Psychoneuroimmunology :Clinical Application of an 

Emerging Field in Medicine

Elizabeth A. Stuller, M.D. ABPN Board Certified in Adult and Addiction Psychiatry

MAOP Maryland Association of Osteopathic Physicians Annual Meeting 2013

December 5‐8, 2013      Baltimore, Maryland  

Learning Objectives

Recognize emerging trends in brain science

Explore the convergence of the fields of psychiatry, neurology, 

immunology, and endocrinology,  the most rapidly advancing 

areas in medical science. 

An overview of the interconnected super system and additional 

applications in addiction psychiatry and medicine.

The Brain Initiative

The Brain InitiativeIn February, 2013,  Obama unveiled  funding for the initiative, called  Brain Research Through Advancing Innovative Neurotechnologies, or BRAIN.

The White House says it "aims to help researchers find new ways to treat, cure, and even prevent brain disorders, such as Alzheimer's disease, epilepsy, and traumatic brain injury."

Global Positioning System ‐GPS

Emerging Neuroimaging Advancements

Emerging Brain Activity Maps

Emerging Genetic Testing

Emerging Biomarker TestingNeurotransmitter, Adrenal, Hormone,, Inflammatory, Cytokine, Lyme Testing 

Technology  Fusion‐ Biomarkers, Imaging, Genetics, QEEG guide treatment interventions

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Putting it all Together

January 1, 2013 on 60 MinutesIncredible Brain‐Machine Interface Research 

Leading To Robotic Prosthetics

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Neurotransmitters are biomarkers of nervous system function

Serotonin

Dopamine

GABA

Glutamate

Epinephrine

Norepinephrine

Histamine

PEA

Irwin, M, et al. Brain, Behavior, and Immunity. 2003:17;365-372Vashadze, S. Georgian Med. News 2007;(150):22-4

Neurotransmitters as Biomarkers

• Have been used in academia for 60 years1

• Can be accurately and affordably measured using ELISA‐

based methods

• Serve as clinical correlates to a host of neuropsychiatric 

conditions2

• Provides insight into deficiencies/imbalances of the neuro‐

endo‐immune supersystem3

1. von Euler, U., et al. (1951). Br J Pharmacol Chemother. 6(2):286-288.

2. See “Urinary Neurotransmitter Testing: Myths & Misconsceptions” for review

3. Cohrs, S., et al. (2004). Neurosci Letters. 360:161-164.

What do urinary neurotransmitter measurements represent?

• Non‐invasive, quantitative analysis of whole body neurotransmitter excretion

• Biomarkers of peripheral and central nervous system function

• Clinical correlates of various neuropsychiatric conditions

• Acts as guide for nutritional, supplemental, pharmaceutical interventions

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Serotonin

Glutamate

Norepinephrine

Dopamine

GABA

Epinephrine

PEA

Serotonin

GABAGlutamate

NorepinephrineDopamine

GABA

Epinephrine

Biomarkers and AddictionPredicting Behavioral Patterns 

For Example : The still developing Pre‐Frontal Cortex

Young and Impaired Prefrontal Cortex  

“Addiction without treatment…

………………is progressive and

can result in 

disability or 

premature death.” 

http://www.asam.org/advocacy/find‐a‐policy‐statement/view‐policy‐statement/public‐policy‐statements/2011/12/15/the‐definition‐of‐addiction

Addiction and the brain:The role of neurotransmitters in the cause and 

treatment of drug dependence 

RECENT SCIENTIFIC ADVANCES HAVE LED to a greater understanding of 

the neurobiological processes that underlie drug abuse and addiction. These 

suggest that multiple neurotransmitter systems may play a key role 

in the development and expression of drug dependence. 

These advances in our knowledge promise not only to help us identify the 

underlying cause of drug abuse and dependence, but also to aid  in the 

development of effective treatment strategies. 

Tomkins DM, et. al. (2001). CMAJ. 164(6): 817‐21.

Neurotransmitter Biomarkers are needed to allow health care providers to choose more accurately and to 

avoid guessing

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Neurotransmitter Testing Applications in Clinical Settings 

• Determine treatment therapy

• Identify individuals with a high‐risk for relapse

• Determine the need for a more aggressive or extended therapy to increase the probability of obtaining sobriety

• A tool for treatment response to medications

Depression

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Insomnia    Panic

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Anxiety

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Insomnia and Early Morning Awakenings

33

Challenges in Treating Complex Patients

Diagnosis often symptomatic in 

Psychiatry

Diagnosis often symptomatic in 

Psychiatry

Patients may present with multiple 

medication failures

Patients may present with multiple 

medication failures

Medications can cause symptomsMedications can cause symptoms

Patients lose trust in practitioner

Patients lose trust in practitioner

Lost quality of life secondary to persistent symptoms

Lost quality of life secondary to persistent symptoms

Poor work productivityPoor work productivity

Relational issues with families and 

coworkers 

Relational issues with families and 

coworkers 

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Fatigue

Optimal Range

Optimal Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPACOptimal Activity

Stores are full

NT Stores

Time (months-years)

1. Dopamine is made from tyrosine

2. Dopamine is degraded by MAO

3. Dopamine is packaged into vesicles & released into the synapse

4. Dopamine is degraded by COMT

NT Activity37

Optimal Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPAC

Stores are full

Optimal Activity

NT Stores

Time (months-years)

NT Activity

Optimal Range

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Time (months-years)

Optimal Range

NT Activity

NT Stores

High Activity

Tyrosine

Dopa

DopamineMAO

DOPAL

DOPAC

Encounter Stressor

Stores depleting

COMT

HVA

Stress increasesneurotransmitter activity and demand

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High Activity

Tyrosine

Dopa

DopamineMAO

DOPAL

DOPAC

Stores depleting

COMT

HVA

Optimal Range

Time (months-years)Encounter with chronic stressors

Encounter StressorStress increases the demandfor neurotransmitter activity

NT Stores

NT Activity

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Optimal “looking”Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPAC

Stores still decreasing

Time (months-years)

Optimal Range

NT Activity

NT Stores

Encounter with chronic stressors

Neurotransmitters are not made as quickly as they are needed

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Optimal “looking” Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPAC

Stores still decreasing

Optimal Range

Encounter with chronic stressors

NT Stores

Neurotransmitters are not made as quickly as they are used

Time (months-years)

NT Activity

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Low Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPAC

Stores Low

Time (months-years)

Optimal Range

SymptomManifestation

NT Activity

NT Stores

Encounter with chronic stressors

Neurotransmitter stores become depleted

Inadequate neurotransmitter levels = improper communication

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Low Activity

Tyrosine

Dopa

Dopamine

COMT

HVA

MAO

DOPAL

DOPAC

Stores Low

Optimal Range

Encounter with chronic stressors

NT Stores

Time (months-years)

Neurotransmitter stores become depleted

Improper communication = symptom development

NT Activity

Inadequate neurotransmitter levels = improper communication

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Recognizing Neurotransmitter Patterns

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Urinary Neurotransmitter Interpretation

46

Why Metabolites ?

Serotonin  Dopamine

MAO –A  MAO‐A

5HIAA DOPAC

Meet the Neurotransmitters

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Norepinephrine (AKA Noradrenaline)

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Epinephrine (AKA Adrenaline)

50

Dopamine

51

Glutamate

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Glutamate is involved in Depression

“Coverging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy.”

“Coverging lines of evidence indicate that the glutamatergic system might be a promising target for a novel antidepressant therapy.”

Palucha, A, et al. (2005) Drug News and Perspectives. 18(4):262.

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PEA (Phenylethylamine)

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Serotonin

55

Taurine

56

GABA

57

Glycine

58

Histamine

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Recognizing Neurotransmitter Patterns

60

Urinary Neurotransmitter Interpretation

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Treble – Excitatory BASE ‐ Inhibitory  ‐Calming

Treble – Excitatory(usually) 

Norepinephrine

Epinephrine

Dopamine

Glutamate

PEA

Histamine

Cortisol 

BASE ‐ Inhibitory  ‐Calming(usually)

• GABA

• Serotonin

• Glycine 

Inhibitory Compensation Mechanism

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InhibitoryInhibitory ExcitatoryExcitatory

GlutamateWhen you see high excitatory levels, expect 

to see elevations in the inhibitory transmitters

Serotonin and Depression

66

Sleep Difficulties

67

Low serotonin can lead to low production of melatonin and subsequent sleep issues

Low serotonin can lead to low production of melatonin and subsequent sleep issues

Everything low…

… drug of choice – Stimulants(Cocaine, Methamphetamines, Adderall)

Everything high…

… drug of choice – sedatives(alcohol, benzodiazepams, opioids)

Biomarkers guide treatment interventions

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NE = Low

Dopamine = Low

Serotonin = LowIntervention Choices:

SNRI

Amino Acid Substrates

(5‐HTP, L‐Tyrosine)

Likely Drug of Choice:

Cocaine, Meth (NE and Dopamine)

NE = High

Dopamine = High

Serotonin = LowIntervention Choices:

SSRI

Amino Acid Substrate 

(5‐HTP)

Likely Drug of Choice:

Ecstasy(Serotonin)

Low GABA and Taurine

Imbalances such as low  GABA and Taurine are 

associated with anxiety, panic, insomnia and 

clinically observed cravings for sedating drugs 

(prescription or recreational) and/or alcohol.

Observed clinical patternsLow Serotonin – enjoys ecstasy

Low GABA – enjoys alcohol and benzdiazepines

Low PEA , NE, Dopamine– enjoys  or abuses stimulants

High  Dopamine – enjoys benzodiazepines, alcohol

High Taurine – metabolic issues

High Norepinephrine and Low Epinephrine – patient needs SAMe as cofactor

Low Serotonin and High 5‐HIAA –Consider 5HTP, SSRI, MAO‐Inhibitor

High Dopamine and Low Serotonin – increasing Serotonin will lower 

Dopamine

High Dopamine and High Serotonin – must use antipsychotic to lower 

dopamine

Adrenal Results

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Modulating  Adrenal/Cortisol  Function

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Phosphadityl Serine

Urinary norepinephrine correlates with severity of depression and anxiety

Hughes, JW, et al. (2004) J Psychosom Res. 57:353‐358. 

“…higher levels of depression and anxiety symptoms are related to increased urinary norepinephine (NE) and cortisol (CORT) among women…”

“…higher levels of depression and anxiety symptoms are related to increased urinary norepinephine (NE) and cortisol (CORT) among women…”

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The Vampires VS The Humans

76

Rhodiola Supports Adrenal Function*

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Low Dose RhodiolaAshagwanda

Holy Basil 

Getting a Good Clinical Historyfor Neurotransmitter Correlation

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The Science of Inflammation79

Hormones

Cytokines

AnxietyDepressionInsomnia

PainInflammationAutoimmunity

HP‐Thyroid HP‐AdrenalHP‐Gonadal

Endocrinology Immunology

Neurology

Stress

Neurotransmitters

Surface SPECTAt Rest Concentration

Internal SPECTat rest concentration

Finding Root Cause

• Food Sensitivities

Mold Toxicity  Metals ToxicityBacterial/Viral

Lyme Disease

Anxiety: the inflammation‐glutamate link84

Gliadin AntibodiesGliadin Antibodies

AnxietyInsomniaTrouble focusingAnger or aggression

Hadjivassi R et al. (2004). Trends in Immunology 11:578‐582.

GlutamineGlutamine

SuccinateSemialdehydeSuccinateSemialdehyde

GlutamateGlutamateGlutamine synthaseGlutamine synthase

Glutamate synthaseGlutamate synthase

GABAGABA

Glutamate DecarboxylaseGlutamate Decarboxylase

4-aminobutyratetransaminase4-aminobutyratetransaminase

Succinate Semialdehydedehydrogenase

Succinate Semialdehydedehydrogenase

Citric AcidCycle

Citric AcidCycle

Glutamate synthaseGlutamate synthase

Is It Thyroid ?

Hi Normal / Low Normal can be symptomatic in psychiatric patients with a  history of mood 

disorders• TSH• Free T4• Free T3• TPO• Reverse T3

Is it Low Vitamin D‐3 (Seasonal Affective Disorder) 

• Check Vitamin D‐25‐OH

• Hint: If levels do not improve with oral supplementation, consider “leaky gut”

• Try Liquid Vitamin D‐3.   Ideal Vitamin D3 – 70‐100 ng/ml

• Vitamin  D3 is a fat soluble vitamin – check and recheck levels, toxicity rare, but possible. 

• Consider light therapy as adjunct treatment

Lyme is defined as an infectious illness caused by tLyme is known as “ The Great Psychiatric Immitator”chete, Borrelia burgdorferi

It may start with skin lesion, however, Lyme disease can affect all tissues and organs in the body, e.g. Lyme neuroborreliosisCheck for “Co-Infections” – Babesia and associated s/s

MTHFR mutations

MTHFR genotypingC677T    A1298C

Homocysteine ‐‐‐X‐‐‐Methionine

• MTHFR ‐‐‐‐inactive folate ‐‐‐‐‐X‐‐‐5‐MTHF

X5‐MTHF

NEDopamine

Serotontin

90

Estrogen’s Effects on

Neurotransmitters Direct

and Indirect

91

SupraphysiologicalTestosterone lab values

Bacterial, Fungal, Parasitic Overgrowth

Mold Toxicity

Creating Brain EnvyMay 2007

October 2009

April 2012

Thank you!