Pediatric Depression from an Integrative Perspective

scott shannon, md faacapuniversity of colorado

Agenda

� Our current situation� New ways of thinking � Depression� Treatment options� Bipolar and Ketamine

Unanticipated Consequences

New York Times Lead Story: April 7, 2018

Depression as a Model

�  Environmental, physical, emotional, mental, social, or spiritual triggers

�  Final common pathway

�  Lack of core pathophysiology

�  Very broad assessment needed

�  Unique expression of imbalance

New ways of thinking

A new wilderness to navigate

Overweight Children in US CDC

0%

5%

10%

15%

20%

71-74 76-80 88-94 99-00 2001-02

2003-04

age 6-11age 12-19

IL-6 Predicts later illness�  4,500 children assessed age 9 and again at 18 years

old (ALSPAC).

�  Measured IL-6. Broken into thirds

�  High group 2x as likely to develop depression or schizophrenia

�  Higher levels associated with risk in dose-dependent manner

Khandaker, GM JAMA Psychiatry 2014 Aug 13 epub 1332

Does inflammation change psychiatric outcomes?

�  Etanercept (Enbrel) improved MDD more than placebo in psoriasis study �  Tyring 2006

�  Adjunctive aspirin speeds response time to SSRI (fluoxetine) for depression phenotype in rats �  Mendlewicz 2006

�  Adjuctive celecoxib (Celebrex) improves outcomes to SNI (reboxetine) for MDD �  Muller 2006

�  In animal models, cytokine antagonists and anti-inflammatory drugs block depression phenotype after immune activation. �  Dantzer 2008

Contributors to inflammation

•  Abnormal microbiome

•  Trauma = ACEs: inflammation via SNS activation

•  Stress

•  Obesity or metabolic syndrome

•  Diet, SAD, GMOs, HFCS, sugar

•  Toxic burden, amalgam fillings, organic pollutants

•  Infections

•  Intestinal permeability (leaky gut)

•  Injury, surgery

Decreasing Inflammation•  Diet – loose weight and eat well

–  Mediterranean, Anti Inflammatory Diet for Dummies, New Atkins Diet, low carb diet.

•  Exercise – reduces cortisol levels • Meditation and other mind/body therapies•  Supplements

–  Omega 3 Fatty Acid, 2G daily–  Ashwaganda, 500mg bid–  N Acetyl Cysteine, 1G bid–  Vitamin D, 5,000iu/day

• Medications–  Statins, TCAs, Lovaza (Omega 3)

Mitochondrial Modulation�  CNS function places huge demands on energy

production

�  There is increasing recognition that mitochondrial dysfunction may play a critical role in major psychiatric illness

�  Symptoms of mito dys: anxiety, mood d/o, cognitive dysfunction, psychosis and OCD

�  Studies correlate anxiety with mitochondrial abn in hippocampus

Anglin RE Transl Psychiatry 2012 November 13

Mitochondrial Modulation Known Modulators:

�  1. N-acetyl Cysteine (NAC)

�  2. Acetyl-L-Carnitine

�  3. S-adenosyl Methionine (SAM-e)

�  4. CoQ10

�  5. Alpha-Lipoic Acid

�  6. Creatine Monohydrate

�  7. Melatonin

Nierenberg AA Aust NZ J Psychiatry 2012, June 18

Huge in US: athletes and body builders

Buff up the Brain?�  Creatine monohydrate (CM) used to build muscle

mass

�  Creatine Kinase (CK) plays key role in energy metabolism

�  Serum CK fluctuates with mood, depression and bipolar phase

�  May be gender differential-only female rats respond

�  3-5 gm q am

Allen PJ Neuroscience Biobehavioral Review 2012, 36 (5): 1442-1462.

Creatine in Teens �  Pilot study with creatine for augmentation and MRI

spectroscopy comparison with controls

�  5 teen girls with TRD who failed fluoxetine

�  4 grams daily for 4 weeks

�  Mean CDRS fell from 69 to 30

�  A significant increase in brain Phosphocreatine (PCr) concentration (p=0.02) on follow-up

Kondo, D J Affective DO 2011 135 (0): 354

Peds: Exercise for Depression

�  Meta-analysis: 50 studies (89, 894 pts). 2000-15

�  Mean effect size: Significant (r = -0.14; 95% confidence interval [CI] = -0.19 to -0.10)

�  Stronger effect sizes: measures of frequency and intensity of physical activity versus intensity alone

Korczak, D et al Pediatrics 2017, 139 (4). 

Chronotherapeutics �  RCT of 62 adolescents (13-18 yrs) with moderate

to severe depression

�  Compared bright light therapy vs wake therapy

�  BLT effective for mood at two weeks post intervention

�  No added benefit with WT to mood

�  Sleep quality improved in both groups

Gest, S et al Eur Child Adol Pyschiatry 2016 Feb;25(2):151-61

Cookbook from the1940’s

St John’s wort: Cochranel 29 studies from a variety of countries with

5,489 patients, randomized and double blind.

l Major Depression only

l Placebo or antidepressants

l Superior to placebo in treating patients with major depression and are "similarly effective" as standard antidepressants

Linde K, et al Cochrane Database of Systematic Reviews 2008, 4. October

Systemic Review of SJW vs Antidepressants

Apayden, E et al, Syst Rev 2016; 5(1): 148.

St. John’s wort: Risks Cytochrome P450 effects-Decreases potency of:l  BCPl  Cyclosporinel  Digoxinl Warfarinl  Protease inhibitorsl  Theophyline

Increases potency of: MAOi, SSRI, Alcohol, triptans, narcotics

St. John’s wort l Safe, effective treatment for depression

(mild to major)

l No Black Box warning

l Use quality product; 0.3% hypericins is a general marker

l Cost $8–20 per month

l BID dosing best: 900mg/day total, age 8 up

SAM-e in Depression

About the same as SSRI

SAM-e

�  S–adenosyl methionine (crucial methyl donor)�  Enhances methylation in body�  Safe and synergistic antidepressant�  Stimulating, works quickly (2 weeks)�  Headache, insomnia, nausea�  200-800 mg twice daily, start low, give on

empty stomach�  Can induce mania

Saffron

Saffron (crocus sativus)�  Greek frescos depict Saffron as medicine 3600

years ago

�  Herbalists: antispasmodic, thymoleptic, carminative, cognition enhancer, aphrodisiac, and emmenagogue.

�  Stigma and petals both studied

�  15 mg-30mg twice daily used in all studies

Saffron in Depression and Anxiety

�  Systemic Review and Meta-analysis

�  23 RCTs

�  Large effect sizes Depression (0.99); Anxiety (0.95)

�  Augmentation helpful: (1.23)

�  Concern: possible publication bias and regional concern

Marx, W Nutrition Review 2019  May 28. pii: nuz023

Depression Treatments: Mental/Emotional

�  Psychotherapy-indiv and family

�  Recreation

�  Social/Relationships

�  Work

�  Hobbies

�  Education

Depression Treatments: Spiritual

�  Retreat and Nature

�  Spiritual Counseling

�  Dream Work

�  Service

�  Existential Exploration

�  Prayer

�  Love, Joy, Hope

Support Energy�  Adaptogens-Rhodiola: 2-400mg/am

�  Acetyl L Carnitine: 1-2,000mg/d

�  CoQ 10: 100-200mg/d

�  B Complex 50 mg in am

�  Vit C: 500-1,000mg BID

�  Think gut and candida

�  Explore sleep, think apnea

�  Retreat

�  Calamity

�  Psychedelics

�  Shamanic journey

�  Spiritual conversion

�  World travel/pilgrimage

�  Near death experiences (NDE)

�  Major events: birth, illness, divorce and death

Catalysts for Profound Change

Depression: tools

�  Supplements

�  CES

�  Exercise

�  Acupuncture

�  Hormones

�  Light

�  Medications

�  Meditation

�  Heavy metals removal

�  Cognitive work (CBT/DBT)

�  Gut/ Food Allergies

�  Diet

�  Family/Couples work

�  New job/career

�  Spiritual work

�  Animals/pets

�  Mitochondria

�  Herbal remedies

Assessment: Lab�  Thyroid: TSH, T3 and T4�  Adrenal: DHEA-s & salivary cortisols�  CBC/ferritin and Cholesterol�  B-12 and folate�  GI/dysbiosis: elimination diet�  Vitamin D �  Homocysteine�  High Sens CRP�  MTHFR

Depression-opinion what to avoid

�  Over emphasizing the physical

�  Over emphasizing medications

�  Getting stuck in a narrow path

�  Forgetting psychotherapy

�  Forgetting family dysfunction

�  Adding medications to medications

Depression: opinion what to do

�  Evaluate all ecosystems

�  Explore and support diet and sleep fully

�  Exercise

�  Supplements: SAM-e, SJW, Vit C, Saffron, Rhodiola, etc.

�  Low energy-diet/gut, adrenals or mitochondria

�  Explore sleep fully

�  Rule out inflammation and toxic overload

�  Address software and family issues

�  Inspire the patient to make changes

Opinion: Depression�  SJW or SAMe or Saffron based on patient

�  B Complex 50mg (B-6 and 1 mg methylfolate)

�  EPA: 1 gram or more

�  Vitamin C: 500-1,000 mg

�  Exercise

�  Higher protein, high quality diet

�  Consider mitochondrial modulation or adaptogen if energy concern

�  Psychotherapy or education

�  Light therapy/sunlight

Bipolar Disorder in Kids �  Previously extremely rare

�  Increasing rates—40 fold rise in Dx in 10 yrs

�  Cultural, nutritional roots

� Omega 3 oil deficiency=inflammatory CNS?

�  ADHD 80-90% co morbid

�  Anxiety, hallucinations, suicidality common Moreno, C. Archives Gen Psychiatry September 64 (9) 2007

Integrative Tx of Bipolar D/O

�  Broad-Spectrum Micronutrients

�  Parenting and Family Therapy

�  Omega-3 (one gram EPA)

�  Inositol (2 to 5 grams TID)

�  Bright Light Therapy (10,000 lux; 18 inches; 30min)

�  Rhodiola/Ashwaganda

�  Others

Ketamine and Depression

“The marked acute antidepressant efficacy of ketamine, even in medication-refractory patients, now seems beyond doubt. A meta-analysis of 9 ketamine RCTs (pooled N = 234) found that ketamine attenuated depression significantly more than did control treatment. The antidepressant benefits were apparent at 40 minutes, peaked at day 1, and were lost by days 10–12.”

Andrade, C J Clinical Psychiatry 2017 Apr;78(4):e415-e419.

Summary

� Our current system has many limitations

� We need to approach each person as a complex ecosystem

�  Evidenced based treatments like SAMe, SJW, exercise and other treatments offer helpful options for depression

Nutrient deficiency can cause disease

“When one input in the metabolic network is inadequate, repercussions are felt on a large number of systems and can lead to…disease.” Ames BN. J Nutr. 2004 Nov;134(11)

What is a broad-spectrum, or multi-ingredient, micronutrient formula?

�  The Original Formula Prototype: EMP, then: �  EMPowerplus™ �  Daily Essential Nutrients™; �  Quiet Minds™

�  ’36-ingredients’ (Minerals and Vitamins, plus some antioxidants, AAs and botanicals)

�  Other Formulas in the Medical Literature �  Berocca™, Swisse Ultivite (Men’s, Women’s) F1™,

Syndion™, Tropamine™, and other proprietary and non-proprietary products

Broad-Spectrum Micronutrients

Daily Essential Nutrients™(and EMPowerplus™,QuietMinds™)

DEN: Serving size = 4; U&C full dose = 4 TID; capsule and powder preps

�  39 ingredients: 16 minerals, 13 vitamins, and 10 in the ‘proprietary blend’ (choline, inositol, AAs, botanicals, trace minerals)

�  Includes, per serving: D (1000 IU), folate (267 mcg as L-5-MTHF ), K (40 mcg as 3:1 K1:K2), and lithium ( ̴333 mcg as orotate)

�  No citrus bioflavonoids, L-glutamine, DL-phenylalanine, or germanium sesquioxide; yet includes αLA, NAC, and ALC which are not in EMP.

E.M. Power Plus

�  Vitamins: A, C, D, E, B1, B2, B3, B6, B9, B12 �  Biotin, Pantothenic Acid, Calcium �  Iron, Phosphorous, Iodine, Magnesium �  Zinc, Selenium, Copper, Manganese �  Phenylalanine, Glutamine, Bioflavanoids �  Grape seed, Ginkgo, Inositol �  Vanadium, Boron, Methionine, Germanium, Nickel �  Currently over 38 peer reviewed studies published,

all done w/o $ support from manufacturer

Next Generation of EMP

�  Daily Essential Nutrients

�  Contains Vitamin K

�  Doubles dose of Vitamin D

�  No citrus bioflavinoids

�  Contains acetylcarnitine and NAC

�  Contains organic lithium

�  Much less nausea and med interaction

Daily Essential Nutrients™ (DEN)

�  This is the foundation nutraceutical biotx for the manic state

� W/O psych meds on board – rapid titration from 2→3→4 TID w/meals over 3-7 days

� W/concurrent psych Rxs – slower titration, depending upon the class(es) of Rx(s), then reduced or tapered off � Monitor for biodynamic interactions and

increased incidence of SEs � 4 TID remains the full-dose goal

dozens of publications later

�  “Ingesting minerals and vitamins in combination makes physiological sense, and research on the use of broad-spectrum formulations for psychiatric symptoms is increasing rapidly.” �  43 original investigations / PRISMA systematic review

covering 5 major areas Rucklidge JJ, Kaplan BJ. Expert Rev. Neurother. (2013)

�  As of March 2020, more than 38 empirical reports on EMPowerplus™ for various mental conditions published in peer-reviewed medical journals; not funded by the manufacturer or its business affiliates

�  Many other publications on bsMCNs for conditions of interest to psychiatrists

Ketamine increases neuroplasticity

Huang YJ et al. Neural Plast. 2017;2017:4605971.

Dore et al, J Psychoactive Drugs 2019, 2019 Apr-Jun;51(2):189-198.

Dore et al 2019.

Troughs and Attractors

Simplified visualization of brain hub and network activity

Placebo Psilocybin

Psilocybin: Creates less rigid and more open connections

Petri G, J R Soc Interface 2014; 11(101):20140873.

Resources Culbert and Olness (ed) Integrative Pediatrics Oxford Univ Press: NY, 2010

Diller, L Running on Ritalin Bantam Books: NYC, 1998

Doidge, N The Brain That Changes Itself, Penguin: NYC, 2007

Greene, R The Explosive Child Harper Collins, NY, 2005

Honos-Webb, L The Gift of ADHD New Harbinger: Oakland, Ca, 2010

Kemper, K Mental Health Naturally AAP Press: Elk Village, Il, 2010

Newmark, S ADHD without Drugs Nurtured Heart Tucson, 2010

Shannon, S Handbook of Complementary and Alternative Therapies in Mental Health, Academic Press: San Diego, CA, 2002

Shannon, S Mental Health for the Whole Child Norton: NY, 2013

Shannon, S Parenting the Whole Child Norton: NY, 2014

ResourcesEmmons, H., The Chemistry of Joy Simon and Schuster: NYC, 2006

Kemper, K., Mental Health, Naturally AAP: Elk Grove, Il, 2010

Lake, J and Spiegel D Complementary and Alternative Treatments in Mental Health Care APPI: Washington DC, 2007.

Lake J Textbook of Integrative Mental Health Care Thieme Medical Publishers: NY, 2007

Larsen, J. Seven Weeks to Sobriety Ballentine Books: NY 1997

Logan, A., The Brain Diet Cumberland House: Nashville TN, 2007

Murray, M., Encyclopedia of Nutritional Supplements, Prima Press: NY 1996

Pizzorno, J. and Murray, M., Encyclopedia of Natural Medicine, Prima Press: NY 1997

Ratey, J., Spark: Exercise and the Brain Little, Brown: NYC, 2008

Shannon, S., Handbook of Complementary and Alternative Therapies in Mental Health, Academic Press: San Diego, CA 2002

Zuess, J., The Wisdom of Depression, Harmony Books: NY 1998

Scott Shannon, MD

Wholeness Center2620 E Prospect Rd. #190

Fort Collins, Colorado 80525970.221.1106 scott@wholeness.com

www.wholeness.com