENESS
ALTHOUGH AT LEAST ON SOME LEVEL
ALL THE BODY’S REGULATORY
SYSTEMS WILL BE IMPACTED,
THE STRESS – INDUCED DYSREGULATION
USUALLY MANIFESTS PRIMARILY IN
ONE OR TWO ORGAN SYSTEMS
21

22. SOMETIMES THE TARGET ORGAN WILL BE
THE CARDIOVASCULAR SYSTEM
(PERHAPS MANIFESTING AS HYPERTENSION)
SOMETIMES THE GASTROINTESTINAL SYSTEM
AND THE ORAL / GUT MICROBIOTA
(PERHAPS MANIFESTING AS GUM DISEASE
AND / OR INFLAMMATORY BOWEL DISEASE)
SOMETIMES THE MUSCULOSKELETAL SYSTEM
(PERHAPS MANIFESTING AS RHEUMATOID ARTHRITIS)
BUT
SOMETIMES THE TARGET ORGAN WILL BE
THE MindBrain
(PERHAPS MANIFESTING AS DEPRESSION)
22

23. WHEN THE TARGET ORGAN
IS THE MindBrain AND
MANIFESTS AS DEPRESSION,
THERE WILL USUALLY HAVE BEEN
ANTECEDENT PRIMING FACTORS
EARLY LIFE ADVERSITIES
DURING CRITICAL DEVELOPMENTAL PERIODS
GENETIC PREDISPOSITION
CAUSED BY MUTATIONS ~ POLYMORPHISMS
EPIGENETIC MODIFICATIONS
CAUSED BY LIFESTYLE CHOICES ~ ENVIRONMENTAL EXPOSURES
PSYCHOSOCIAL STRESSORS
RESULTING FROM
SOCIAL REJECTION ~ BULLYING ~ JOB STRESS ~ SOCIAL ISOLATION
23

24. AS IF BY “SCULPTING” SPECIFIC PATHWAYS IN THE BRAIN,
THESE FIRST – ORDER STRESSORS WILL
CREATE A LATENT VULNERABILITY
TO THE DEVELOPMENT OF
PSYCHOLOGICAL DIFFICULTIES
DYSREGULATED MENTAL STATES
WHEN LATER TRIGGERED BY
SECOND – ORDER STRESSORS
PSYCHOLOGICAL ~ PHYSIOLOGICAL ~ ENERGETIC
IN OTHER WORDS
THE GROUNDWORK IS BEING LAID
BY THESE SENSITIZING FACTORS FOR
SUBSEQUENT DEVELOPMENT OF
HYPERSENSITIVITY TO STRESS
24

25. THE LIMBIC SYSTEM IN THE BRAIN
MEDIATES THE STRESS RESPONSE
AND, WITH SUSTAINED STRESS, THE RESULT WILL BE
LIMBIC KINDLING
“THE MOST EXCITING CONCEPT IN NEUROSCIENCE
THAT MOST PEOPLE HAVE NEVER HEARD OF”
(GRATRIX 2014)
A FORM OF CLASSICAL (PAVLOVIAN) CONDITIONING
WHEREBY REPEATED EXPOSURES, OVER TIME,
TO A STRESSOR WILL SENSITIZE THE BRAIN
SUCH THAT EVENTUALLY EVEN MILD
STRESSORS WILL PROVOKE REACTIVITY
IN ESSENCE
LIMBIC KINDLING HARDWIRES THE
BRAIN FOR HYPERSENSITIVITY TO
STRESS AND CHRONIC ILLNESS
25

26. 26

27. 27
… the limbic system (the “feeling and reacting” brain)
is positioned between the cortex (the “thinking” brain)
and the reptilian brain (the “old” brain connecting
the nervous system to the rest of the body) …
… the limbic system deals
with emotions, arousal,
and memory …

28. LIMBIC STRUCTURES INCLUDE
THE AMYGDALAE (THERE ARE ACTUALLY TWO OF THEM)
WHICH SOUND THE ALERT WHEN TRIGGERED
(WHETHER FROM “ABOVE” OR “BELOW”)
THE HYPOTHALAMUS
WHICH THEN INITIATES THE STRESS RESPONSE
LEADING TO STRESS – INDUCED ACTIVATION OF NOT ONLY
THE SYMPATHETIC NERVOUS SYSTEM BUT ALSO
THE NEUROENDOCRINE SYSTEM
PROMPTING THE RELEASE OF CORTISOL
FROM AN UPREGULATED
HYPOTHALAMIC – PITUITARY – ADRENAL (HPA) “STRESS” AXIS
AND
THE NEUROIMMUNE SYSTEM
PROMPTING THE RELEASE OF PRO – INFLAMMATORY CYTOKINES
FROM UPREGULATED PERIPHERAL MACROPHAGES (IN THE BODY)
AND UPREGULATED CENTRAL MICROGLIA (IN THE BRAIN) 28

29. AND, AGAIN, WHEN THE BRAIN
(FOR WHATEVER COMPLEX MIX OF PROPRIETARY REASONS)
IS THE PRIMARY SYSTEM AFFECTED BY THE STRESS,
THE NET RESULT WILL BE
NEUROINFLAMMATION AND
A DYSREGULATED STATE OF MIND
BUT NOW WE ENCOUNTER AN INTRIGUING PARADOX
ON THE ONE HAND
STRESS ACTIVATES THE HPA AXIS,
RESULTING IN THE RELEASE OF CORTISOL,
WHICH IS AN ANTI – INFLAMMATORY HORMONE
ON THE OTHER HAND
STRESS ACTIVATES THE IMMUNE SYSTEM,
RESULTING IN THE RELEASE OF
PRO – INFLAMMATORY CYTOKINES
HOW DO WE RECONCILE THESE OPPOSING
STRESS – INDUCED “INFLAMMATORY” REACTIONS?
29

30. LATER I WILL SHARE WITH YOU THE EXPLANATION
THAT RESEARCHERS HAVE OFFERED
IN AN EFFORT TO RESOLVE THIS CONUNDRUM
BUT, FOR NOW, SUFFICE IT TO SAY THAT
RESEARCHERS HAVE INDEED FOUND
A DIRECT LINK BETWEEN CHRONIC STRESS,
INCREASED LEVELS OF ANTI – INFLAMMATORY CORTISOL,
INCREASED LEVELS OF PRO – INFLAMMATORY CYTOKINES,
AND CHRONIC INFLAMMATION
AND THAT
THOSE PATIENTS WHO HAVE DEVELOPED
HYPERSENSITIVITY TO STRESS
BY VIRTUE OF EARLY LIFE ADVERSITIES
AND OTHER SENSITIZING STRESSORS
AND FOR WHOM THEIR MindBrain
IS THE PRIMARY TARGET ORGAN
WILL BE AT PARTICULAR RISK FOR THE DEVELOPMENT OF
DEPRESSION 30

31. BIOMARKERS OF SYSTEMIC INFLAMMATION
HIGH – SENSITIVITY C – REACTIVE PROTEIN ~ HOMOCYSTEINE ~ FIBRINOGEN
PRO – INFLAMMATORY CYTOKINES (IMMUNOSORBENT ASSAY)
UNFORTUNATELY, HOWEVER, THESE BIOMARKERS ARE COMMON TO
ALL INFLAMMATORY CONDITIONS AND ARE THEREFORE NONSPECIFIC
FURTHERMORE, THEY NEITHER DIFFERENTIATE
BETWEEN ACUTE AND CHRONIC INFLAMMATION
NOR DEMONSTRATE LOW – GRADE INFLAMMATION
NONETHELESS, THEY CAN BE USED BOTH TO
PROVIDE A BALLPARK ESTIMATE OF THE LEVEL
OF GENERALIZED INFLAMMATION IN THE BODY
AND TO MONITOR TREATMENT PROGRESS
AS NOTED EARLIER
THESE SYSTEMIC INFLAMMATORY BIOMARKERS HAVE BEEN FOUND
TO BE ELEVATED IN ABOUT ONE THIRD OF DEPRESSED PATIENTS
WHICH MAKES POSSIBLE THE TAILORING OF TREATMENTS
FOR DEPRESSION THAT SPECIFICALLY TARGET INFLAMMATION
31

32. 32
… a subgroup of individuals with depression have
evidence of increased inflammatory biomarkers and
it is in these individuals that anti-inflammatory agents
show promise for reducing depressive symptoms …
(Raison 2016)

33. NATURAL NEUROPROTECTIVE ANTI – INFLAMMATORIES
AS EITHER MONOTHERAPY OR ADJUNCTIVE THERAPY FOR DEPRESSION
A KETOGENIC DIET (HIGH IN HEALTHY FATS / LOW IN CARBS)
ORGANIC RAW NUTS (MACADAMIAS AND PECANS)
OMEGA – 3 FATTY ACIDS
“BALANCED” COMBINATION OF EICOSAPENTAENOIC ACID (EPA) /
DOCOSAHEXAENOIC ACID (DHA) / GAMMA – LINOLENIC ACID (GLA) / VITAMIN E
CURCUMIN (TURMERIC) NEUTRALIZES INFLAMMATION – CAUSING
FREE RADICALS WITH A FLOOD OF ANTIOXIDANTS
VAGUS NERVE STIMULATION ~ MEDITATION ~ MERIDIAN TAPPING
YOGA ~ DEEP (ABDOMINAL) BREATHING
ALL OF WHICH INDUCE THE RELAXATION RESPONSE BY STIMULATING THE
VAGUS NERVE, THEREBY TRIGGERING THE RELEASE OF ACETYLCHOLINE
AND INITIATION OF THE CHOLINERGIC ANTI – INFLAMMATORY PATHWAY
(ROSAS – BALLINA AND TRACEY 2009)
SHEDDING TEARS RELEASES PRO – INFLAMMATORY CYTOKINES
GARLIC ~ GINGER ~ CINNAMON ~ GREEN TEA ~ RESVERATROL
SUNSHINE ~ VITAMIN D ~ VITAMIN A
AEROBIC EXERCISE AND STRENGTH TRAINING 33

34. 34
bipolar patients on high-dose lithium carbonate (e.g., 900 – 1,500 mg / day)
have recently been found to have a reduced incidence of Alzheimer’s disease
this and other findings have led researchers to hypothesize that lithium
(whether at its standard dose or in trace amounts)
is powerfully anti-inflammatory and therefore neuroprotective
so even low-dose lithium orotate (e.g., 5 – 20 mg / day)
may well have “cognitive benefits for dementia prevention” 
(Mauer et al. 2014)

35. ~ ANTI – INFLAMMATORY HERBS AND COOKING SPICES ~
CURCUMIN (A COMPOUND IN TURMERIC); CELERY SEED; GINGER; CINNAMON;
GARLIC; CLOVES; CAYENNE (RED PEPPER); CAPSAICIN (A COMPOUND IN
CHILI PEPPERS); BLACK PEPPER; ROSEMARY; BARBERRY; OREGANO;
SAGE; THYME; HOLY BASIL; CHINESE SKULLCAP ROOT
FLAVORING YOUR MEALS WITH ANTI – INFLAMMATORY HERBS AND SPICES
ENABLES YOU TO UPGRADE YOUR FOOD WITHOUT ADDING A SINGLE CALORIE
~ ANTI – INFLAMMATORY SUPPLEMENTS ~
WHITE WILLOW BARK; PYCNOGENOL (PINE BARK); RESVERATROL (FROM GRAPES);
GRAPE SEED EXTRACT; BOSWELLIA SERRATA RESIN; CAT’S CLAW; ALPHA LIPOIC ACID
~ ANTI – INFLAMMATORY FOODS ~
OMEGA – 3 ESSENTIAL FATTY ACIDS (SALMON AND SARDINES); OLIVE OIL;
WHOLE GRAINS (NOT REFINED GRAINS LIKE WHITE BREAD, WHITE RICE, AND PASTA);
DARK LEAFY GREENS (SPINACH, KALE, BROCCOLI, AND COLLARD GREENS); BEETS;
NUTS (ALMONDS AND WALNUTS); BERRIES (BLUEBERRIES AND RASPBERRIES);
TART CHERRIES; GREEN TEA; FERMENTED FOODS; ONIONS; SHIITAKE MUSHROOMS
~ ANTI – INFLAMMATORY ACTIVITIES ~
EXERCISE; DEEP BREATHING; YOGA AND PILATES; TAPPING (EFT); MEDITATION (FOCUSED
AWARENESS ON THE PRESENT MOMENT); OTHER MINDFULNESS – BASED STRESS
REDUCTION PRACTICES (FOCUSED ATTENTION ON THE BREATH OR BODILY SENSATIONS
AND PROGRESSIVE RELAXATION); SOCIAL SUPPORT; LOVEMAKING (PRODUCTION OF
ANTI – INFLAMMATORIES LIKE OXYTOCIN AND BETA – ENDORPHINS); SUNSHINE
(WHICH STIMULATES THE PRODUCTION OF VITAMIN D, WHICH IN TURN INSTRUCTS
THE IMMUNE SYSTEM TO TURN OFF ITS INFLAMMATORY RESPONSE); SLEEP 35

36. UNLIKE MOST MEDICAL CONDITIONS
FOR WHICH THERE ARE PATHOGNOMONIC LAB TESTS
PSYCHIATRIC CONDITIONS HAVE
NO OBVIOUS ORGANIC BASIS AND ARE
DIAGNOSED SIMPLY ON THE BASIS OF
“CLINICAL PHENOMENOLOGY”
(THE PATIENT’S SELF – REPORT)
THE PATIENT COMES IN AND SAYS
“I’M FEELING REALLY DOWN AND
I’VE BEEN FEELING THAT WAY FOR SOME TIME NOW.
I DON’T HAVE MUCH INTEREST IN ANYTHING.
I HAVE TROUBLE SLEEPING, NOT MUCH APPETITE,
AND LOW ENERGY.”
AND THE PSYCHIATRIST DECLARES
“YOU’RE DEPRESSED!”
36

37. DEPRESSION IS AN
INCREDIBLY COMMON MENTAL DISORDER
THE WORLD HEALTH ORGANIZATION ESTIMATES
THAT ~350,000,000 PEOPLE SUFFER FROM IT
IT IS THE LEADING CAUSE
OF DISABILITY WORLDWIDE
AND A MAJOR CONTRIBUTOR TO THE
OVERALL GLOBAL BURDEN OF DISEASE
NEARLY 1 IN 4 WOMEN AND 1 IN 6 MEN
WILL HAVE EXPERIENCED DEPRESSION
AT SOME POINT DURING THEIR LIFETIME
AND MORE THAN HALF OF THESE PEOPLE
WILL HAVE RECURRENT EPISODES
37

38. DEPRESSION OR DEPRESSIONS?
SO MANY DIFFERENT KINDS OF DEPRESSION
MAJOR DEPRESSIVE DISORDER (MDD) ~ MAJOR DEPRESSIVE EPISODE (MDE)
ACUTE DEPRESSION ~ CHRONIC DEPRESSION
DYSTHYMIC DISORDER ~ CYCLOTHYMIC DISORDER
SEASONAL AFFECTIVE DISORDER (SAD)
PREMENSTRUAL DYSPHORIC DISORDER (PMDD)
POSTPARTUM DEPRESSION ~ PERIMENOPAUSAL MELANCHOLIA
ATYPICAL DEPRESSION ~ PSYCHOTIC DEPRESSION
BIPOLAR DISORDER (MANIC DEPRESSION) ~ UNIPOLAR DISORDER
AGITATED DEPRESSION ~ RETARDED DEPRESSION
ENDOGENOUS DEPRESSION ~ EXOGENOUS DEPRESSION
REACTIVE DEPRESSION ~ SITUATIONAL DEPRESSION
SUBSTANCE – INDUCED MOOD DISORDER
MOOD DISORDER RESULTING FROM A MEDICAL CONDITION
UNFORTUNATELY, “DEPRESSION” IS SO ILL – DEFINED AND
ENCOMPASSES SUCH A HETEROGENEOUS GROUP OF
DISORDERS THAT EMPIRICAL STUDIES OFTEN PRODUCE
RESULTS THAT ARE NOT REPRODUCIBLE AND / OR
GIVE RISE TO ENTIRELY DIFFERENT CONCLUSIONS
38

39. 39
… a pervasive limitation in existing research is the
heterogeneity inherent in depression studies, which
impacts the validity of biomarker data …
(Young et al. 2016)

40. AS A “PSYCHOANALYTIC” ASIDE
ANGRY, GUILT – RIDDEN DEPRESSIONS
ACCOMPANIED BY GUILT AND
A SENSE OF ONESELF AS “BAD”
WORKED THROUGH IN THERAPY
BY HELPING THE PATIENT RAGE
EMPTY, SHAME – FILLED DEPRESSIONS
ACCOMPANIED BY SHAME AND
A SENSE OF ONESELF AS “NOT GOOD ENOUGH,”
AS “LACKING SOMEHOW,”
OR AS “FALLING SHORT OF EXPECTATIONS”
WORKED THROUGH IN THERAPY
BY HELPING THE PATIENT GRIEVE
40

41. THE MOST COMPELLING DEFINITION OF
DEPRESSION
“A GENETIC – NEUROCHEMICAL DISORDER
REQUIRING A STRONG ENVIRONMENTAL TRIGGER
AND CHARACTERIZED BY
AN INABILITY TO APPRECIATE SUNSETS”
(SAPOLSKY 1998)
INTERESTINGLY, BECAUSE SUFFERERS TEND TO
SEE THE WORLD IN A DISTORTED (NEGATIVE) WAY,
COGNITIVE THERAPISTS CONSIDER DEPRESSION TO BE
NOT A DISORDER OF AFFECT
CHARACTERIZED BY EMOTIONAL DISTRESS AND IRRITABILITY
BUT A DISORDER OF THOUGHT
CHARACTERIZED BY EXAGGERATEDLY NEGATIVE SELF – PERCEPTIONS
41

42. 42

43. 43
PAST EXPERIENCE BECOMES A FILTER THROUGH
WHICH WE NOW PERCEIVE THE WORLD
WHAT ARE THE WORDS
APPEARING IN THE RED
TRIANGLES?
IF YOU THINK THEY SAY
“ONCE UPON A TIME” AND
“SHOT IN THE DARK,”
THINK AGAIN 
PRIOR LEARNING PROMPTS
US TO SEE THE WORLD
AS WE EXPECT IT TO BE,
NOT AS IT REALLY IS
ONCE A SCHEMA IS IN PLACE
AND THE CUES AROUND
US LOOK “RIGHT ENOUGH,”
WE ARE BLIND TO
DETAILS AND CONTEXT
WE AUTOMATICALLY PROCESS INFORMATION AS WE EXPECT
IT TO APPEAR, WITHOUT INVESTING ANY MENTAL EFFORT

44. ANOTHER DISCLAIMER
BECAUSE I DID MY PSYCHIATRIC TRAINING
AT THE HARVARD MEDICAL SCHOOL TEACHING HOSPITAL
THAT WAS HOME TO JOSEPH SCHILDKRAUT,
FATHER OF THE “CATECHOLAMINE THEORY OF DEPRESSION,”
FOR ANY PATIENT WHO PRESENTED WITH DEPRESSION,
I WAS TAUGHT TO THINK “ANTIDEPRESSANT”
TO CORRECT FOR “CHEMICAL IMBALANCES” IN THE BRAIN
NOT THAT THE UNDERLYING CAUSES OF THOSE CHEMICAL
IMBALANCES WERE EVER SPECIFICALLY ADDRESSED
INDEED, IT WAS OVER 50 YEARS AGO THAT SCHILDKRAUT FIRST
ADVANCED HIS THEORY THAT DEPRESSION WAS CORRELATED
WITH DECREASED LEVELS OF NEUROTRANSMITTERS IN THE BRAIN
SEROTONIN, NOREPINEPHRINE, AND DOPAMINE
AND THAT ANTIDEPRESSANTS WORKED BY EFFECTIVELY
INCREASING THEIR “FUNCTIONAL” LEVELS
WHETHER BY INCREASING THEIR SYNTHESIS,
PREVENTING THEIR BREAKDOWN, OR INHIBITING THEIR REUPTAKE
44

45. IN FACT
THE ORIGINAL 1965 PAPER BY SCHILDKRAUT
IS THE MOST FREQUENTLY CITED
OF ALL ARTICLES EVER PUBLISHED
IN THE AMERICAN JOURNAL OF PSYCHIATRY
AND ONE OF THE MOST FREQUENTLY CITED
PAPERS IN ALL OF PSYCHIATRY
WE WERE NOT SUPPOSED TO BE CONCERNED THAT
ONLY ONE THIRD OF OUR DEPRESSED PATIENTS WERE GETTING BETTER,
ONE THIRD STAYING THE SAME, AND ONE THIRD ACTUALLY GETTING WORSE
NOR WERE WE SUPPOSED TO WONDER WHY IT WOULD BE THAT ALTHOUGH
ANTIDEPRESSANTS IMMEDIATELY INCREASED NEUROTRANSMITTER LEVELS,
IT USUALLY TOOK A FEW WEEKS BEFORE PATIENTS WOULD FEEL BETTER
AND WITH RESPECT TO THE VARIOUS ANTIDEPRESSANT SIDE EFFECTS,
INSTEAD OF BEING TAUGHT THAT THOSE SIDE EFFECTS WERE THE
BODY’S WAY OF SIGNALING “PROTEST,” WE WERE TAUGHT TO
DISREGARD THE “WISDOM OF THE BODY” AND INSTEAD TO REASSURE OUR
PATIENTS THAT THEIR SIDE EFFECTS WOULD SIMPLY “PASS” IN TIME
45

46. NOR DID WE UNDERSTAND THEN WHAT WE HAVE SINCE COME TO KNOW, NAMELY,
THAT CERTAIN ANTIDEPRESSANTS MAY BE A RISK FACTOR FOR
THE DEVELOPMENT OF IRREVERSIBLE COGNITIVE IMPAIRMENT
TRICYCLICS IN PARTICULAR
(AMITRIPTYLINE, IMIPRAMINE, AND DOXEPIN)
NOT ONLY INCREASE LEVELS OF SEROTONIN
AND NOREPINEPHRINE IN THE BRAIN
(WHICH IS THE DESIRED EFFECT)
BUT ALSO BLOCK THE ACTION OF ACETYLCHOLINE
(WHICH IS AN UNDESIRABLE SIDE EFFECT)
A 2015 PROSPECTIVE COHORT STUDY CONCLUDED THAT
“HIGHER CUMULATIVE ANTICHOLINERGIC USE” IS
ASSOCIATED WITH AN “INCREASED RISK FOR DEMENTIA”
INCLUDING TRICYCLIC ANTIDEPRESSANTS, CERTAIN ANTIHISTAMINES,
AND MEDICATIONS TO CONTROL AN OVERACTIVE BLADDER
(GRAY et al. 2015)
PERHAPS NOT ENTIRELY SURPRISING BECAUSE, IN ADDITION TO
DROWSINESS, DRY MOUTH, URINARY RETENTION, AND CONSTIPATION,
AT THE TOP OF THE LIST OF ANTICHOLINERGIC SIDE EFFECTS
ARE CONFUSION AND PROBLEMS WITH REASONING / SHORT – TERM MEMORY
46

47. SO I WAS TAUGHT THE MAINSTREAM
APPROACH TO TREATING DEPRESSION,
WHICH DOES NOT ATTEMPT TO FERRET OUT
UNDERLYING DISEASE PROCESSES,
BUT, RATHER, TREATS THE SYMPTOMS AND SIGNS WITH
ALLOPATHIC DRUGS DESIGNED TO PRODUCE EFFECTS
OPPOSITE TO THOSE PRODUCED BY THE DISEASE
IN OTHER WORDS, TREATMENT INVOLVES OFFERING
ANTI – SYMPTOM MEDICATIONS TO PROVIDE SYMPTOMATIC RELIEF
A DOWNSTREAM, RATHER THAN AN UPSTREAM, APPROACH
IF THE PATIENT HAS A FEVER, GIVE HER AN ANTIPYRETIC
A COUGH, AN ANTITUSSIVE
HIGH BLOOD PRESSURE, AN ANTIHYPERTENSIVE
NAUSEA AND VOMITING, AN ANTIEMETIC
IF THE PATIENT’S MOTHER HAS JUST DIED
AND THE PATIENT IS DEPRESSED,
GIVE HER A PILL SO SHE WON’T FEEL SO BAD ABOUT IT
(STARK 2006) 47

48. BUT AS JONATHAN WRIGHT IS WONT TO SAY
SIMPLY ATTEMPTING TO ELIMINATE A SYMPTOM
INSTEAD OF DEALING WITH ITS UNDERLYING CAUSES
IS LIKE PUTTING THE LID ON A BOILING POT OF WATER
TO KEEP IT FROM SPILLING OVER
INSTEAD OF TURNING OFF THE STOVE
OR COVERING AN ILLUMINATED INDICATOR LIGHT
ON YOUR CAR’S INSTRUMENT PANEL
SO THAT IT IS NO LONGER VISIBLE
INSTEAD OF DEALING WITH YOUR CAR’S
UNDERLYING MECHANICAL ISSUES
48

49. BUT BECAUSE I HAVE BECOME
OVER THE COURSE OF THE PAST 25 YEARS
A HOLISTIC ~ INTEGRATIVE ~ FUNCTIONAL MEDICINE
COMPLEMENTARY AND ALTERNATIVE ~ ENVIRONMENTAL
PSYCHIATRIST / PSYCHOANALYST
I NOW RARELY CONSIDER ANTIDEPRESSANTS TO BE
THE FIRST LINE OF DEFENSE AGAINST DEPRESSION
RATHER
MY INTEREST LIES IN FERRETING OUT
THE UNDERLYING DYSREGULATION – INDUCING
ENVIRONMENTAL STRESSORS
PSYCHOLOGICAL ~ PHYSIOLOGICAL ~ ENERGETIC
INTRINSIC ~ EXTRINSIC
ENVIRONMENTAL TOXICITIES (“TOO MUCH BAD”)
ENVIRONMENTAL DEFICIENCIES (“NOT ENOUGH GOOD”)
THE CUMULATIVE IMPACT OF WHICH
HAS GIVEN RISE TO DEPRESSION 49

50. STARK REALITY
STRESS CAUSES ALL SORTS OF THINGS BAD
INCLUDING MAKING YOU SO SAD
‘CAUSE WHEN IT’S CHRONIC
YOUR MIND IT GETS SICK
PLEASE DON’T THINK I’M STARK RAVING MAD
(STARK 2016)
50

51. TODAY I WILL BE PROPOSING A
“UNIFIED INTERDISCIPLINARY THEORY OF DEPRESSION”
ONE THAT CONCEIVES OF DEPRESSION AS A
STRESS – INDUCED DYSREGULATED STATE
OF MindBrain USUALLY ACCOMPANIED
AT LEAST SECONDARILY
BY STRESS – INDUCED DYSREGULATION
OF ALL THE BODY’S REGULATORY SYSTEMS
MOST NOTABLY, THE NERVOUS, ENDOCRINE, AND IMMUNE SYSTEMS
INTERDEPENDENT REGULATORY SYSTEMS
THAT USE EXTENSIVE “CROSSTALK” TO MAINTAIN HOMEOSTASIS
FOR THE PATIENT TO BE IN A STATE OF
MENTAL AND PHYSICAL WELL – BEING,
THESE REGULATORY SYSTEMS MUST BE
FUNCTIONING WELL NOT ONLY INDIVIDUALLY
BUT ALSO IN RELATION TO ONE ANOTHER
51

52. BUT THE MOST IMPORTANT
OF THE BODY’S REGULATORY SYSTEMS IS THE
GROUND REGULATION SYSTEM
ALSO KNOWN AS THE
CONNECTIVE TISSUE MATRIX ~ EXTRACELLULAR MATRIX
MILIEU INTERIEUR ~ INTERNAL ENVIRONMENT ~ BIOLOGICAL TERRAIN
WEB OF LIFE ~ LIVING MATRIX ~ DIVINE MATRIX
THIS GROUND REGULATION SYSTEM
IS AN INTRICATE WEB OF
INTERDEPENDENT CONNECTIVE TISSUE
THAT EXTENDS FROM
THE SURFACE OF THE BODY
TO ITS INNERMOST RECESSES,
ULTIMATELY PENETRATING
EVERY SINGLE CELL IN THE BODY
ASTOUNDINGLY, THIS REGULATORY SYSTEM IS OFTEN IGNORED
AND HAS NO “MEDICAL SPECIALTY” DEVOTED TO ITS CARE
(THE CLOSEST “DISCIPLINES” BEING OSTEOPATHY AND PHYSIATRY)
52

53. WALTER B. CANNON (1932) AND HANS SELYE (1936)
ADVANCED THE IDEA THAT THE MAINTENANCE OF
HOMEOSTASIS INVOLVED REGULATORY ORGAN SYSTEMS
MOST NOTABLY, THE NERVOUS AND ENDOCRINE SYSTEMS
IT WAS NOT UNTIL FOUR DECADES LATER THAT
THE HISTOLOGIST ALFRED PISCHINGER (1975) WAS ABLE TO
DEMONSTRATE THAT NERVE ENDINGS AND CAPILLARY BEDS
NEVER ACTUALLY HAVE DIRECT CONTACT
WITH FUNCTIONING (PARENCHYMAL) CELLS
RATHER, THE NERVOUS AND ENDOCRINE SYSTEMS
COMMUNICATE WITH THESE CELLS ONLY BY WAY OF
THE INTERVENING GROUND REGULATION SYSTEM
A GLOBAL COMMUNICATION SYSTEM IN WHICH ALL THE BODY’S
ORGAN SYSTEMS, TISSUES, AND CELLS ARE EMBEDDED
AND THROUGH WHICH ALL “MESSENGER SIGNALS” FLOW
IT IS THEREFORE THIS SYSTEM THAT IS FUNDAMENTALLY
THE MOST IMPORTANT REGULATORY SYSTEM OF ALL
BECAUSE THIS SYSTEM MUST BE FUNCTIONING PROPERLY IF THE BODY’S
OTHER REGULATORY SYSTEMS ARE TO DO THEIR JOBS EFFECTIVELY 53

54. IN THE LANGUAGE OF SOLID – STATE PHYSICS
BECAUSE THIS GROUND REGULATION SYSTEM
IS A HIGHLY ORDERED ARRAY OF MOLECULES
IMMERSED IN SALT WATER
AN ARRAY OF MOLECULES THAT IS
CLOSELY PACKED AND TIGHTLY ORGANIZED
IN A CRYSTAL – LIKE LATTICE STRUCTURE
IT HAS THE SEMICONDUCTING
PROPERTIES OF A LIQUID CRYSTAL
WHICH MAKES OF IT AN IDEAL CANDIDATE
FOR THE NEAR – INSTANTANEOUS FLOW OF
REGULATORY INFORMATION AND VIBRATORY ENERGY
THROUGHOUT THE ENTIRE SYSTEM
54

55. THIS “DIVINE MATRIX” (BRADEN 2008) HAS BEEN DESCRIBED AS
“INTELLIGENT ENERGY WITH CONSCIOUSNESS ATTACHED TO IT”
OPTIMAL FUNCTIONALITY OF WHICH REQUIRES THAT IT BE KEPT
UNCONGESTED
ENERGETICALLY UNBLOCKED
NUTRIENT – RICH
WELL – OXYGENATED
ALKALINE
ELECTRON – RICH
WELL – HYDRATED
ADEQUATELY METHYLATED
ELECTROLYTE – BALANCED
STRUCTURALLY ALIGNED
WELL – RESTED
RELAXED
EMOTIONALLY UNENCUMBERED
THIS GROUND REGULATION SYSTEM CONSTITUTES A BODY CONSCIOUSNESS
WORKING IN TANDEM WITH THE CONSCIOUSNESS OF THE MindBrain
55

56. IT COULD BE SAID THAT
THE HALLMARK OF A HEALTHY SYSTEM IS
ITS CAPACITY TO COPE WITH STRESS,
WHICH WILL BE A REFLECTION OF ITS ABILITY
TO PROCESS, INTEGRATE, AND ADAPT TO
THE IMPACT OF THE MYRIAD
ENVIRONMENTAL STRESSORS TO WHICH
IT IS BEING CONTINUOUSLY EXPOSED,
WHICH WILL BE A REFLECTION OF
THE UNDERLYING ORDEREDNESS OF
THE GROUND REGULATION SYSTEM
AND THE RESULTANT EASE WITH WHICH
INFORMATION AND ENERGY CAN BE
TRANSMITTED THROUGHOUT ITS EXPANSE
INDEED
STRESS TOLERANCE IS THE KEY
TO LONGEVITY AND HEALTHY AG(E)ING
56

57. BUT WHEN THE GROUND REGULATION SYSTEM
BECOMES DYSREGULATED BECAUSE OF THE
CUMULATIVE IMPACT OF ENVIRONMENTAL STRESSORS
THAT CANNOT BE ADEQUATELY PROCESSED AND INTEGRATED,
NO LONGER CAN THE ORDEREDNESS OF ITS INFRASTRUCTURE
BE MAINTAINED AND, AS A RESULT, NO LONGER CAN THERE BE
EASE OF FLOW OF INFORMATION AND ENERGY
THROUGHOUT ITS EXPANSE
THE NET RESULT OF THIS
STRESS – INDUCED DYSREGULATION
WILL BE “LACK OF ORDEREDNESS”
AND “DISRUPTED EASE OF FLOW”
MANIFESTING ULTIMATELY AS
PSYCHIATRIC AND MEDICAL
“DIS – ORDER” / “DIS – EASE”
(STARK 2008, 2012, 2014)
57

58. TO REVERSE THE UNDERLYING DYSFUNCTION
THE ORDEREDNESS AND FLUIDITY OF THE
GROUND REGULATION SYSTEM MUST BE
RESTORED WITH TARGETED THERAPIES THAT
AS NOTED EARLIER
“LIGHTEN THE LOAD”
TO CORRECT FOR TOXICITIES
AND “REPLENISH THE RESERVES”
TO CORRECT FOR DEFICIENCIES
ALL WITH AN EYE TO “FACILITATING THE FLOW”
OF INFORMATION AND ENERGY
THROUGHOUT THE LIVING SYSTEM
BE THAT “INTELLIGENT ENERGY” IN THE FORM OF “CHEMICAL MESSENGERS”
(HORMONES ~ CYTOKINES ~ NEUROTRANSMITTERS)
OR “ENERGY QUANTA” (BIOPHOTONS)
THEREBY RESTORING HOMEOSTATIC BALANCE, RESILIENCE,
AND THE CAPACITY TO COPE WITH THE STRESS OF LIFE
(STARK 2008, 2012, 2015a, 2015b) 58

59. FOR THE MOMENT
LET US THINK OF THE LIVING SYSTEM AS A
COMPLEX ADAPTIVE,
SELF – ORGANIZING (CHAOTIC) SYSTEM
COMPLEX – INTRICATE INTERDEPENDENCE
OF THE SYSTEM’S COMPONENTS
ADAPTIVE – THE CAPACITY TO LEARN FROM EXPERIENCE
SELF – ORGANIZING – THE SPONTANEOUS EMERGENCE
OF SYSTEM – WIDE PATTERNS ARISING FROM
INTERPLAY OF THE SYSTEM’S COMPONENTS
CHAOTIC – DESPITE THE SYSTEM’S APPARENT RANDOMNESS,
AN UNDERLYING ORDEREDNESS THAT WILL
EMERGE OVER TIME AS THE SYSTEM EVOLVES
OR, WHEN OUR FOCUS IS ON STRESS – INDUCED DYSREGULATION,
AN UNDERLYING (AND FAIRLY “ROBUST”)
DIS – ORDEREDNESS THAT WILL
EMERGE OVER TIME AS THE SYSTEM DEVOLVES
59

60. ALL HEALTHCARE PRACTITIONERS
SHOULD KEEP IN MIND THAT
“SELF – ORGANIZING SYSTEMS
(INCLUDING US)
RESIST PERTURBATION”
(KREBS 2013)
WHETHER ORDERED OR DIS – ORDERED,
FUNCTIONAL OR DYSFUNCTIONAL,
WELL – REGULATED OR DYSREGULATED,
THE LIVING SYSTEM WILL RESIST CHANGE
THUS THE IMPORTANCE OF “OPTIMALLY STRESSFUL”
THERAPEUTIC INTERVENTIONS STRATEGICALLY DESIGNED
TO PROVOKE A “STUCK” SYSTEM’S CAPACITY TO
SELF – CORRECT IN THE FACE OF MANAGEABLE CHALLENGE
PRECIPITATING DISRUPTION
IN ORDER TO TRIGGER REPAIR 60

61. THE THERAPEUTIC USE OF OPTIMAL STRESS
TO PROVOKE RECOVERY
DEPRIVING ONESELF OF HALF A NIGHT’S SLEEP ONCE A WEEK
PREFERABLY THE SECOND HALF OF THE NIGHT (FOR EXAMPLE, FROM 3 TO 7 AM)
CAN PRODUCE A RAPID, EVEN IF SHORT – LIVED,
RESTABILIZATION OF MOOD AND RECOVERY FROM DEPRESSION
THE “STRESS” OF INTERRUPTING NORMAL SLEEP PATTERNS
MAY “RESYNCHRONIZE DISTURBED CIRCADIAN RHYTHMS”
(LEIBENLUFT AND WEHR 1992)
INTERMITTENT FASTING
A 36 – HOUR WATER FAST ONCE A WEEK
(FOR EXAMPLE, FROM AFTER DINNER ON MONDAY TO BEFORE BREAKFAST ON WEDNESDAY)
CAN SO SIGNIFICANTLY REDUCE THE TOTAL BODY BURDEN
THAT MENTAL CLARITY AND FOCUS
CAN BE IMPROVED DRAMATICALLY AND
A SENSE OF OVERALL WELL – BEING RESTORED
IT IS ALSO ASSOCIATED WITH INCREASED LEVELS OF
BRAIN – DERIVED NEUROTROPHIC FACTOR (BDNF)
DEPLETED LEVELS OF WHICH ARE THOUGHT TO BE ASSOCIATED WITH DEPRESSION
(MATTSON 2015) 61

62. ACUTE STRESS CAN “OPTIMIZE”
BY PROVOKING “HEIGHTENED FUNCTIONALITY,”
A RESULT OF THE BODY’S “ADAPTIVE UPREGULATION”
IN FACT
SUPERIMPOSING AN ACUTE INJURY ON TOP OF
A CHRONIC ONE IS SOMETIMES EXACTLY
WHAT THE BODY NEEDS IN ORDER TO HEAL
MORE SPECIFICALLY
OFFERING AN
OPTIMALLY STRESSFUL CHALLENGE
THAT INITIALLY “DESTABILIZES”
A “DIS – ORDERED” SYSTEM
IS SOMETIMES THE MAGIC INGREDIENT
NEEDED TO PROVOKE HEALING
AND “RESTABILIZATION” OF THE SYSTEM
AT A HIGHER LEVEL OF INTEGRATION,
BALANCE, AND “ORDEREDNESS”
62

63. IN MY WORK AS A PSYCHOANALYST
AGAINST THE BACKDROP OF AN EMPATHICALLY ATTUNED
AND AUTHENTICALLY ENGAGED THERAPY RELATIONSHIP
I OFFER OPTIMALLY STRESSFUL INTERVENTIONS PAINSTAKINGLY
FORMULATED TO PROVIDE JUST THE RIGHT COMBINATION OF
(DESTABILIZING) CHALLENGE AND (RESTABILIZING) SUPPORT
AS SUCH
THEY ARE INITIALLY ANXIETY – PROVOKING
BUT ULTIMATELY HEALTH – PROMOTING
BY TAPPING INTO THE BODY’S RESILIENCE AND
INNATE CAPACITY TO SELF – STABILIZE
IN THE FACE OF THERAPEUTIC STRESS, THESE
“CONFLICT STATEMENTS” ARE CUSTOM DESIGNED TO
PRECIPITATE DISRUPTION IN ORDER TO TRIGGER REPAIR
“YOU KNOW THAT EVENTUALLY YOU WILL NEED TO START EATING MORE
HEALTHILY IF YOU ARE EVER TO GET BETTER; BUT, FOR NOW, YOU
FIND YOURSELF FEELING OVERWHELMED AT THE THOUGHT OF HAVING
TO GIVE UP ONE OF THE FEW REMAINING PLEASURES IN YOUR LIFE.”
63

64. SO ACUTE STRESS CAN “OPTIMIZE”
BUT CHRONIC STRESS WILL “TRAUMATIZE”
THE CUMULATIVE IMPACT OF WHICH WILL CONTRIBUTE
TO EVER – INCREASING WEAR AND TEAR ON THE BODY
OVER TIME, DEPLETING THE BODY’S ADAPTATION RESERVES
(ITS NUTRIENT AND ENERGETIC RESOURCES)
HORMESIS IS THE TERM USED BY AVANT – GARDE
TOXICOLOGISTS (MATTSON AND CALABRESE 2009) TO
DESCRIBE THIS BIPHASIC RESPONSE TO STRESS
LOW – DOSE “OPTIMIZATION” / HIGHER – DOSE “TRAUMATIZATION”
ACUTE STRESS “GOOD” / CHRONIC STRESS “BAD”
ACUTE INFLAMMATION “GOOD” / CHRONIC INFLAMMATION “BAD”
“THE DIFFERENCE BETWEEN A POISON AND A MEDICATION
IS THE DOSAGE THEREOF” (PARACELSUS 2004)
ULTIMATELY, CHRONIC STRESS CAUSES DYSREGULATION
OF ALL THE BODY’S REGULATORY ORGAN SYSTEMS …
64

65. … BECAUSE, AS IS TRUE FOR ALL COMPLEX ADAPTIVE,
SELF – ORGANIZING (CHAOTIC) SYSTEMS
BASICALLY EVERYTHING IN THE BODY
AFFECTS EVERYTHING ELSE 
(aka THE RIPPLE OR DOMINO EFFECT)
IN ANY EVENT
WHEN REGULATORY CAPACITY AND
HOMEOSTATIC BALANCE IN THE BODY
CANNOT BE MAINTAINED BY VIRTUE OF
THE OVERWHELMING IMPACT OF
ENVIRONMENTAL STRESSORS THAT ARE
SIMPLY “TOO MUCH” TO BE
ADEQUATELY PROCESSED AND INTEGRATED,
CHAOS AND GENERALIZED
DISTRESS WILL RESULT
65

66. SO WHAT HAPPENS WHEN THE PRIMARY DOMAIN OF
DYSREGULATION, DISTRESS, AND PAIN IS THE BRAIN?
BE IT PSYCHOLOGICAL OR PHYSIOLOGICAL
PAIN IS GENERALLY THE RESULT OF
DYSREGULATED OR OBSTRUCTED FLOW
AND
WHEN THAT DISRUPTED FLOW IS IN THE BRAIN
AS HAPPENS, FOR EXAMPLE, WHEN THE BRAIN HAS BECOME
INFLAMED BECAUSE OF STRESS – INDUCED IMMUNE ACTIVATION
THE INFLAMMATORY PAIN
THAT RESULTS MAY ULTIMATELY
MANIFEST AS DEPRESSION
66

67. MORE SPECIFICALLY, WHEN THE BRAIN IS INVOLVED …
DIS – ORDER, DIS – EASE,
AND BRAIN INFLAMMATION
WHEN REDNESS, HEAT, SWELLING, AND PAIN
AFFECT THE TERRAIN OF THE BRAIN
THE FLOW IT DISRUPTS
AND CHAOS ERUPTS
TILL ONCE AGAIN ORDER DOES REIGN
(STARK 2016)
67

68. ACUTE vs. CHRONIC INFLAMMATION
ACUTE INFLAMMATION IN RESPONSE TO STRESS
IS IN THE INTEREST OF RESTORING HOMEOSTASIS
SO ACTIVATION OF THE IMMUNE SYSTEM IS
INITIALLY ADAPTIVE AND PART OF THE SOLUTION
BUT IF THE INFLAMMATION CONTINUES INDEFINITELY,
IT WILL EVENTUALLY BECOME PART OF THE PROBLEM
“TOO MUCH OF A GOOD THING”
A PROBLEM THAT WILL LEAD ULTIMATELY TO CHRONIC DISEASE
AND, WHEN THE TARGET ORGAN IS THE BRAIN, TO DEPRESSION
IN OTHER WORDS
WHEREAS ACUTE INFLAMMATION
IS PART OF THE IMMUNE SYSTEM’S
HEALTHY RESPONSE TO STRESS,
IF THE INFLAMMATION BECOMES CHRONIC,
THE INFLAMMATION ITSELF
WILL BECOME A STRESSOR
68

69. WHICH LEADS ME TO PONDER THE FOLLOWING CONUNDRUM –
WHAT DOES IMMUNE
DYSREGULATION REALLY MEAN?
AN OVERACTIVE IMMUNE SYSTEM?
THAT IS “DOING ITS JOB TOO WELL”
AS HAPPENS, FOR EXAMPLE, WHEN YOU HAVE AN AUTOIMMUNE DISEASE
CLEARLY THE RESULT OF A DYSREGULATED IMMUNE SYSTEM
THAT IS INAPPROPRIATELY “ROBUST” AND PROTECTING ALL TOO WELL
OR AN UNDERACTIVE IMMUNE SYSTEM?
THAT IS “NOT DOING ITS JOB WELL ENOUGH”
AS HAPPENS, FOR EXAMPLE, WHEN YOU GET SICK WITH A BAD COLD
CLEARLY THE RESULT OF A DYSREGULATED IMMUNE SYSTEM
THAT IS “COMPROMISED” IN ITS FUNCTIONING, DEFICIENT, WEAK, AND INEFFECTUAL
SO IMMUNE DYSREGULATION MUST MEAN
AN IMMUNE SYSTEM THAT
IS PROVIDING INADEQUATE PROTECTION
SOMETIMES TOO MUCH AND SOMETIMES TOO LITTLE
69

70. BASED ON A COMPREHENSIVE REVIEW OF THE LITERATURE,
I HAVE DEVELOPED AN INTEGRATIVE THEORY OF DEPRESSION
THAT TAKES INTO CONSIDERATION A MULTITUDE OF FACTORS
PSYCHOSOCIAL STRESSORS
ADVERSE CHILDHOOD EXPERIENCES AND CURRENT REAL – LIFE STRESSORS
GENETIC PREDISPOSITION
IRREVERSIBLE MUTATIONS AND POLYMORPHISMS
LIFESTYLE AND ENVIRONMENTAL FACTORS
REVERSIBLE EPIGENETIC MODIFICATIONS
A DYSREGULATED GUT MICROBIOME
AN IMBALANCE OF GOOD AND BAD MICROBES IN THE GASTROINTESTINAL TRACT
A DYSREGULATED CENTRAL NERVOUS SYSTEM
DEPLETED LEVELS OF SEROTONIN, NOREPINEPHRINE, AND DOPAMINE
A DYSREGULATED NEUROENDOCRINE SYSTEM
DYSREGULATED HYPOTHALAMIC – PITUITARY – ADRENAL AXIS
(ELEVATED LEVELS OF ANTI – INFLAMMATORY CORTISOL)
A DYSREGULATED NEUROIMMUNE SYSTEM
ACTIVATED PERIPHERAL MACROPHAGES AND CENTRAL MICROGLIA
(ELEVATED LEVELS OF PRO – INFLAMMATORY CYTOKINES)
70

71. A PSYCHO –
SOCIO –
GENO –
ENVIRO –
GASTROENTERO –
NEURO –
IMMUNO –
ENDOCRINO –
LOGIC THEORY OF DEPRESSION
(STARK 2016)
71

72. THE “PSYCHO” COMPONENT OF DEPRESSION
A MNEMONIC FOR THE SYMPTOMS AND SIGNS OF DEPRESSION
SIGeCAPS = SIG (LET IT BE LABELED) + ENERGY + CAPSules
SLEEP DISORDER (DECREASED OR INCREASED)
INTEREST DEFICIT (ANHEDONIA)
INABILITY TO EXPERIENCE PLEASURE OR ENJOY SUNSETS
GUILT (EXCESSIVE SELF – REPROACH AND REGRET)
FEELINGS OF WORTHLESSNESS AND HELPLESSNESS
ENERGY DEFICIT
FATIGUE, LOW LIBIDO, AND SOCIAL AVOIDANCE
CONCENTRATION DEFICIT
DIFFICULTY STAYING FOCUSED AND MAKING DECISIONS
APPETITE DISORDER (DECREASED OR INCREASED)
PSYCHOMOTOR RETARDATION OR AGITATION
SUICIDALITY
DESPAIR AND HOPELESSNESS 72

73. THE “PSYCHOSOCIO” COMPONENT OF DEPRESSION
PSYCHOSOCIAL STRESSORS
EXPERIENCED BY THE CHILD
IN RELATION TO THE
PARENTAL / SOCIAL ENVIRONMENT
WHETHER TRAUMA AND ABUSE (TOXICITIES)
OR DEPRIVATION AND NEGLECT (DEFICIENCIES)
ARE RISK FACTORS THAT WILL PRIME
THE CHILD FOR SUBSEQUENT DEVELOPMENT
OF DEPRESSION WHEN LATER TRIGGERED
BY STRESSFUL SOCIAL INTERACTIONS
REMINISCENT OF THE ORIGINAL TRAUMA
73

74. 74
… psychosocial stress is capable of causing
immune dysregulation and increased
neuroinflammatory signaling, which may contribute
to the development of depression …
(Ramirez et al. 2016)

75. THERE ARE SEVERAL DIFFERENT
PSYCHOSOCIAL THEORIES OF DEPRESSION
THAT PRIVILEGE EARLY LIFE ADVERSITIES AS PRIMING EVENTS
ONE OF THE BEST KNOWN OF WHICH IS ADVANCED
BY AARON BECK (1979), A COGNITIVE THERAPIST WHO
ATTRIBUTES THE ONSET AND RECURRENCE OF DEPRESSION
TO “NEGATIVE COGNITIONS” AND CORRESPONDING
“MALADAPTIVE PATTERNS OF INFORMATION PROCESSING”
HIS MODEL ADVANCES THE IDEA THAT PEOPLE WHO EXPERIENCE
ADVERSITY IN CHILDHOOD DEVELOP NEGATIVE SELF – SCHEMAS
WHICH REMAIN DORMANT UNTIL A STRESSFUL LIFE EVENT
REMINISCENT OF THE ORIGINAL STRESSOR
IS LATER ENCOUNTERED,
AT WHICH POINT THE SCHEMAS BECOME ACTIVATED AND
THEN SERVE AS FILTERS THROUGH WHICH (NEGATIVE)
“MEANING IS MADE” OF THE “NEW” EXPERIENCE
aka SELF – FULFILLING PROPHECIES
LEADING ULTIMATELY TO “DEPRESSIVE AFFECT”
AND REINFORCEMENT OF
THE PRECONCEIVED NEGATIVE COGNITIONS
75

76. PSYCHOTHERAPY WILL THEN INVOLVE
INCREASING THE PATIENT’S AWARENESS OF
NOT JUST THE PRICE SHE PAYS FOR CLINGING SO TENACIOUSLY
TO HER NEGATIVE SELF – SABOTAGING SCHEMAS (THE PAIN)
BUT ALSO THE BENEFIT SHE DERIVES FROM DOING SO (THE GAIN)
AS LONG AS THE GAIN IS GREATER THAN THE PAIN,
THE PATIENT WILL MAINTAIN THE DYSFUNCTION AND REMAIN ENTRENCHED
BUT ONCE THE PAIN BECOMES GREATER THAN THE GAIN,
THE STRESS AND STRAIN THEREBY CREATED
WILL PROVIDE THE THERAPEUTIC LEVERAGE NEEDED
FOR THE PATIENT GRADUALLY TO RELINQUISH
HER ATTACHMENT TO THE NEGATIVE SELF – SCHEMAS
THE IMPETUS FOR WHICH WILL BE HER NEED
TO RESTORE HER PSYCHOLOGICAL EQUILIBRIUM
IN ESSENCE
THERAPY WILL INVOLVE “WORKING THROUGH” THE “OPTIMAL
STRESS” GENERATED BY THE PATIENT’S EVER – INCREASING
AWARENESS OF THE “COGNITIVE DISSONANCE” BETWEEN
“COST” (PAIN) AND “BENEFIT” (GAIN), PROMPTING HER
ULTIMATELY TO “LET GO” OF HER DISTORTED PERCEPTIONS
(STARK 1999, 2014, 2015a, 2015b, 2016) 76

77. THE “GENO” COMPONENT OF DEPRESSION
THE GENOME
AN INDIVIDUAL’S UNIQUE GENETIC (DNA) MAKEUP
ARE THERE GENETIC PREDISPOSITIONS
TO DEPRESSION?
WHETHER THE RESULT OF MUTATIONS
GENETIC VARIANTS THAT ARE UNIQUE TO AN INDIVIDUAL
OR SINGLE NUCLEOTIDE POLYMORPHISMS (SNPs)
GENETIC VARIANTS THAT ARE MORE COMMON ACROSS A POPULATION
HETEROZYGOUS SNPs
WHEN THE VARIANT AFFECTS ONLY ONE OF THE ALLELES
(BECAUSE IT WAS INHERITED FROM ONLY ONE OF THE PARENTS)
HOMOZYGOUS SNPs
WHEN THE VARIANT AFFECTS BOTH OF THE ALLELES
(BECAUSE IT WAS INHERITED FROM BOTH OF THE PARENTS)
77

78. 78
… multiple genetic factors in conjunction with
environmental factors are likely necessary for the
development of depression …
… but despite all efforts, thus far no single genetic
variation has been identified that increases the risk
of depression substantially …
(Lohoff 2010)

79. THE “GENO” COMPONENT OF DEPRESSION
… EXCEPT THAT DEPRESSION DOES TEND TO RUN IN FAMILIES AND
WOULD THEREFORE APPEAR TO HAVE SOME DEGREE OF INHERITABILITY
EVEN IF WE CANNOT YET UNDERSTAND WHY
IF A TWIN HAS MAJOR DEPRESSION, THERE IS A 50% CHANCE
THAT AN IDENTICAL TWIN WILL ALSO HAVE DEPRESSION
AND A 25% CHANCE THAT A FRATERNAL TWIN WILL
BUT IF ONLY A CERTAIN PERCENTAGE
WILL ALSO HAVE DEPRESSION,
THEN “GENETIC” MUST NOT MEAN
INEVITABILITY BUT VULNERABILITY
WHICH IS WHERE “EPIGENETICS” COMES IN
THAT IS, LIFESTYLE CHOICES AND ENVIRONMENTAL EXPOSURES
THAT REGULATE THE EXPRESSION OF GENES
EQUIPOTENTIALITY IS THE TERM USED IN SYSTEMS THEORY TO
DESCRIBE WHAT HAPPENS WHEN THINGS WITH THE SAME ORIGINAL
CONDITIONS (THE SAME “POTENTIAL”) GO IN DIFFERENT DIRECTIONS
EPIGENETIC MODIFICATIONS SPEAK TO THE IMPACT
OF THE ENVIRONMENT ON THE GENOME 79

80. THE “ENVIRO” COMPONENT OF DEPRESSION
GENE – ENVIRONMENT INTERACTIONS
(aka NATURE vs. NURTURE)
INCLUDE NOT JUST THE PARENTAL / SOCIAL ENVIRONMENT
BUT ALSO, MORE GENERALLY, THE PHYSICAL ENVIRONMENT
WHEREAS MANY ILLNESSES WERE ONCE THOUGHT TO BE
80 – 90% GENETIC AND ONLY 10 – 20% ENVIRONMENTAL,
NOW MOST ARE THOUGHT TO BE
ONLY 10 – 20% GENETIC AND 80 – 90% ENVIRONMENTAL
“EPIGENETICS”
MEANS LITERALLY “ON TOP OF GENETICS” AND REFERS TO
REVERSIBLE EXTERNAL MODIFICATIONS OF GENE EXPRESSION
AND NOT TO ALTERATIONS IN THE GENETIC CODE ITSELF
IN OTHER WORDS, EPIGENETIC MODIFICATIONS CHANGE NOT
THE SEQUENCE OF NUCLEOTIDES IN THE DNA STRAND
BUT THE PHYSICAL STRUCTURE OF THE DNA
SUCH THAT HOW THE GENES ARE “READ” BECOMES MODIFIED
ONE EXAMPLE OF WHICH IS DNA METHYLATION
(THE ADDITION OF A METHYL GROUP TO PART OF THE DNA MOLECULE)
WHICH CAN PREVENT A GENE FROM BEING EXPRESSED 80

81. LIFESTYLE CHOICES THAT CAN INDUCE EPIGENETIC MODIFICATIONS
STRESSORS CONTRIBUTING TO THE ALLOSTATIC LOAD
SUGAR; HIGH GLYCEMIC LOAD (CAUSED BY FOODS THAT RAISE THE BLOOD SUGAR
LEVEL); REFINED AND PROCESSED FOODS; SATURATED AND TRANS FATTY ACIDS; FOOD
ADDITIVES (ARTIFICIAL COLORINGS, SWEETENERS, AND FLAVORINGS; MONOSODIUM
GLUTAMATE (MSG); SODIUM BENZOATE; HIGH FRUCTOSE CORN SYRUP); CAFFEINE, NICOTINE,
AND ALCOHOL; LOW – FIBER DIET; PRESCRIPTION AND RECREATIONAL DRUGS; NATURAL
GAS STOVES; WATER BEDS AND ELECTRIC BLANKETS; POOR QUALITY SLEEP; LIVING
CLOSE TO MAJOR HIGHWAYS AND INTERSECTIONS; SEDENTARY LIFESTYLE; OBESITY;
TELEVISION; TOO LITTLE TIME OUTDOORS AND IN FRESH AIR; IMBALANCE BETWEEN
WORK AND PLAY; NEGATIVE THOUGHTS; CHRONIC ANGER; FINANCIAL DIFFICULTIES;
CHRONIC RELATIONSHIP CONFLICT; SOCIAL REJECTION AND ISOLATION; LONELINESS
ENVIRONMENTAL EXPOSURES THAT CAN INDUCE EPIGENETIC MODIFICATIONS
STRESSORS CONTRIBUTING TO THE ALLOSTATIC LOAD
PESTICIDES; HERBICIDES (GLYPHOSATE); PETROLEUM – BASED SOLVENTS (TOLUENE
AND BENZENE); VOLATILE ORGANIC COMPOUNDS (FORMALDEHYDE); HEAVY METALS
(MERCURY AND ALUMINUM); MOLDS AND THE DANGEROUS MYCOTOXINS THEY RELEASE;
TOBACCO SMOKE; PHTHALATES AND OTHER ENDOCRINE – DISRUPTING COMPOUNDS
(BISPHENOL A IN PLASTICS); FLAME RETARDANTS (PBDEs); AUTOMOBILE EXHAUST FUMES;
ELECTROMAGNETIC FIELDS (EMFs); HIGH VOLTAGE POWER LINES; CELL TOWERS;
CELL PHONES; SYNTHETIC FRAGRANCES (PERFUMES, AIR FRESHENERS, AND OTHER
“PLEASANT – SCENTED” PRODUCTS); NEWSPAPER PRINT; PERSONAL CARE PRODUCTS;
LAUNDRY DETERGENTS AND FABRIC SOFTENERS; HOUSEHOLD CLEANERS; ANTIBACTERIAL
SOAPS AND HAND SANITIZERS; FLUORIDE – CONTAINING WATER AND TOOTHPASTE;
MORE GENERALLY – THE MYRIAD POLLUTANTS AND ENVIRONMENTAL TOXICANTS
IN THE AIR WE BREATHE, THE WATER WE DRINK, AND THE FOOD WE EAT 81

82. 82

83. THE “GASTROENTERO” COMPONENT OF DEPRESSION
THE GUT MICROBIOTA (aka THE GUT FLORA)
(THE MICROBIAL CELLS LIVING INSIDE THE GI TRACT)
AND THE MICROBIOME
(THEIR GENETIC MATERIAL)
BIDIRECTIONAL COMMUNICATION
(BOTTOM – UP FROM GUT TO BRAIN AND TOP – DOWN FROM BRAIN TO GUT)
BETWEEN THE COMPLEX GUT MICROBIAL ECOSYSTEM
AND THE BRAIN
(aka THE MICROBIOTA – GUT – BRAIN AXIS)
AN INFORMATION SUPERHIGHWAY
CONTINUOUS SIGNALING BETWEEN GUT AND BRAIN VIA MESSENGER MOLECULES
HORMONES (NEUROENDOCRINE SYSTEM)
PRO – INFLAMMATORY CYTOKINES (NEUROIMMUNE SYSTEM)
NEUROTRANSMITTERS (AUTONOMIC AND ENTERIC NERVOUS SYSTEMS)
NEUROTRANSMITTERS ARE ALSO PRODUCED BY THE GUT MICROBIOTA
WHICH PRODUCE 90% OF THE BODY’S SEROTONIN AND 50% OF THE BODY’S DOPAMINE
THE ENTERIC NERVOUS SYSTEM, WHICH RESIDES WITHIN THE WALL OF
THE DIGESTIVE TRACT, IS SOMETIMES CALLED THE “SECOND BRAIN”
BECAUSE IT IS “SMART” ENOUGH TO FUNCTION AUTONOMOUSLY
83

84. THE “GASTROENTERO” COMPONENT OF DEPRESSION
WHEN THE BALANCE OF GUT MICROBES
(GOOD AND BAD)
BECOMES DISRUPTED AND DYSBIOSIS RESULTS,
THE GUT WALL BECOMES INFLAMED AND
INTESTINAL PERMEABILITY INCREASES
(aka LEAKY GUT)
ALTHOUGH THE ACTUAL MECHANISMS OF ACTION
ARE NOT YET FULLY UNDERSTOOD,
DYSBIOSIS AND THE INFLAMMATION
THAT ACCOMPANIES IT ARE THOUGHT
TO GIVE RISE TO A BROAD RANGE
OF STRESS – RELATED PHYSICAL, MENTAL,
AND EMOTIONAL DISORDERS
(INCLUDING DEPRESSION)
84

85. 85
… deficits in intestinal permeability may underlie
the chronic low-grade inflammation observed
in disorders such as depression …
(Kelly et al. 2015)

86. 86
…reciprocal interactions between gut
microbiota, inflammation, and depression …
(Meyrel et al. 2017)

87. THE “GASTROENTERO” COMPONENT OF DEPRESSION
THE EMERGING LINK BETWEEN THE GUT MICROBIOTA
AND THE CENTRAL NERVOUS SYSTEM OFFERS
PROMISE FOR THE DESIGN OF NOVEL TREATMENTS FOR
STRESS – INDUCED PSYCHIATRIC DISORDERS, SUCH AS DEPRESSION
THE NEW FIELD OF PSYCHOBIOTICS
PROBIOTICS THAT, WHEN INGESTED IN ADEQUATE AMOUNTS,
PRODUCE HEALTH BENEFITS IN PATIENTS
SUFFERING FROM PSYCHIATRIC ILLNESSES
PRECLINICAL EVALUATION IN RODENTS
SUGGESTS THAT CERTAIN PSYCHOBIOTICS
(MOST NOTABLY BIFIDOBACTERIUM AND LACTOBACILLUS)
MITIGATE THE STRESS RESPONSE
AND POSSESS ANTIDEPRESSANT ACTIVITY
SUCH BENEFITS MAY BE RELATED TO BOTH THEIR CAPACITY TO
REDUCE HPA AXIS ACTIVITY AND THEIR ANTI – INFLAMMATORY ACTIONS
(DINAN et al. 2013)
THE SCIENTIFIC LITERATURE HAS DEMONSTRATED THAT PSYCHOBIOTICS DO
INDEED HAVE A BROAD SPECTRUM OF THERAPEUTIC ACTIVITY; BUT
THE RESULTS ARE, SADLY, OFTEN CONTRADICTORY AND INCONCLUSIVE
87

88. THE “NEURO” COMPONENT OF DEPRESSION
BOTH THE CENTRAL AND THE AUTONOMIC NERVOUS SYSTEMS
ALREADY DISCUSSED
CENTRAL NERVOUS SYSTEM
DEPLETED LEVELS OF NEUROTRANSMITTERS IN THE BRAIN
ESPECIALLY IN THE LIMBIC SYSTEM
SEROTONIN, NOREPINEPHRINE, AND DOPAMINE
THE CATECHOLAMINE / MONOAMINE THEORY OF DEPRESSION
SEROTONIN REGULATES CALMNESS
(ALSO PROMINENT IN THE GASTROINTESTINAL TRACT)
REDUCED LEVELS OF WHICH CAUSE AN OBSESSIVE SENSE OF GUILT
NOREPINEPHRINE REGULATES ALERTNESS, CONCENTRATION, AND MOTIVATION
REDUCED LEVELS OF WHICH CAUSE PSYCHOMOTOR RETARDATION
DOPAMINE IS INVOLVED IN FEELINGS OF PLEASURE AND IS
THEREFORE CALLED THE “REWARD CHEMICAL” OF THE BRAIN
REDUCED LEVELS OF WHICH CAUSE ANHEDONIA
CHOOSE THE ANTIDEPRESSANT (SSRI / SNRI / NDRI / SNDRI)
WITH THE MECHANISM OF ACTION THAT
WILL TARGET THE MOST PROBLEMATIC SYMPTOMS
88

89. THE “NEURO” COMPONENT OF DEPRESSION
THE STRESS RESPONSE
BOTH ACUTE AND CHRONIC
IS REGULATED BY THE LIMBIC SYSTEM
AND INVOLVES BOTH THE SYMPATHETIC NERVOUS SYSTEM
AND THE HYPOTHALAMIC – PITUITARY – ADRENAL “STRESS” AXIS
MORE SPECIFICALLY
IN THE FACE OF REAL OR IMAGINED “STRESSORS,”
THE AMYGDALA IS ACTIVATED
WHICH PROCESSES EMOTIONS LIKE FEAR AND ANXIETY
THE AMYGDALA THEN SENDS A “DISTRESS SIGNAL”
TO THE HYPOTHALAMUS
WHICH IS THE “COMMAND CENTER” OF THE BRAIN AND REGULATES
BOTH THE SYMPATHETIC NERVOUS SYSTEM AND THE HPA AXIS
THE HYPOTHALAMUS THEN INITIATES
THE “STRESS RESPONSE,” WHICH ACTIVATES
THE BODY’S ENSEMBLE OF REGULATORY SYSTEMS
SO THAT HOMEOSTATIC BALANCE CAN BE RESTORED
89

90. HANS SELYE (1936) – THE FATHER OF STRESS
GENERAL ADAPTATION SYNDROME
SPEAKS TO THE BODY’S HOMEOSTATIC EFFORTS
TO PROTECT ITSELF AGAINST
ALL MANNER OF NONSPECIFIC STRESSORS
A MANIFESTATION OF WALTER B CANNON’S
“WISDOM OF THE BODY” (1932)
ALARM STAGE
HEIGHTENED AROUSAL / CALL TO ACTION
FIGHT – OR – FLIGHT
RESISTANCE / ADAPTATION STAGE
MOBILIZATION OF THE BODY’S DEFENSES
IN AN EFFORT FIRST TO RESIST AND
ULTIMATELY TO ADAPT TO THE ONGOING STRESS
EXHAUSTION STAGE
DEPLETION OF THE BODY’S RESOURCES
MALADAPTATION / DYSHOMEOSTASIS 90

91. THE “NEUROIMMUNE” COMPONENT OF DEPRESSION
STRESS ACTIVATES
NOT ONLY THE SYMPATHETIC NERVOUS SYSTEM
AND THE HYPOTHALAMIC – PITUITARY – ADRENAL AXIS
BUT ALSO THE IMMUNE SYSTEM
MACROPHAGES IN THE BODY
AND MICROGLIA IN THE BRAIN
THE “RESIDENT MACROPHAGES” IN THE CENTRAL NERVOUS SYSTEM
IMMUNE CELLS THAT ARE THEN
TRIGGERED TO RELEASE
PRO – INFLAMMATORY CYTOKINES
INTERLEUKIN (IL) – 1 ~ INTERLEUKIN (IL) – 6 ~ TUMOR NECROSIS FACTOR ALPHA
INTERFERON GAMMA
THE RELEASE OF WHICH UPREGULATES
INFLAMMATORY PROCESSES
91

92. THE “NEUROIMMUNE” COMPONENT OF DEPRESSION
THE PERIPHERAL IMMUNE (BODY) AND
NEUROIMMUNE (BRAIN) SYSTEMS
ARE STRUCTURALLY DISTINCT
ALTHOUGH ONCE THOUGHT TO BE “IMMUNE PRIVILEGED,”
THE BRAIN IS NOW KNOWN TO HAVE
A ROBUST NEUROIMMUNE SYSTEM
COMPOSED PREDOMINANTLY OF GLIAL CELLS
MICROGLIA ~ ASTROCYTES ~ OLIGODENDROCYTES
WHICH MAKE UP ALMOST
90% OF THE CELLS IN THE BRAIN
THESE GLIAL CELLS ARE THE BRAIN’S
“CONNECTIVE TISSUE”
(AS SUCH, THEY ARE PART OF THE GROUND REGULATION SYSTEM)
92

93. THE “NEUROIMMUNE” COMPONENT OF DEPRESSION
THE NEUROINFLAMMATORY
THEORY OF DEPRESSION
(SETIAWAN et al. 2015)
POSITRON EMISSION TOMOGRAPHY (PET) SCANS WERE DONE
ON 20 PATIENTS WITH DEPRESSION AND 20 HEALTHY CONTROLS
INCREASED DENSITY OF TRANSLOCATOR PROTEIN
A GLIAL PROTEIN USED AS A BIOMARKER OF BRAIN INFLAMMATION
WAS FOUND IN THE PREFRONTAL CORTEX,
NUCLEUS ACCUMBENS, AND INSULA
OF THE BRAINS OF THE DEPRESSED PATIENTS
THE RESEARCHERS CONCLUDED
“THIS FINDING PROVIDES THE MOST COMPELLING
EVIDENCE TO DATE OF BRAIN INFLAMMATION AND,
MORE SPECIFICALLY, MICROGLIAL ACTIVATION
IN MAJOR DEPRESSIVE EPISODES”
93

94. 94
… this finding is important for improving
treatment because it implies that therapeutics
known to reduce microglial activation
should be promising for depression …
(Setiawan et al. 2015)

95. THE SIGNIFICANCE OF GLIAL CELLS
AN INTERESTING ASIDE
WHEN EINSTEIN DIED IN 1955,
HIS BRAIN WAS PRESERVED IN A JAR OF FORMALDEHYDE
MOST PEOPLE EXPECTED THAT HIS BRAIN WOULD BE
LARGER THAN AVERAGE – BUT IT WAS NOT
THIRTY YEARS LATER, HOWEVER, SOMETHING DIFFERENT
ABOUT HIS BRAIN WAS DISCOVERED
EINSTEIN’S BRAIN HAD EXTRA GLIAL CELLS
ESPECIALLY IN THE ASSOCIATION CORTEX
THE BRAIN AREA INVOLVED WITH IMAGINATION AND COMPLEX THINKING
IT HAD LONG BEEN KNOWN THAT NEURONS
“SPOKE” ACROSS SYNAPSES
BUT NOW IT BECAME CLEAR THAT GLIA ALSO “TALKED”
NOT ONLY WITH ONE ANOTHER BUT ALSO WITH NEURONS
95

96. THE SIGNIFICANCE OF GLIAL CELLS
GLIA HAVE RECEPTORS FOR MANY OF THE SAME
CHEMICAL MESSENGERS USED BY NEURONS
WHICH ENABLES THEM TO “EAVESDROP” ON NEURONS AND
TO RESPOND IN WAYS THAT WILL FACILITATE NEUROTRANSMISSION
AND A CERTAIN VARIETY OF GLIA WRAPS ITSELF AROUND
NERVE AXONS TO FORM “INSULATING” MYELIN SHEATHS
THEREBY ACCELERATING TRANSMISSION SPEEDS 50 – FOLD
IN FACT, WHEN ANIMALS ARE RAISED IN LEARNING – RICH
ENVIRONMENTS, MYELINATION INCREASES
SUGGESTING THAT GLIA MAY ACTIVELY CONTRIBUTE TO LEARNING
GLIA ALSO CONTRIBUTE TO THE NORMAL APOPTOTIC
DESTRUCTION OF SYNAPSES DURING BRAIN DEVELOPMENT
UNNECESSARY CONNECTIONS ARE CONTINUOUSLY BEING CUT BACK
IN ORDER TO STREAMLINE THE NEURAL CIRCUITRY
BECAUSE OF THE CRITICAL ROLES PLAYED BY GLIA IN
NEUROTRANSMISSION AND NEURAL / SYNAPTIC PLASTICITY,
IT IS NO SURPRISE THAT EINSTEIN HAD SO MANY OF THEM
96

97. THE “NEUROIMMUNE” COMPONENT OF DEPRESSION
BUT STRESS – INDUCED ABNORMAL GLIAL ACTIVITY
IS NOW BEING ASSOCIATED WITH NOT ONLY
DEPRESSION BUT ALSO SUCH DISORDERS AS
DYSLEXIA ~ AUTISM ~ STUTTERING
TONE DEAFNESS ~ CHRONIC PAIN
SLEEP DISORDERS ~ EVEN PATHOLOGICAL LYING
AND OVERZEALOUS “PRUNING”
OF HEALTHY SYNAPSES
BY ROBUSTLY ACTIVATED GLIA
MAY BE A FACTOR IN SUCH
NEURODEGENERATIVE DISORDERS
AS ALZHEIMER’S DISEASE
PARENTHETICALLY, BOTH ALZHEIMER’S AND CHRONIC DEPRESSION
ARE ASSOCIATED WITH DECREASED HIPPOCAMPAL VOLUME
PARTICULARLY ALARMING INASMUCH AS
THE HIPPOCAMPUS PLAYS SUCH AN IMPORTANT ROLE IN MEMORY
ESPECIALLY THE CONSOLIDATION OF INFORMATION
FROM SHORT – TERM TO LONG – TERM MEMORY 97

98. MOVING NOW TO
THE “NEUROENDOCRINE” COMPONENT OF DEPRESSION
IMPORTANTLY
EXPOSURE TO CHRONIC STRESS RESULTS IN
PROLONGED HYPERACTIVATION OF THE HPA AXIS,
WHICH LEADS TO INCREASED LEVELS OF CORTISOL
BUT THIS, IN TURN, EVENTUALLY CAUSES DOWNREGULATION
OR DESENSITIZATION
OF THE CORTISOL RECEPTORS IN
THE HYPOTHALAMUS AND THE PITUITARY
CONSEQUENTLY
INSTEAD OF A NEGATIVE FEEDBACK LOOP
DESIGNED TO RESTORE HOMEOSTASIS
BY RETURNING THE CORTISOL LEVELS TO NORMAL
ONCE THE DANGER HAS PASSED
A POSITIVE (AMPLIFYING) FEEDBACK LOOP WILL BE ESTABLISHED,
RESULTING IN EVER – INCREASING LEVELS OF CORTISOL
98

99. 99
DESIGNED TO RESTORE
HOMEOSTASIS
POSITIVE
FEEDBACK
LOOPS CAN
CREATE
RUNAWAY
SITUATIONS

100. THE “ENDO – IMMUNE” COMPONENT OF DEPRESSION
FURTHERMORE AND EQUALLY SIGNIFICANTLY
THE EVER – INCREASING LEVELS OF CORTISOL
WILL ALSO CAUSE DOWNREGULATION
OF THE CORTISOL RECEPTORS ON BOTH
MACROPHAGES (PERIPHERALLY)
AND MICROGLIA (CENTRALLY)
THE NET RESULT OF WHICH
WILL BE DESENSITIZATION
OF THE IMMUNE SYSTEM
TO THE ANTI – INFLAMMATORY
AND IMMUNOSUPPRESSIVE
EFFECTS OF CORTISOL
100

101. THE “ENDO – IMMUNE” COMPONENT OF DEPRESSION
IN SUM
CHRONIC STRESS LEADS TO
A HYPERACTIVATED HPA AXIS,
CHRONICALLY ELEVATED
CORTISOL LEVELS,
CHRONICALLY DECREASED SENSITIVITY
OF THE IMMUNE CELLS TO CORTISOL,
AND CHRONIC FAILURE TO
INHIBIT INFLAMMATORY PROCESSES,
THEREBY EFFECTIVELY STIMULATING
INFLAMMATORY PROCESSES
RESULTING IN CHRONIC INFLAMMATION
101

102. 102
… these data provide support for a model suggesting that
prolonged exposure to stress results in cortisol resistance,
which in turn interferes with appropriate regulation of
inflammation … (Cohen et al. 2012)

103. 103
… reduced glucocorticoid signaling, as a result of
glucocorticoid resistance, creates a permissive
environment for an overactive innate immune system …
(Horowitz and Zunszain 2015)

104. EXTENSIVE CROSSTALK
NOT ONLY
DO ELEVATED LEVELS OF CORTISOL ULTIMATELY
INCREASE INFLAMMATION
THROUGH THEIR FAILURE TO DOWNREGULATE
THE INFLAMMATORY RESPONSE
AN INSTANCE OF THE ENDOCRINE SYSTEM’S
IMPACT ON THE IMMUNE SYSTEM
BUT ALSO
PRO – INFLAMMATORY CYTOKINES GIVE RISE TO
EVER – INCREASING LEVELS OF CORTISOL
THROUGH THEIR “POTENT ACTIVATION” OF THE HPA AXIS
AN INSTANCE OF THE IMMUNE SYSTEM’S
IMPACT ON THE ENDOCRINE SYSTEM
THE NET RESULT OF WHICH WILL BE TOTAL
DYSREGULATION OF THE IMMUNE SYSTEM
AND A RUNAWAY INFLAMMATORY CASCADE 104

105. 105
… some of the pro-inflammatory cytokines are
potent activators of the HPA axis …
(Leonard 2001)

106. IN SUM
IN AT LEAST A COHORT
OF VULNERABLE INDIVIDUALS
INFLAMMATION MAY INDEED
PLAY A MAJOR ROLE
IN THE ETIOLOGY OF DEPRESSION
ACTING NOT ONLY
AS A PRECIPITATING FACTOR
THAT PROPELS THE INDIVIDUAL INTO DEPRESSION
BUT ALSO AS A PERPETUATING FACTOR
THAT MAY POSE AN OBSTACLE TO RECOVERY
IN ESSENCE
WE ARE SPEAKING TO A PIVOTAL ROLE FOR
THE IMMUNE SYSTEM IN MODULATING AFFECT
106

107. SO THIS IS
MY PSYCHO –
SOCIO –
GENO –
ENVIRO –
GASTROENTERO –
NEURO –
IMMUNO –
ENDOCRINO –
LOGIC THEORY OF DEPRESSION
WHICH POSTULATES THAT STRESS – INDUCED
INFLAMMATION AND A DYSREGULATED MindBrain
RESULT FROM THE COMPLEX INTERDEPENDENCE OF
ANTECEDENT SENSITIZING FACTORS AND DYSFUNCTIONAL
REGULATORY SYSTEMS THROUGHOUT THE LIVING SYSTEM
(STARK 2016)
107

108. MY PSYCHO – SOCIO – GENO – ENVIRO – GASTROENTERO –
NEURO – IMMUNO – ENDOCRINO – LOGIC THEORY OF DEPRESSION
NEUROENDOCRINE DYSFUNCTION
NEUROIMMUNE ALTERATION
CAUSE INFLAMMATION
AND THEN DEPRESSION
BUT I HAVE A GOOD SOLUTION
ELIMINATE TOXICITY
AND REPLENISH DEFICIENCY
NOW YOU’LL BE LESS STRESSED
NO LONGER DEPRESSED
I HOPE YOU LIKE MY THEORY
(STARK 2016)
108

109. IMPLICATIONS FOR TREATMENT
TARGETED THERAPEUTIC REGIMENS
DESIGNED TO REDUCE INFLAMMATION
GIVEN THE DIRECT LINK BETWEEN INFLAMMATION
AND DEPRESSION IN AT LEAST A SUBSET OF PATIENTS,
IN ADDITION TO FERRETING OUT UNDERLYING CAUSES
FOR BOTH THE INFLAMMATION AND THE DEPRESSION
SEVERAL SIMPLE BLOOD TESTS
SHOULD BE ROUTINELY PERFORMED
ON ALL DEPRESSED PATIENTS
IN ORDER TO GET A “READ” ON THE
INFLAMMATORY STATUS OF THEIR BODY
AND THEN ANTI – INFLAMMATORY (NEUROPROTECTIVE)
SUPPLEMENTS AND ACTIVITIES CAN BE PRESCRIBED
AS EITHER REPLACEMENTS FOR OR ADJUNCTS TO WHATEVER
OTHER ANTIDEPRESSANT REGIMENS ARE ALREADY IN PLACE
109

110. BIOMARKERS OF SYSTEMIC INFLAMMATION
HIGH SENSITIVITY C – REACTIVE PROTEIN (hs – CRP)
CRP IS ONE OF A GROUP OF PROTEINS (“ACUTE – PHASE REACTANTS”)
PRODUCED BY THE LIVER AS PART OF THE IMMUNE SYSTEM’S
EARLY INFLAMMATORY RESPONSE TO HARMFUL STIMULI
hs – CRP IS THE BEST BIOMARKER OF
ACUTE INFLAMMATION IN BLOOD VESSELS
AT THE MICROVASCULAR LEVEL
PARTICULARLY RELEVANT FOR HEART AND BRAIN
IN FACT
hs – CRP IS A MORE ACCURATE AND SENSITIVE INDICATOR
OF THE ACUTE PHASE RESPONSE
THAN THE ERYTHROCYTE SEDIMENTATION RATE (ESR)
OPTIMAL hs – CRP BLOOD LEVELS
ARE < 1.0 MILLIGRAM PER LITER
HIGHER LEVELS SUGGEST SYSTEMIC INFLAMMATION
110

111. BIOMARKERS OF SYSTEMIC INFLAMMATION
HOMOCYSTEINE
AN INTERMEDIARY IN THE METHIONINE – HOMOCYSTEINE (METHYLATION) CYCLE
A TOXIC SULFUR – CONTAINING AMINO ACID THAT NEEDS TO BE
METHYLATED IN ORDER TO BE CONVERTED BACK TO METHIONINE
(AN ESSENTIAL AMINO ACID THAT PLAYS SEVERAL VITAL PHYSIOLOGICAL ROLES IN THE BODY)
ELEVATED LEVELS OF HOMOCYSTEINE ARE ASSOCIATED
WITH OXIDATIVE STRESS, FREE RADICAL DAMAGE,
DYSREGULATED NEUROTRANSMISSION, CHRONIC INFLAMMATION,
COGNITIVE DECLINE, AND DEPRESSION
SEVERAL RESEARCHERS HAVE EVEN ADVANCED
THE HOMOCYSTEINE THEORY OF DEPRESSION
(FOLSTEIN et al. 2007; MECH AND FARAH 2016)
COMMON SYMPTOMS OF WHICH INCLUDE
PERFECTIONISM, INTENSE COMPETITIVENESS, DRIVENNESS,
HIGH ACHIEVEMENT, OBSESSIVE – COMPULSIVE TRAITS,
ANXIETY, RITUALISTIC BEHAVIORS, AND ADDICTIVE TENDENCIES
OPTIMAL HOMOCYSTEINE BLOOD LEVELS
ARE < 6.0 MICROMOLES PER LITER 111

112. 112
… high homocysteine levels cause cerebrovascular
disease, neurotransmitter deficiency, and depression …
(Folstein et al. 2007)

113. BIOMARKERS OF SYSTEMIC INFLAMMATION
MORE SPECIFICALLY, ELEVATED LEVELS OF HOMOCYSTEINE
ARE OFTEN FOUND IN UNDERMETHYLATORS
UNDERMETHYLATION CAN BE THE RESULT OF EITHER GENETICS OR EPIGENETICS
METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR)
IS A COMMON GENETIC POLYMORPHISM
ASSOCIATED WITH UNDERMETHYLATION
BETWEEN 30% AND 60% OF THE POPULATION ARE UNDERMETHYLATORS
THE MTHFR ENZYME, ENCODED BY THE MTHFR GENE,
IS RESPONSIBLE FOR METHYLATING FOLATE
WITH THE ASSISTANCE OF VITAMIN B12 AS A COFACTOR
THIS “ACTIVATED” FORM OF FOLATE (METHYLFOLATE) CATALYZES
THE CONVERSION OF HOMOCYSTEINE BACK TO METHIONINE
(A POWERFUL ANTIOXIDANT)
BY DONATING ITS METHYL GROUP
THEREBY PREVENTING TOXIC BUILDUP OF HOMOCYSTEINE
IT IS EASY ENOUGH TO SUPPLEMENT A DEPRESSED PATIENT’S DIET
WITH THE ACTIVATED (METHYLATED) FORMS OF
VITAMIN B12 (METHYLCOBALAMIN) AND FOLATE (L – METHYLFOLATE)
113

114. 114

115. BIOMARKERS OF SYSTEMIC INFLAMMATION
VITAMIN D BLOOD LEVEL
PROVIDES AN INDIRECT MEASUREMENT
OF THE BODY’S INFLAMMATORY STATUS
THE LOWER THE VITAMIN D LEVEL,
THE HIGHER THE DEGREE OF INFLAMMATION
INSULIN BLOOD LEVEL
CAN BE USED NOT ONLY TO SCREEN FOR DIABETES
BUT ALSO AS A ROUGH MARKER FOR INFLAMMATION
THE HIGHER THE FASTING INSULIN LEVEL,
THE HIGHER THE DEGREE OF INFLAMMATION
IMMUNOASSAYS TO DETECT CYTOKINE LEVELS
ALTHOUGH STILL QUITE PRICEY
ARE BECOMING AN INCREASINGLY POPULAR WAY
TO QUANTIFY CYTOKINES IN THE BLOOD
115

116. ANTI – INFLAMMATORY
TREATMENT OPTIONS
THE MOST EFFECTIVE WAY
TO COMBAT
CHRONIC INFLAMMATION
IS THROUGH
EXERCISE AND DIET
116

117. REGULAR PHYSICAL EXERCISE TO
ALLEVIATE SYMPTOMS OF DEPRESSION
BOTH AEROBIC TRAINING
(ENDURANCE TRAINING)
AND STRENGTH TRAINING
(MUSCLE CONTRACTION AGAINST RESISTANCE)
WHEREAS BOUTS OF EXERCISE INCREASE ACUTE INFLAMMATION,
WHEN DONE REGULARLY OVER THE LONG TERM,
EXERCISE DECREASES CHRONIC INFLAMMATION
EXERCISE STIMULATES THE PRODUCTION
OF ANTI – INFLAMMATORY CYTOKINES
EXERCISE ALSO ENHANCES THE PRODUCTION
OF ENDORPHINS
“ENDOGENOUS MORPHINE” ~ ENDOGENOUS OPIOID NEUROPEPTIDES
WHICH INHIBIT THE TRANSMISSION OF PAIN SIGNALS
AND PRODUCE A FEELING OF EUPHORIA
SIMILAR TO THAT PRODUCED BY OTHER OPIOIDS
117

118. 118
… recent findings confirm that physical activity
induces an increase in the systemic levels of
a number of anti-inflammatory cytokines …
(Pinto et al. 2012)

119. PARENTHETICALLY
EXERCISE ALSO INCREASES THE PRODUCTION OF
BRAIN – DERIVED NEUROTROPHIC FACTOR (BDNF)
“TROPHIC” MEANS “GROWTH – PROMOTING”
“MIRACLE – GRO FOR THE BRAIN” (RATEY 2013)
BDNF IS A GROWTH FACTOR
ASSOCIATED WITH COGNITIVE IMPROVEMENT
IT PROMOTES NEUROGENESIS AND SYNAPTIC PLASTICITY
IN SPECIFIC AREAS OF THE BRAIN
MOST NOTABLY THE HIPPOCAMPUS
STRESS IS KNOWN TO DECREASE BDNF LEVELS
THE NEUROTROPHIC THEORY OF DEPRESSION
IMPLICATES REDUCED LEVELS OF BDNF,
ATROPHY OF STRESS – VULNERABLE HIPPOCAMPAL NEURONS,
AND DECREASED HIPPOCAMPAL VOLUME
IN THE PATHOGENESIS OF DEPRESSION
CORROBORATED BY THE FINDING THAT ANTIDEPRESSANTS APPEAR TO
INCREASE BDNF LEVELS, REVERSE ATROPHY OF HIPPOCAMPAL NEURONS,
AND INCREASE HIPPOCAMPAL VOLUME
(DUMAN et al. 1997) 119

120. 120
… stress can decrease the expression of BDNF and lead to
atrophy of stress-vulnerable hippocampal neurons …
… the possibility that the decreased size and impaired
function of these neurons may be involved in depression
is supported by recent clinical imaging studies …
(Duman et al. 1997)

121. ELIMINATE PRO – INFLAMMATORY FOODS
PRO – INFLAMMATORY CYTOKINES
ARE PRODUCED BY AN UNHEALTHY DIET
SUGAR AND HIGH FRUCTOSE CORN SYRUP,
REFINED GRAINS, PROCESSED FOODS, AND TRANS FATS
AVOID THE NIGHTSHADES
POTATOES, TOMATOES, PEPPERS, AND EGGPLANT
EAT AN ANTI – INFLAMMATORY DIET
WHOLE, UNPROCESSED, ORGANIC “REAL” FOOD
FERMENTED FOODS (KEFIR, MISO, PICKLES, OLIVES, SAUERKRAUT)
PROBIOTICS (INCLUDING RAW YOGURT)
TO “RESEED” THE GUT WITH BENEFICIAL BACTERIA
HIGH – QUALITY, ANTI – INFLAMMATORY HERBS AND SPICES
HIGH – QUALITY, UNPROCESSED FATS
121

122. TURMERIC
THE SPICE THAT GIVES CURRY ITS YELLOW COLOR
ONE OF THE MOST THOROUGHLY RESEARCHED PLANTS ON THE PLANET
ITS PROFOUND HEALING ABILITIES CAN BE TRACED
TO ITS POWERFUL ANTI – INFLAMMATORY ACTION
IT IS ALSO A VERY STRONG ANTIOXIDANT
TAKE A FULL – SPECTRUM TURMERIC EXTRACT
(AS OPPOSED TO AN ISOLATED CURCUMIN EXTRACT)
AND ONE THAT IS “LIPOSOMALIZED”
LIPOSOMES ARE USED AS VEHICLES FOR ADMINISTRATION
OF NUTRIENTS AND PHARMACEUTICAL DRUGS
THAT MIGHT OTHERWISE BE HARD FOR THE BODY TO ABSORB
LIPOSOMALIZATION INVOLVES ENCAPSULATING
THE TURMERIC EXTRACT IN A PHOSPHOLIPID BILAYER
IN ORDER TO INCREASE ITS BIOAVAILABILITY
122

123. OMEGA – 3 FATTY ACIDS
POLYUNSATURATED FATTY ACIDS (PUFAs)
EICOSAPENTAENOIC ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA)
A 2012 GROUNDBREAKING STUDY CONDUCTED AT THE
UNIVERSITY OF CALIFORNIA (SAN DIEGO) UNCOVERED A CLASS
OF “SPECIALIZED” INFLAMMATION – REGULATING MOLECULES
THAT ARE PRODUCED INSIDE THE BODY’S TISSUES
FROM THE OMEGA – 3 FATTY ACIDS FOUND IN FISH OIL
THESE “PRO – RESOLUTION MOLECULES”
(LIPOXINS, RESOLVINS, AND PROTECTINS)
STIMULATE ACTIVE RESOLUTION OF INFLAMMATION
(NORRIS AND DENNIS 2012)
SUPPLEMENTING WITH 2 – 3 GRAMS PER DAY OF
OMEGA – 3 FATTY ACIDS FROM A HIGH – QUALITY
FISH OIL WILL BOOST PRODUCTION OF THESE
ENDOGENOUS CHEMICAL MEDIATORS, THEREBY
SERVING TO “RESOLVE AND PROTECT AGAINST”
INFLAMMATORY CONDITIONS
123

124. BUT A WORD OF CAUTION
ALWAYS TAKE THE FAT – SOLUBLE ANTIOXIDANT VITAMIN E
ALONG WITH THE ANTI – INFLAMMATORY EPA AND DHA
POLYUNSATURATED FATTY ACIDS (PUFAs)
(LIKE EPA AND DHA – TWO OF THE MOST IMPORTANT OMEGA – 3s)
ARE LIPIDS WITH TWO OR MORE CARBON – CARBON DOUBLE BONDS
THE GREATER THE DEGREE OF UNSATURATION
(THAT IS, THE GREATER THE NUMBER OF DOUBLE BONDS IN ITS HYDROCARBON CHAIN),
THE MORE “FRAGILE” IT IS AND THE MORE EASILY IT CAN BE “OXIDIZED”
(THAT IS, HAVE ITS ELECTRONS STOLEN)
BY “FREE RADICALS” IN SEARCH OF ELECTRONS
TO RESTORE THEIR ELECTRON BALANCE
REMOVAL OF ELECTRONS FROM THE FATTY ACID
(THAT IS, “OXIDATIVE DEGRADATION OF THE FATTY ACID” OR “LIPID PEROXIDATION”)
WILL CONVERT IT INTO A TOXIC “REACTIVE OXYGEN SPECIES” (ROS)
(THAT IS, IT WILL ITSELF BECOME A “FREE RADICAL” OR “OXIDANT”)
NOW “OXIDIZED” AND A “FREE RADICAL,” THE FATTY ACID
WILL WREAK HAVOC THROUGHOUT THE BODY BY CAUSING
“OXIDATIVE DAMAGE” (“OXIDATIVE STRESS”) TO MEMBRANES, PROTEINS,
AND CELLULAR DNA AS IT SCAVENGES FOR ELECTRONS TO COMPLETE ITSELF
THUS THE IMPORTANCE OF TAKING EPA AND DHA WITH VITAMIN E
(AN “ANTIOXIDANT” THAT WILL SLOW OR EVEN PREVENT THE “OXIDATIVE PROCESS”)
124

125. NOVEL TREATMENT APPROACHES FOR HARD – TO – TREAT DEPRESSIONS
BOTULINUM TOXIN
A DRAMATIC ILLUSTRATION OF THE
HORMETIC (BIPHASIC) DOSE – RESPONSE
IN HIGH DOSES,
BOTULINUM IS NEUROTOXIC
IT IS THE MOST POISONOUS BIOLOGICAL AGENT KNOWN
BUT IN LOWER DOSES,
BOTULINUM IS ANTI – INFLAMMATORY
AND USED FOR TEMPORARY ERASING
OF FROWN LINES AND CROW’S FEET
“IF YOU CAN’T FROWN, YOU WON’T BE SO SAD”
A SINGLE INJECTION INTO THE FACIAL “FROWN MUSCLES”
CAN PROVIDE LASTING RELIEF FROM DEPRESSION
(FINZI AND ROSENTHAL 2014)
125

126. 126
… a single treatment with onabotulinumtoxinA (OBA)
<injected into frown muscles> appears to induce a
significant and sustained antidepressant effect
in patients with major depression …
(Finzi and Rosenthal 2014)

127. NOVEL TREATMENT APPROACHES FOR HARD – TO – TREAT DEPRESSIONS
SMILING 
“IF YOU SMILE MORE, YOU WON’T BE SO SAD”
FAKE IT UNTIL YOU MAKE IT
SMILING IS A POWERFUL IMMUNE BOOSTER
AND MOOD STABILIZER
STUDIES HAVE SHOWN THAT SMILING
RELEASES ENDORPHINS AND SEROTONIN
“SMILING IS A WAY OF TRICKING YOUR BRAIN
INTO THINKING THAT EVERYTHING’S OK,
EVEN IF IT’S NOT”
(PLANT AND STEPHENSON 2011)
127

128. WHO KNEW ?!?
ANTIDEPRESSANTS THEMSELVES
ARE ANTI – INFLAMMATORY
THE PRIMARY MECHANISM OF ACTION
OF ANTIDEPRESSANTS
HAD LONG BEEN THOUGHT
TO INVOLVE CORRECTING
CHEMICAL IMBALANCES IN THE BRAIN
ONLY MORE RECENTLY, HOWEVER,
HAS IT BECOME APPARENT THAT
ANTIDEPRESSANTS ALSO EXERT
ANTI – INFLAMMATORY EFFECTS
WHICH MIGHT BE RESPONSIBLE, AT LEAST IN PART,
FOR THE SEVERAL – WEEK DELAY IN ACTION (“LATENCY PERIOD”)
THAT CHARACTERIZES MOST ANTIDEPRESSANTS
128

129. 129
… studies have demonstrated that antidepressants can
inhibit the production and/or release of pro-inflammatory
cytokines and stimulate the production of anti-
inflammatory cytokines, suggesting that reduction in
inflammation might contribute to treatment response …
(DeBerardis et al. 2010)

130. 130
… these findings suggest that antidepressants may
owe at least some of their therapeutic effectiveness
to their anti-inflammatory properties …
(Tynan et al. 2012)

131. I CONCLUDE WITH MY FINAL LIMERICK …
NEUROINFLAMMATION
AND DEPRESSION
TO HEAL DISORDER AND DISEASE
TRY ANTI – INFLAMMATORIES
BUT FIRST YOU ADDRESS
UNDERLYING STRESS
AND THEN PRESCRIBE OMEGA – 3s
(STARK 2016)
131

132. BIBLIOGRAPHY
Beck A (1979). Cognitive therapy and the emotional disorders. New York, NY: Plume.
Braden G (2008). The divine matrix: bridging time, space, miracles, and belief.
Carlsbad, CA: Hay House.
Cannon WB (1932). The wisdom of the body. New York, NY: WW Norton.
Chambers JC, Ueland PM, Wright M, Dore CJ, Refsum H, Kooner JS. Investigation of
relationship between reduced, oxidized, and protein-bound homocysteine and vascular
endothelial function in healthy human subjects. Circ Res. 2001 Jul 20;89(2):187-92.
Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, Turner RB.
Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.
Proc Natl Acad Sci USA. 2012 Apr 17;109(16):5995-9.
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation
to sickness and depression: when the immune system subjugates the brain.
Nat Rev Neurosci. 2008 Jan;9(1):46-56.
DeBerardis D, Conti CM, Serroni N, Moschetta FS, Olivieri L, Carano A, Salerno RM,
Cavuto M, Farina B, Alessandrini M, Janiri L, Pozzi G, DiGiannantonio M. The effect of
newer serotonin-noradrenaline antidepressants on cytokine production: a review of
the current literature. Int J Immunopathol Pharmacol. 2010 Apr-Jun;23(2):417-22. 132

133. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic.
Biol Psychiatry. 2013 Nov 15;74(10):720-6.
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression.
Arch Gen Psychiat. 1997 Jul;54(7):597-606.
Finzi E, Rosenthal NE. Treatment of depression with onabotulinumtoxinA: a
randomized, double-blind, placebo controlled trial. J Psychiat Res. 2014 May;52:1-6.
Folstein M, Liu T, Peter I, Buell J, Arsenault L, Scott T, Qiu WW. The homocysteine
hypothesis of depression. Am J Psychiat. 2007 Jun;164(6):861-7.
Freud S (1917). Mourning and melancholia. The standard edition of the complete
psychological works of Sigmund Freud, volume XIV (1914-1916). London, UK: The
Hogarth Press, 237-258.
Gratrix N. Limbic kindling: hard-wiring the brain for hypersensitivities. CAM – The
Magazine for Complementary and Alternative Medicine Professionals. Feb 2014.
Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK,
Larson EB. Cumulative use of strong anticholinergics and incident dementia: a
prospective cohort study. JAMA Intern Med. 2015 Mar;175(3):401-7.
Horowitz MA, Zunszain PA. Neuroimmune and neuroendocrine abnormalities in
depression: two sides of the same coin. Ann N Y Acad Sci. 2015 Sep;1351:68-79. 133

134. Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down
the barriers: the gut microbiome, intestinal permeability and stress-related
psychiatric disorders. Front Cell Neurosci. 2015 Oct 14;9:392.
Krebs C (2013). Energetic kinesiology: principles and practice. London, UK:
Handspring Publishing.
Krishnadas R, Cavanagh J. Depression: an inflammatory illness? J Neurol Neurosur
Ps. 2012 May;83(5):495-502.
Leibenluft E, Wehr TA. Is sleep deprivation useful in the treatment of depression?
Am J Psychiat. 1992 Feb;149(2):159-68.
Leonard BE. The immune system, depression and the action of antidepressants.
Prog Neuro-Psychoph. 2001 May;25(4):767-80.
Leonard BE. Major depression as a neuroprogressive prelude to dementia: what is
the evidence? Mod Trends Pharmacopsychiatry. 2017;31:56-66.
Lohoff FW. Overview of the genetics of major depressive disorder. Curr Psychiatry
Rep. 2010 Dec;12(6):539-46.
Mattson MP, Calabrese EJ (2009). Hormesis: a revolution in biology, toxicology, and
medicine. New York, NY: Humana Press.
134

135. Mattson MP. Lifelong brain health is a lifelong challenge: from evolutionary principles
to empirical evidence. Ageing Res Rev. 2015 Mar;20:37-45.
Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review
of dementia prevention and other behavioral benefits. Aust NZ J Psychiatry. 2014
Sep;48(9):809-18.
Mech AW, Farah A. Correlation of clinical response with homocysteine reduction
during therapy with reduced B vitamins in patients with MDD who are positive for
MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-
controlled study. J Clin Psychiat. 2016 May;77(5):668-71.
Meyrel M, Varin L, Detaint B, Mouaffak F. The intestinal microbiota: a new player in
depression? Encephale. 2017 Apr.
Muller N. Immunology of major depression. Neuroimmunomodulat. 2014;
21(2-3):123-30.
Norris PC, Dennis EA. Omega-3 fatty acids cause dramatic changes in TLR4 and
purinergic eicosanoid signaling. Proc Natl Acad Sci USA. 2012 May 29;109(22):8517-22.
Paracelsus T (2004). The archidoxes of magic. Turner R, trans. Temecula, CA: Ibis.
Pinto A, DiRaimondo D, Tuttolomondo A, Butta C, Milio G, Licata G. Effects of physical
exercise on inflammatory markers of atherosclerosis. Curr Pharm Des. 2012;
18(28):4326-49. 135

136. Pischinger A (1991). Matrix and matrix regulation: basis for a holistic theory in
medicine. Brussels, Belgium: Haug International.
Plant J, Stephenson J (2011). Beating stress, anxiety, and depression:
groundbreaking ways to help you feel better. London, UK: Piatkus Books.
Raison CL. The promise and limitations of anti-inflammatory agents for the treatment
of major depressive disorder. Curr Top Behav Neurosci. 2016 Jun 9.
Ramirez K, Fornaguera-Trias J, Sheridan JF. Stress-induced microglia activation and
monocyte trafficking to the brain underlie the development of anxiety and depression.
Curr Top Behav Neurosci. 2016 Jun 20.
Ratey J (2013). Spark: the revolutionary new science of exercise and the brain.
Boston, MA: Little, Brown and Company.
Rosas-Ballina M, Tracey KJ. Cholinergic control of inflammation. J Intern Med. 2009
Jun;265(6):663-79.
Sapolsky R (1998). Why zebras don’t get ulcers. New York, NY: WH Freeman..
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of
supporting evidence. Am J Psychiat. 1965 Nov;122(5):509-22.
Selye H (1978). The stress of life. New York, NY: McGraw-Hill.
136

137. Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miller L, Rajkowska G, Suridjan I,
Kennedy JL, Rekkas PV, Houle S, Meyer JH. Role of translocator protein density, a
marker of neuroinflammation, in the brain during major depressive episodes. JAMA
Psychiatry. 2015 Mar;72(3):268-75.
Stark M (1999). Modes of therapeutic action: enhancement of knowledge, provision of
experience, and engagement in relationship. Northvale, NJ: Jason Aronson.
Stark M. Neurotransmitters, pharmacologic synergy, and clinical strategies. Feature
Article in Psychiatric Times Special Edition. 2006 Oct;23(12):1-8.
Stark M. Hormesis, adaptation, and the sandpile model. Crit Rev Toxicol.
2008;38(7):641-4.
Stark M. The sandpile model: optimal stress and hormesis. Dose-Response.
2012;10(1):66-74.
Stark M (2014). Optimal stress, psychological resilience, and the sandpile model. In:
Rattan S, LeBourg E, eds. Hormesis in health and disease. Boca Raton, FL: CRC
Press (Taylor & Francis Group), 201-24.
Stark M (2015a). Integrative psychotherapy: healing the MindBodyMatrix. In:
Greenblatt J, Brogan K, eds. Integrative psychiatry for depression: redefining
models for assessment, treatment, and prevention of mood disorders. Boca Raton,
FL: CRC Press (Taylor & Francis Group), 403-19.
137

138. Stark M (2015b). The transformative power of optimal stress: from cursing the
darkness to lighting a candle (International Psychotherapy Institute eBook).
www. FreePsychotherapyBooks.org
Stark M (2016). How does psychotherapy work? (International Psychotherapy
Institute eBook). www. FreePsychotherapyBooks.org
Su KP. Nutrition, psychoneuroimmunology and depression: the therapeutic
implications of omega-3 fatty acids in interferon-alpha-induced depression.
Biomedicine. 2015 Dec;5(4):21.
Tynan RJ, Weidenhofer J, Hinwood M, Caims MJ, Day TA, Walker FR. A comparative
examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on
LPS stimulated microglia. Brain Behav Immun. 2012 Mar;26(3):469-79.
Williams R (1956). Biochemical individuality: the basis for the genetotrophic concept.
Hoboken, NJ: Wiley.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the
neurobiology of depression. Nat Rev Neurosci. 2016 Aug;17(8):497-511.
Young JJ, Silber T, Bruno D, Galatzer-Levy IR, Pomara N, Marmar CR. Is there
progress? An overview of selecting biomarker candidates for major depressive
disorder. Front Psychiat. 2016 Apr 25;7:72.
138