Referenced-EEG Redefining the Medical Management of

Psychiatric Disorders

James M. Greenblatt, M.D.November 17, 2007

The Referenced EEG

• A patient’s pretreatment QEEG data is obtained and statistically compared with similar QEEG data from patients with known medication responsivity.

• The result is a prediction of the patient’s likely responsivity to particular medications.

• This, in turn, informs the treatment strategy for the patient.

The rEEG Conjecture

• Resting EEG is stable

• Resting EEG Changes with Medications

• Use Medications to normalize the EEG

• Normalized EEG leads to normalized behavior

Why is Psychiatry Different?

• Medical treatment for mental disorders differs from treatment of all other medical specialties.

• Psychiatrists typically do not use objective measurements to guide treatment of mental or addictive illness

Medical Testing includes

• Blood, Urine, Saliva Assays

• Microbiology

• Tissue analysis

• X-Ray, MRI, CT Scans, PET Scans

• EKGs, EEGs, Myograms

Psychiatric Testing

Diagnosis and Treatment

Psychiatric Treatment:

Symptoms

“Anti”-Symptom treatment given

Measure symptoms

General Medical Treatment:

Symptoms

Measure Physiology

“Anti”-physiology treatment

Measure physiology and symptoms

How good is symptom based treatment?

The “Art” of Psychopharmacology

• Heterogeneity of medication response,

• One class of medication treats multiple disorders

• SSRI’s:

• PMPD• SAD• MDD• Bulimia

• Panic Disorder• Generalized Anxiety• Social Phobia• “No name distress”

Response to Psychopharmacologic Treatment

• 50% improvement of the primary symptoms of depression is the standard measure of treatment response

–20-40% do not show substantial clinical improvement

–50% who show improvement have residual symptoms that impact functioning

St. John’s Wort vs Placebo

8 weeks double blind placebo controlled

31.9% responded to placebo

24.8% responded to Zoloft

23.9% responded to St. John’s Wort

A New Model

• Currently in Psychiatry only symptoms are available to guide therapy.

• Currently there are no pharmacological interventions better than placebo for AN.

• Selecting neuroactive medications by physiological criteria may improve therapeutic outcome

A New Model

Referenced EEG

Case History

HistoryHistory• 44 year old employed female• “Depressed since childhood.”• Anxiety, anergia, weight gain, irritability, negativity, hopelessness, low self-esteem, poor

concentration “like walking through Jell-O…”• Active treatment for 14 years with internist, endocrinologist, psychiatrist• Unsatisfactory response to fluoxetine (Prozac), sertraline (Zoloft), bupropion (Wellbutrin),

paroxetine (Paxil), doxepin (Serzone), venlafaxine (Effexor) and fluvoxamine (Luvox)

rEEG Medication PredictionrEEG Medication Prediction• Anticonvulsant and Stimulant in combination• Physician selected Lamictal and Ritalin

ResponseResponse• Improved concentration, increased tolerance• Significant decrease in negativity and anxiety• Experienced modest weight loss over several weeks• Feelings of hopelessness and low self-esteem have diminished markedly

After seven antidepressant trials, rEEG identified non-intuitive medication sensitivities.

Case History

• 23 y/o female• ED beginning age 16• Restrictive eating, purging, depression, passive SI• 3 month treatment at Laurel Hill Inn, 11/04 - 2/05 • Shephard Pratt, 4/05 – 7/05• WBC Alcott unit approx 2 wks 11/05• WBC Thoreau unit approx 2 wks 12/05• WBC Residential Program 12/05-2/06• rEEG completed 12/28/05

Past Medication Trials

• Medication– Trazadone, Abilify, Ativan, Lamictal, Zoloft,

Effexor, Prozac, Ambien, Naltrexone

• rEEG data– Trileptal/Cymbalta

• Current status– Engaged in Outpatient Treatment

– Recommending rEEG to friends

Brain wave patterns of ADD children

• Theta waves are associated with daydreaming and inattentiveness

• Beta waves are associated with concentration and focus

• Brain Wave patterns of ADD children show an abundance of theta, and diminished beta

Is it possible ...

• Is there a relationship between neurophysiological findings and medication response?

• Can this relationship be used to predict response?

• Can these predictions be used to inform treatment design?

Yes!

• Major depression with excess alpha responds to antidepressants

• ADHD with excess slow waves respond to stimulants

• OCD with excess Theta are non responders to anti-depressants

• Low voltage EEGs are poor responders to anti-depressants and anti-psychotics

Significant EEG heterogenities within Neuropsychiatric disorders

Different patients within the same neuropsychiatric disorder would have different response to medications

39 Patients with a similar EEG feature

• 39 Patients with 17 different DSM-based diagnoses (x axis)

• All have the same rEEG defined abnormality

• All responded well to the same specific agent

• Conclusion:DSM-diagnosis does not correlate well with drug responsivity. rEEG does correlate well.

0 2 4 6 8

DSM

Axi

s I

diag

nosi

s

Number of patients

293.83

296.2

296.22

296.23

296.3

296.32

296.33

296.7

299.8

300.01

300.4

301.13

309.89

311

312.3

312.39

314

Family History/Genetics

• Inherited EEG patterns have been documented

• Clinicians use family history of medication response as guides for selecting a psychotropic medication

• EEG abnormalities maybe a marker for familiar medication responses

• Two Generation rEEG study

Resting EEG is stable

Resting EEG Changes with Medications

Use Medications to normalize EEG

Normalized EEG leads to normalized behavior

rEEG - Characteristics

rEEG is a measure of abnormal brain function,

NOT mental illness

Database Comparison

• 1600 patients followed for at least 26 wks

• 84 medications tracked for effectiveness over more then 6000 treatment episodes

• 8467 patient follow-up assessments

• Outcome assessment using clinical Global Improvement scale (CGI)

Normal Subject Database: 2082 QEEG’s, Subjects 6-90

Original Pharmacotherapy Outcome Database

rEEG

How does it work?

Z s

core

(deg

ree

of a

bn

orm

alit

y)When appropriately medicated, abnormal brain function can be improved or normalized

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Fp1 Fpz Fp2 F3 Fz F4 F7 F8 C3 Cz C4 T3 T4 T5 T6 P3 Pz P4 O1 Oz O2

Electrode sitesPrior to medication

After medication with rEEG recommended drugs

Patient 1: Pre and Post Treatment

Z s

core

(deg

ree

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Using rEEG, medications are selected which affect neurophysiology in known ways

Patient 2: Pre-treatment

Z s

core

(deg

ree

of a

bn

orm

alit

y)Medications that are not compatible for a neurophysiology* can yield iatrogenic illness

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Fp1 Fpz Fp2 F3 Fz F4 F7 F8 C3 Cz C4 T3 T4 T5 T6 P3 Pz P4 O1 Oz O2

Electrode sitesPrior to medication After medication

Patient 2: Pre and Post treatment

* Frequently occurs with symptom/behavioral-based treatment selection

EEG Guidance of Psychopharmacologic Treatment: Multi-Site Experience

Mark J. Schiller, M.D., W. Hamlin Emory, M.D., Jay Shaffer, M.D., James T. Hamilton, M.D., Daniel A. Hoffman, M.D., Albert Davis, M.D., Stephen S. Suffin, M.D.

APA May 2005 Scientific Poster - 500 patients

Size Results

ADD & Depression Trial 100 >80%

VA Blinded Study 13 85%

CIGNA-Atlanta Pilot 56 70%

Dr. Davis Case Series 15 100%

Monte Nido Case Series 150 80%

Dr. Hamilton Case Series 34 78%

Dr. Hoffman Case Series 74 76%

Rancho L’Abri Case Series 58 93%

Eating Disorder rEEG CASES

16 y/o AN (RT) - Lamictal, Adderall

21 y/o AN (BD) -Trileptal, Zoloft, Wellbutrin

22 y/o ED NOS - Topamax, Parnate

25 y/o ED NOS/AL DUP - Lamictal, Wellbutrin

16 y/o AN - Neurontin, Parnate

43 y/o ED NOS/Depress - Neurontin, Wellbutrin

22 y/o AN (RT) - Lamictal, Effexor

29 y/o Bulimia/OCD/Depress

- Trileptal, Wellbutrin

Drug Class Correlations

Sensitive– Greater than 80% of the neurophysiological similar patients exhibit a

change in CGI of two or more• Minimum of 45 days post treatment

Resistant– Less than 35% of patients with similar neurophysiology had a CGI

change of two or more

Intermediate– Between 35-85% of patients with similar neurophysiology had a CGI

change of two or more

Patient name: Referring physician: Bill Richardson, M.D. Date of Birth: Address: Bill Richardson, M.D.

Age: 64.1 33 Overlook Rd., Suite 210 Date of Test: 9/15/2005 Summit, NJ 07901

Test medications: None Phone: (908) 598-0008 CNSR Patient ID: 6651 Technician: S.P.

A. Summary of rEEG Type I Findings The overall level of neurophysiologic abnormality as measured by rEEG features is: High/Moderate/Low

Section 1: Drug Class Correlations Drug Class Sensitivity Biomarker Predominance

Beta Blockers Sensitive/Intermediate/Resistive High/Moderate/Low Anticonvulsants Sensitive/Intermediate/Resistive High/Moderate/Low Antidepressants Sensitive/Intermediate/Resistive High/Moderate/Low Stimulants Sensitive/Intermediate/Resistive High/Moderate/Low Correlations are based on a subset of more than 1,600 patients in the rEEG database having (1) similar rEEG features to this patient and (2) a change of two or more improvement in their Clinical Global Improvement Index (CGI).

Section 2: Individual Medication Responsivity Subgroup ratings (S, I & R) are based on comparison to other subgroups within the overall medication group. Within the subgroup individual medications ratings (1, 2, 3) are relative to other medications in the subgroup only. When there is only one medication in a subgroup only the subgroup rating appears. Specific medication combinations may be incompatible.

Anticonvulsants (Sensitive) Stimulants (Sensitive) Trade Name Generic Name Sensitivity Trade Name Generic Name Sensitivity

Benzodiazepines R MAOI I Xanax Alprazolam Manerix

Moclobemide 1

Ativan Lorazepam Parnate Tranylcypromine 3 Klonopin Clonazepam Eldepryl Selegiline 2 Tegretol Carbamazepine R Nardil Phenelzine ND Depakote Divalproex S Ritalin Methylphenidate R Neurontin Gabapentin I Dexedrine d-Amphetamine S Lithane Lithium I Adderall d,l-Amphetamine R Gabitril Tiagabine ND Provigil Modafinil ND

Beta Blockers (Intermediate) Trade Name Generic Name Sensitivity

Lopressor Metoprolol I Inderal Propranolol I Tenormin Atenolol I

Key to symbols: S = sensitive, patients with similar neurophysiology were most often responsive to medications with this designation. R = resistant, patients with similar neurophysiology were least often responsive to medications with this designation. I = intermediate, patients with similar neurophysiology were neither consistently sensitive or consistently resistant to medications with this designation ND = No data in the database to support recommendations 1,2,3 = relative rankings amongst agents in a subgroup where 1 is highest and 3 is lowest.

- Available in Canada

Referenced-EEGSection 2: Individual Medication Responsivity

Subgroup ratings (S, I & R) are based on comparison to other subgroups within the overall medication group. Within the subgroup individual medications ratings (1, 2, 3) are relative to other medications in the subgroup only. When there is only one medication in a subgroup only the subgroup rating appears. Specific medication combinations may be incompatible.

Anticonvulsants (Intermediate)   Antidepressants (Sensitive)

Trade Name Generic Name Sensitivity   Trade Name Generic Name Sensitivity

Benzodiazepines

  I   SSRI   I

Xanax Alprazolam 2   Prozac Fluoxetine 3

Ativan Lorazepam 1   Zoloft Sertraline 3

Klonopin Clonazepam 3   Paxil Paroxetine 1

Tegretol Carbamazepine S   Luvox Fluvoxamine 2

Depakote Divalproex R   Celexa Citalopram 2

Neurontin Gabapentin S   TCA   S

Lithane Lithium R   Norpramin Desipramine 2

        Tofranil Imipramine 1

Beta Blockers (Intermediate)   Pamelor Nortriptyline 3

Trade Name Generic Name Sensitivity   Elavil Amitriptyline 2

Lopressor Metoprolol I   Anafranil Clomipramine 2

Inderal Propranolol I   Wellbutrin Bupropion S

Tenormin Atenolol I   Effexor Venlafaxine S

Key to symbols:S = sensitive, patients with similar neurophysiology were most often very responsive to medications with this designation.R = resistant, patients with similar neurophysiology were least often very responsive to medications with this designation.I = intermediate, patients with similar neurophysiology were neither consistently sensitive or consistently resistant to medication with this designationND = No data in the database to support recommendations1,2,3 = relative rankings amongst agents in a subgroup where 1 is highest and 3 is lowest.

Benefits of Referenced EEG

• rEEG can indicate and support non-intuitive recommendations

• - Prescribing stimulants for anorexics

• rEEG helps physician organize complex cases

• rEEG helps physician avoid unnecessary and costly therapies

Who’s not suitable

• Under 6 or over 90 years old

• Intramuscular depo-neuroleptic therapy within the preceding twelve months

• History of craniotomy (with or without metal prostheses) or cerebral vascular accident

• Spikes on the conventional EEG

• Current diagnosis of seizure disorder or dementia

• Mental retardation

• Current use of marijuana; cocaine, hallucinogens or other drugs of abuse or alcohol in the last three days

• Significant abnormality of the CBC, chemistry or thyroid function tests including TSH until corrected

rEEG Data Flow

Digital EEG’s

Age NormalizedDatabase

Clinical ResponseDatabase

AnalysisAnalysis

MedicationRecommendation

Summary

• The Problem• DSM directed (symptom based) therapeutic regimens

often require extensive trial and error.

• In Eating Disorders medications are often ineffective.

• A Solution• Directly assess the physiology of the brain in a way

that is predictive of medication responsivity.

• Multi site Research Study starting for Treatment Refractory Depression

Conclusion

• Psychiatric disorders are strongly familial and biological and can no longer be seen as disorders of choice!

• We can directly assess the physiology of the brain in a way that is predictive of medication responsivity.

• Using that information allows us to medicate more effectively and with much less trial and error.

rEEG Based on the Following Assumptions

1. Significant heterogeneity within any diagnostic category

2. Different electrophysiologic abnormalities are predictably responsive to specific medications

• rEEG is a tehnology that compares the quantative EEG of medication free patients to a large database of asymptomatic, medication free, “normal” EEGs in order to

define an abnormality

Conclusion

• Early clinical trials show that rEEG is more than 80% effective in guiding the treatment of patients with a range of psychiatric diagnoses including, major depression, Bipolar Disorder, ADHD, Anxiety Disorder, OCD and Eating Disorders.

Thank You

Thank You