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The Holistic Medicine Approach to
the Treatment of Schizophrenia
Louis B. Cady, MD, FAPA
CEO, Founder – Cady Wellness Inst...
“There are two objects of medical education: to
heal the sick and to advance the science.”
- Charles H. Mayo, MD
“The glor...
Review …
2 tips!
• ALL SLIDES from this presentation are at:
–www.slideshare.net/lcadymd
• I will point out the slides dea...
Schizophrenia – multiple domains and
defects
• Positive symptoms
– (delusions, auditory & visual hallucinations)
• Morris ...
Schizophrenia
• Historically:
– “Dementia praecox” - Heinrich Schule in 1886.
– Emil Krapelin (1893) refined classificatio...
Etiopathogenesis of schizophrenia
• In utero exposure – Toxoplamsa
gondii
• Maternal malnutrition:
– decreased PUFAs, oxid...
Multiple pathways for Alzheimer’s
Disease…
“Dopamine hypothesis of
schizophrenia”
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
How much D2 blockade is enough?
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
Clozapine – a problem with the D2 blockade
theory
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
Holistic Treatment of Schizophrenia
•Psychodynamic
•Biological
•Holistic
Artist: Craig Finn
(schizophrenia
patient) – in PLOS
Medicine – “How
prevalent is
schizophrenia?”
May 31, 2005
Web link:
h...
“If you can only read one article
in your entire career at Mayo on
psychotherapy, read this one.”
- John Graf, MD
“If you ...
Psychodynamics and holistic medicine
• Some therapists stand out as uniquely
effective.
• Academics are no better.
• “Ever...
Greben’s “Seven Habits”
• Empathy & concern
• Warmth
• Interaction
• Ability to arouse hope
• Expectation of improvement
•...
Psychodynamics 101
• Patients can be vexing.
• Therapeutic impasses provoke narcissistic angst
(psychodynamic OR biologica...
Case presentation
• Alan – presents on Feb 16, 2007,
diagnosed with depression vs. psychosis.
– Previous treatment at Pfei...
Past history
• “Ever since I can remember, I’ve always had
the same feelings about things – how people
treat each other an...
• Treated with fluoxetine in the past for depression
• Stopped being able to do homework as a
sophomore in high school
• “...
March 2007
• Evaluated for obstructive sleep apnea & now on
CPAP (continuous positive airway pressure
device).
• Improved ...
Clinical course through July 2007
• Continued in treatment with me every 1 – 3
month appointments. Still isolated.
• Seeme...
2007 - 2009
• More explosive outbursts. Lamotrigine
(200 mg) added topirimate continued
• “I know that I’m acting ridiculo...
June 30, 2009
• He comments that he feels
his “mouth is going faster
than his thoughts.”
• Mom reports that
“traveling out...
Integrative (“functional”) medical
testing done TESTING
• Micronutrient analysis (functional
intracellular analysis) – def...
8/12/2009 Follow-up
• Very irritable and sarcastic at
appointment.
• Continue baseline Rx as is.
• NEW: start diet – dairy...
Last four months January 21,
2010
• On IgG diet. “He has been doing well on it.”
• At Christmas, however, he “went off of ...
November 18, 2012
January 2010 to 2014
• November 2012 – high IgG allergies to dairy and
wheat. Diet again emphasized.
• Elemental lithium d...
April 15, 2013
Low dose Lithium orotate started
August 31, 2014Fungal markers went up; Nystatin
started.
May 16, 2018
Conclusion:
These significant changes in synapsin I and II expression
may implicate a common transcription factor, early g...
Repeat testing 13 months later – May 21, 2014
As of May 16, 2018
Candida – what is it?
• “C. albicans is a diploid, polymorphic
yeast residing in mucosal surfaces of
the human respiratory...
4 of 5 papers in the literature
“schizophrenia candida”
• 1. Clozapine found to inhibit yeast budding to
hyphal transition...
3. Odds ratio of schizophrenia with
candida albicans seropositivity
• Case control differences investigated regarding cand...
4. Probiotic normalization of Candida albicans in
schizophrenia: A randomized, placebo-controlled,
longitudinal pilot stud...
How to order the labs (Lab Corp, or
Quest):
• Candida antibodies – IgG, IgA, Ig M with
QUANTITATIVE TITERS
• Gluten:
– Ant...
Note for posted slide deck: This and the next slide show functional testing first, and
conventional testing, second. Conve...
Off-target effects of psychoactive drugs
revealed by genome-wide assays in yeast
Drug effect
81 compounds “inhibited wild-...
June 23, 2015
• “The past few days I’m
doing pretty good. It’s
been a miraculous few
days. This week has
been pretty good....
2015 supplementation – in collaboration
with CWI biomedical specialist
• N-acetyl cysteine complex (glutathione
precursor)...
Schizophrenia and Gluten
As of May 13, 2018
Differential antibody responses to gliadin-derived
indigestible peptides in patients with schizophrenia
• Evaluation: IgG ...
Gliadin – a definition
“GLIADIN is the alcohol soluble fraction
of gluten and is the primary antigen
leading to an inflamm...
Patient “Alan”
Another recent schizophrenic patient for comparison
Note for posted slide deck: This and the next slide show functional testing first, and
conventional testing, second. Conve...
Schizophrenia & Vitamin D
*
*
As of May 13, 2018
Feb 2018 – latest article as
of May 13, 2018
Anti-inflammatory strategies
Vitamin D & Omega 3 fatty acids –
relevance for SCHIZOPHRENIA
“VITAMIN D & marine omega 3 fatty acid intake may help preve...
B-vitamins and inflammation
References: Mikkelsen K, et al. Maturitas. 2017;’96:58-71.
Brown HE et al. Vitamin Supplementa...
Decreased Brain levels of Vitamin
B12 in Aging, Autism and
Schizophrenia• Cobalamin exists in multiple forms, including
me...
Stahl SM. L-methylfolate: a vitamin for your monoamines. J
Clin Psychiatry. 20089 Sep;69(9):1352-3
Strategy: test for “MTH...
SEARCH: “n-acetyl cysteine schizophrenia” 05 13 2018
RELEVANT FACTS:
•3600 mg NAC daily
•52 week double blind, placebo controlled trials
• NAC significantly improved PANSS tot...
Alan – the rest of the story
October 25, 2014
http://cadywellness.com/a-shattered-mind-and-music-within/
Tip: www.youtube....
Alan & Clozapine
• Maximum benefit on meds and supplements
reached. Still symptomatic.
• Clozapine was suggested in 2016.
...
What it’s like from the inside-
March 30, 2017
• Alan: “I am not as dizzy – still feel like I’m in a dreamlike
state – but...
March 30, 2017
• Clozapine – 100 mg
a.m. + 175 mg pm
• Olanzapine +
Aripiprazole stopped
• Nystatin1.5 million IU
2 – 3X/d...
April 14, 2017
Psychotherapy
• 9,271 citations on “psychotherapy
schizophrenia” May 16, 2018
– 243 citations on “psychoanalysis schizophr...
So what the
heck am I
supposed to
do with this
stuff?
Kitrick – the CWI “therapy baby”
© Louis B. Cady, MD – image used
wi...
Rational holistic considerations
• Vitamin D
• Omega 3 fatty acids
• B-vitamins (full complex)
• Antioxidants (and good di...
Concluding thoughts
• Just because someone has a classic “biological
psychiatry” diagnosis doesn’t mean that there
can’t/w...
Perhaps the ability not only to acquire
the confidence of the patient, but to
deserve it, to see what the patient
desires ...
Louis B. Cady, MD
Cady Wellness Institute
4727 Rosebud Lane – Suite F
Newburgh, IN 47630 USA
Office (812) 429-0772
info@ca...
APPENDIX:
(These are slides that were not
presented due to the inherent
time limitations of a grand
rounds talk.)
Schizophrenia Etiopathogeneses:
some theories
• Immuno-inflammatory response
–From dysfunctions of brain-gut axis
–Intesti...
As of May 13, 2018
Inflammation and the Mind
Gut bugs and brain
• “Intestinal microbes in
the gastrointestinal tract
regulate peripheral
immune responses,
CNS function...
Inflammation and schizophrenia
• Short chain fatty acids (SCFAs) linked to a
shortened lifespan with schizophrenia. Use of...
Immunoglobulin G genotypes and risk
of schizophrenia
• Assessment of highly polymorphic immunoglobulin GM
(gamma marker) g...
“Bread and Other Edible Agents of
Mental Disease”
• Cereal grains – the world’s most abundant food source –
can affect hum...
Some current research
• “Patients with schizophrenia have low plasma Vitamin D level.”
(Does not appear to be associated w...
More Vitamin D Research
• Evaluation of 80 patients with chronic stable schizophrenia with residual
symptoms and Vitamin D...
Patients vs. professional staff
• Naturalistic study – the Netherlands
• Study:
– Vitamin D levels measured in therapy-res...
“The movers and shapers in immune
privilege of the CNS.”
BioPsychoSocial – the “ACT” model
•A ssertive
•C ommunity
•T reatment
• Help with finding jobs, integrating
into society. ...
Normal colon vs.
pseudomembranous colitis
• HPHPA found in higher concentration in urine samples of children
with autism compared to controls.
• Highest value ever ...
Folinic acid treatment for schizophrenia
associated with folate receptor
autoantibodies
• Autoantibodies against folate re...
Modified Mediterranean Diet for Enrichment of Short Chain
Fatty Acids: Potential Adjunctive Therapeutic to Target Immune
a...
Modified Mediterranean Diet for Enrichment of Short Chain
Fatty Acids: Potential Adjunctive Therapeutic to Target
Immune a...
• Case reports of two patients
with schizoaffective disorder
• Both had failed clozapine
– 1 patient failed 12 Rx.
– 1 pat...
www.cadywellness.com
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
The Holistic Treatment of Schizophrenia
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The Holistic Treatment of Schizophrenia

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In this Grand Rounds presentation, delivered to the Dept. of Psychiatry of the University of Cincinnati, Dr. Cady reviews the multiplicity of potential causes, as well as the multiplicity of pharmacological, psychological, and holistic interventions.

Among the topics covered are the following:
- the multidimensional matrix of causality posited to be relevant for schizophrenia
- the deficiency of the "dopamine hypothesis of schizophrenia and the overly simplistic mental model that has been programmed into at least two generations of practitioners
- the rationale for looking at other things besides "drugs" or "psych meds"
- an admonition to the practitioner to not forsake the origins of our profession where the dyadic relationship is honored; further, to be aware of how therapeutic impasses with schizophrenic patients may be frustrating to the practitioner and interfere with treatment;
- the relevant exploration and use of Vitamin D, omega e fatty acids, N-acetyl cysteine, gluten & casein free diets, *elemental* lithium, antifungals.

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The Holistic Treatment of Schizophrenia

  1. 1. The Holistic Medicine Approach to the Treatment of Schizophrenia Louis B. Cady, MD, FAPA CEO, Founder – Cady Wellness Institute Adjunct Clinical Lecturer in Psychiatry – Indiana University Department of Psychiatry Presented to: The Department of Psychiatry - Grand Rounds May 16, 2018
  2. 2. “There are two objects of medical education: to heal the sick and to advance the science.” - Charles H. Mayo, MD “The glory of medicine is that it is always moving forward, that there is always more to learn.” - William J. Mayo, MD© 1994 – Louis B. Cady, MD
  3. 3. Review … 2 tips! • ALL SLIDES from this presentation are at: –www.slideshare.net/lcadymd • I will point out the slides dealing with the CME questions as I go. – (I’m interested in your LEARNING, not “gotchas.”)
  4. 4. Schizophrenia – multiple domains and defects • Positive symptoms – (delusions, auditory & visual hallucinations) • Morris R et al. Schizophrenia Bulletin (2012). 39, 575-582 • Negative symptoms – Anhedonia, apathy, amotivation, and inappropriate (blunted) affect. • Rabinowitz J et al. (2012) Schizophrenia Research 137, 147-150. • Neurocognitive dysfunction, including attention deficits – Fioravanti M et al. Neuropsychol. Rev. 15, 73-95. • Learning & memory problems – Goldman-Rakie PS. (1994). J Neuropsychiatry Clin. Neurosci. 6,348-357. • Decreases in executive functioning, processing speed, and IQ – Hutton SB et al. (1998) Psychol Med. 28, 463-473. – Rodriguez-Sanches JM et al. (2007) Br. J Psychiatry Suppl. 51, s107-s110. • More recently noted: defects in social cognition and function. – Nuechterlein K H, et al. (2004) Schizophrenia Res. 72,29-39. – Fett AK et al. (2011) Neurosci. Biobehavioral Research Rev. 35, 573-588.
  5. 5. Schizophrenia • Historically: – “Dementia praecox” - Heinrich Schule in 1886. – Emil Krapelin (1893) refined classification between dementia praecox and a mood disorder. – Eugene Bleuler(1908) – coined term schizophrenia – a “splitting of the mind.” • Currently - diagnosed per American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, or the World Health Organization’s International Statistical Classification of Diseases and Related Health Problems (ICD-10). – DSM 5 removed all previous subtypes (paranoid type, disorganized, catatonic, undifferentiated, and residual types)
  6. 6. Etiopathogenesis of schizophrenia • In utero exposure – Toxoplamsa gondii • Maternal malnutrition: – decreased PUFAs, oxidative stress • NMDA receptor hyposignaling • Antibodies against NMDA receptors • Alterations in hippocampal pruning • Mitochondrial dysfunction • Early use of marijuana • Inflammation • Glutamate (1980’s) • Genetics • TNF-alpha, TNF-beta polymoprhisms (Saudi) • “kyurenic acid hypothesis” • Food antigens (IgG reactions) • Alterations in endocannabinoid system • Low serum levels of PTX3 (pentraxin-3) – US Military personnel • Asymmetric dimethylarginine (ADMA) • Alterations in inflammatory and immune systems (check CRP) • Oxidative stress • Low glutathione • Immune alterations and microbiome variances • “Mild encephalitis” theory • MTHFR deficiency • Vitamin D deficiency https://www.ncbi.nlm.nih.gov/pubmed/?term=etiopathogenesis+schizohrenia Accessed: May 13,2018 - 173 citations
  7. 7. Multiple pathways for Alzheimer’s Disease…
  8. 8. “Dopamine hypothesis of schizophrenia” From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  9. 9. How much D2 blockade is enough? From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  10. 10. Clozapine – a problem with the D2 blockade theory From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  11. 11. Holistic Treatment of Schizophrenia •Psychodynamic •Biological •Holistic
  12. 12. Artist: Craig Finn (schizophrenia patient) – in PLOS Medicine – “How prevalent is schizophrenia?” May 31, 2005 Web link: http://journals.plos.or Image used with Wikipedia Creative Commons license
  13. 13. “If you can only read one article in your entire career at Mayo on psychotherapy, read this one.” - John Graf, MD “If you can only read one article in your entire career at Mayo on psychotherapy, read this one.” - John Graf, MD Greben, S. Can Psychiatr. Assoc Journ. Vol 22 (1977): 371-380 “On Being Therapeutic” “On Being Therapeutic”
  14. 14. Psychodynamics and holistic medicine • Some therapists stand out as uniquely effective. • Academics are no better. • “Every potential therapist must have a floor and a ceiling to his therapeutic capacity.” • Some gifted therapists are able to say why they succeed; others can’t explain it. “A great deal of what they do ‘right’ is intuitive.” “On Being Therapeutic” - Stanley Greben, MD [Canadian Psychiatric Association Journal. Vol. 22(1977) 371-380].
  15. 15. Greben’s “Seven Habits” • Empathy & concern • Warmth • Interaction • Ability to arouse hope • Expectation of improvement • “Not to despair” • Reliability & Friendliness *Requires clinical depth and breadth of knowledge *
  16. 16. Psychodynamics 101 • Patients can be vexing. • Therapeutic impasses provoke narcissistic angst (psychodynamic OR biological). • Frustrated clinicians do not relate well with patients. • The more tools and capabilities one has, the greater the freedom, the options, and the ability to positively impact the patient. • The greater the success, the better the patient feels, the doctor feels, and the doctor-patient relationship feels. • The converse, worrisomely, also exists.
  17. 17. Case presentation • Alan – presents on Feb 16, 2007, diagnosed with depression vs. psychosis. – Previous treatment at Pfeiffer Treatment Center • He appeared notably fatigued and grossly over-sedated. • Morose and depressed. Lucid. Intelligent.
  18. 18. Past history • “Ever since I can remember, I’ve always had the same feelings about things – how people treat each other and stuff like that.” “My feelings just kept getting worse and worse the more I was picked on. That was the only thing that was wrong, people just calling you names and stuff.” • Alan became suicidal in middle school – 8th grade year. “I just thought everyone was making fun of me, so why should I go on?”
  19. 19. • Treated with fluoxetine in the past for depression • Stopped being able to do homework as a sophomore in high school • “I was just really resentful of my parents a lot during the past few months [at that time] – I just started yelling at them in front of the therapist guy.” • Ultimately stabilized by previous MD on aripiprazole (20 mg), olanzapine (20 mg) and sertraline (50mg). • Per Mom – “It was hard for him to be out and be around a lot of people.” Past history
  20. 20. March 2007 • Evaluated for obstructive sleep apnea & now on CPAP (continuous positive airway pressure device). • Improved energy. • Conventional labs ordered • Sertraline changed to duloxetine, which helped. • Sertraline and olanzapine both decreased by 5 mg. Modafanil stable at 100 mg • Very specific about self-identified “Paranoid thoughts.” “I didn’t used to have them.”
  21. 21. Clinical course through July 2007 • Continued in treatment with me every 1 – 3 month appointments. Still isolated. • Seemed to improve on; – Duloxetine 60 mg twice daily – Olanzapine 30 mg @ 9 pm – Aripiprazole 20 mg in the a.m. – Topirimate – 100 mg at bedtime (originally for weight loss, but improved mood). – L-methylfolate 7.5 mg per day, empirically started – 5HTP 100 mg tid
  22. 22. 2007 - 2009 • More explosive outbursts. Lamotrigine (200 mg) added topirimate continued • “I know that I’m acting ridiculous – like a schizophrenic, but I feel good, and I’m talking more to everybody, and I’m trying to get my point across, and I don’t feel as evil as I used to.”
  23. 23. June 30, 2009 • He comments that he feels his “mouth is going faster than his thoughts.” • Mom reports that “traveling out here (to appointment) wears on him.” “He does better when he’s quiet and in the house.” • RX: – Olanzapine 30 mg 9 pm – Aripiprazole 20 mg a.m. – Topirimate 100 mg HS – Lamotrigine 200 mg in a.m. – Duloxetine – 120 day – Modafanil – 100 mg daily – 5HTP 100 mg in the a.m. INTEGRATIVE MEDICINE TESTING finally ordered!
  24. 24. Integrative (“functional”) medical testing done TESTING • Micronutrient analysis (functional intracellular analysis) – deficiencies in: – Vitamins A & D, zinc, Oleic acid, antioxidant capacity • IgG food allergy testing 7/22/2009 – 12 total sensitivities • 2+ to eggs, cow’s milk, wheat, brewer’s yeast • 1+ to cheese, mung bean, oat, pork, pumpkin, sesame, tuna & baker’s yeast.
  25. 25. 8/12/2009 Follow-up • Very irritable and sarcastic at appointment. • Continue baseline Rx as is. • NEW: start diet – dairy free, gluten free • NEW: start vitamins: – 4000 IU Vitamin D daily – Flavored cod liver oil – “ACES” – A, C, E, and Selenium
  26. 26. Last four months January 21, 2010 • On IgG diet. “He has been doing well on it.” • At Christmas, however, he “went off of it.” Had cookies everywhere – couldn’t keep him out of the wheat. Following that gluten feast he exploded on New Year’s eve. • Prior to that, his last explosive episode was in May – and has been good pretty well up until New Year’s eve. When the two brothers got in the car it set Alan off. “It was bad.” • After the outburst, Alan specifically wanted to go back on the diet program. “He seems really good [now].” • More functional medicine testing ordered.
  27. 27. November 18, 2012
  28. 28. January 2010 to 2014 • November 2012 – high IgG allergies to dairy and wheat. Diet again emphasized. • Elemental lithium deficiency noted (functional testing) • August 2014 – elevated Arabinose on OAT test – treated with Nystatin • Probiotics added to deal with acid reflux • Macro and Micronutrient deficiencies identified in hair testing and organic acid testing. • Generally stable. Subtle improvement. No more meltdowns. No more concerns about going out in public.
  29. 29. April 15, 2013 Low dose Lithium orotate started
  30. 30. August 31, 2014Fungal markers went up; Nystatin started.
  31. 31. May 16, 2018
  32. 32. Conclusion: These significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics Conclusion: These significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics
  33. 33. Repeat testing 13 months later – May 21, 2014
  34. 34. As of May 16, 2018
  35. 35. Candida – what is it? • “C. albicans is a diploid, polymorphic yeast residing in mucosal surfaces of the human respiratory, gastrointestinal (GI) and genitourinary tracts.” – Severance EG . NPJ Schizophr. 2016; 2: 16018.
  36. 36. 4 of 5 papers in the literature “schizophrenia candida” • 1. Clozapine found to inhibit yeast budding to hyphal transition. This and other antifungals might have therapeutic activity in the future. – Midkif J et al. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways. PLoS One. 2011;6(9):e25395. • 2. Cyclic dipeptides from food and intestinal yeast cyclic dipeptides may play a role in causing psychiatric disorders such as schizophrenia. From cancer research, cyclic dipeptides such as cyclo (proline-phenylalanine) have been found to activate the pathways of apoptosis and to cause programmed cell death. – Semon BA. Dietary cyclic dipeptides, apoptosis and psychiatric disorders: a hypothesis. Med Hypotheses. 2014 Jun;82(6):740-3.
  37. 37. 3. Odds ratio of schizophrenia with candida albicans seropositivity • Case control differences investigated regarding candida albicans. • 947 individuals studied – 261 with schizophrenia (139 of which had 1st episode schizophrenia – 270 with bipolar disorder – 277 non-psychiatric controls • C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04-9.53, P 0.0001⩽ ). – Severance EG et al. Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ Schizophr. 2016; 2: 16018. • Published online 2016 May 4. – Full article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898895/
  38. 38. 4. Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study. • Longitudinal, double-blind, placebo-controlled pilot investigation of 56 outpatients with schizophrenia. Studied impact of probiotic treatments on yeast antibody levels, and between levels of antibodies and abdominal discomfort/ psychiatric symptoms. • “Results from this pilot study hint at an association of C. albicans seropositivity with worse positive psychiatric symptoms, which was confirmed in a larger cohort of 384 males with schizophrenia.” Severance EG et al. Brain Behav Immun. 2017 May;62:41-45.
  39. 39. How to order the labs (Lab Corp, or Quest): • Candida antibodies – IgG, IgA, Ig M with QUANTITATIVE TITERS • Gluten: – Anti-gliadin antibodies - IgG, IgA, IgM with quantitative titers – Tissue trans-glutaminase
  40. 40. Note for posted slide deck: This and the next slide show functional testing first, and conventional testing, second. Conventional testing is useful.
  41. 41. Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast Drug effect 81 compounds “inhibited wild-type yeast growth” Fluoxetine “interfered with establishment of cell polarity Cyproheptadine Targeted essential genes with chromatine-remodeling roles Paroxetine Interfered with RNA metabolism genes Clozapine Haloperidol Pimozide All had “off target” effects in yeast Ericson E et al. PLoS Genet. 2008 Aug 8;4(8):e1000151. doi: 10.1371/journal.pgen.1000151.on
  42. 42. June 23, 2015 • “The past few days I’m doing pretty good. It’s been a miraculous few days. This week has been pretty good. We have been going out a little bit more. We’re going to Biaggi’s after this. That’s going to be a first in a long long time.” • RX: – Olanzapine 30 mg 9 pm – Aripiprazole 20 mg a.m. – Topirimate 100 mg HS – Lamotrigine 100 mg in a.m. – Duloxetine – 60mg / day – Liothyronine 5 MICROgrams 2x/day • PLUS SUPPLEMENTS
  43. 43. 2015 supplementation – in collaboration with CWI biomedical specialist • N-acetyl cysteine complex (glutathione precursor) – 3 two times/day • D3 (2,000 IU) – one per day • ACES – one tablet per day (Vitamin A – 10,000 IU in 2 soft gels, Vitamin C 1000 mg in two capsules, Vitamin E 400 IU in two capsules , Calcium 119 mg in two capsules • Selenium 100ug in two capsules). • Vitamin C (500 mg. twice daily) • Zinc (25 mg. 2x/day) – 50 mg per day • Lithium Orotate (10 mg./day) • CoQ10 (200 mg.) • Fish Oil - Previous had (EPA 1100 mg.; DHA 720 mg.; Other Omega 3: 230 mg.) • Niacinamide – 500 mg three times daily recommended by Marci. • B5 (Pantothenic Acid) – 250 mg. 1x/day MWF • Manganese 15 mg./day • Chromium polynicotinate 200 mcg./day • Magnesium glycinate 200 mg 2x/day • P-5-P 50 mg. 2x/day • Grapefruit Seed Extract – as recommended on the label (for yeast) – liquid form • Olive Leaf Extract – 1 per day (for yeast and bacterial overgrowth) – liquid form (with the grapefruit seed extract) • Enzymedica Digest + Probiotics – take 1 capsule at the beginning of each meal – Probiotic: Ther Biotic Complete from Klaire Labs – 1 capsule per day • Copper (1 mg./day) – added in a multivitamin (“Headache Free”) • Potassium was added 99mEq twice daily
  44. 44. Schizophrenia and Gluten
  45. 45. As of May 13, 2018
  46. 46. Differential antibody responses to gliadin-derived indigestible peptides in patients with schizophrenia • Evaluation: IgG and IgA antibodies against indigestible gliadin-derived peptide antigens by ELISA • 169 patients with schizophrenia; 236 controls. • RESULTS: – Patients with schizophrenia had increased levels of plasma IgG against the gamma-gliadin- derived fragment (AAQ6C) compared to control subjects. – No difference against NATIVE gliadins between patient and control groups. McLean RT et al. Translational Psychiatry. 2017 May 9;7(5):e1121.
  47. 47. Gliadin – a definition “GLIADIN is the alcohol soluble fraction of gluten and is the primary antigen leading to an inflammatory reaction in the small intestine, characterized by chronic inflammatory infiltrate and villous atrophy.” From Chapter 17 – Molecular Basis of Diseases of Immunity. Beenhouwer, DO. Molecular Pathology, © 2009, pages 291-304. (https://www.sciencedirect.com/science/article/pii/B9780123744197000172 )
  48. 48. Patient “Alan”
  49. 49. Another recent schizophrenic patient for comparison
  50. 50. Note for posted slide deck: This and the next slide show functional testing first, and conventional testing, second. Conventional testing is useful.
  51. 51. Schizophrenia & Vitamin D
  52. 52. * * As of May 13, 2018
  53. 53. Feb 2018 – latest article as of May 13, 2018
  54. 54. Anti-inflammatory strategies
  55. 55. Vitamin D & Omega 3 fatty acids – relevance for SCHIZOPHRENIA “VITAMIN D & marine omega 3 fatty acid intake may help prevent and modulate the severity of brain dysfunction.” “VITAMIN D & marine omega 3 fatty acid intake may help prevent and modulate the severity of brain dysfunction.” JUNE 2015
  56. 56. B-vitamins and inflammation References: Mikkelsen K, et al. Maturitas. 2017;’96:58-71. Brown HE et al. Vitamin Supplementation in the Treatment of Schizophrenia. CNS Drugs. 2014 Jul;28(7):611-622. B vitamin Immune response Deficiency outcome B1 – Thiamin Antioxidative effect Suppressed oxidative stress activation of NF- kB Neuroinflammation Stimulation of CD40 & CD40L which triggers death of neurons Memory defects, cognitive decline emotional disturbances B2 – Riboflavin Activates MAIT [mucosal-associated invariant T cells] Interferes with macrophages adherent Enhances apoptotic death B3 – Niacin Positive benefits on lipids Dampens inflammation Inhibits NF-kB activity Historically used by Abram Hoffer to treat schizophrenia B6 – (P5P) – pyridoxal-5- phosphate Down regulates NF-kB activity levles in LPS stimulated mouse macrophages Adverse effects on methylation reactions Altered lymphocyte differentiation and maturation Triggers many diseases related to chronic inflammation; possible consequences in depression B9 Folic acid Regulation of immune response Inhibits homocysteine induced NF-kB activation in cultured human monocytes IMPAIRED IMMUNE RESPONSE Decreased response of T lymphocytes Alterations of thymus function . B12 - Cobalamin Immune system regulation Immunomodulator of cellular immunity Involved in cell division Reduced cytotoxic T cells (CD 8+) Reduced natural killer cells Ghigh CD4/CD8 ratio High levels of TNF-alpha; IL-6 decreased
  57. 57. Decreased Brain levels of Vitamin B12 in Aging, Autism and Schizophrenia• Cobalamin exists in multiple forms, including methylcobalamin & adenosylcobalamin • Cobalamin levels measured in postmortem human frontal cortex of: – 43 controls – from 19 weeks of fetal development through 80 years of age. – 12 autistic subjects – 9 schizophrenic subjects. • In autistic and schizophrenic subjects: methyl- and adenosylcobalamin levels [in post- mortem brains] were 3 times lower than age- matched controls. Zhang Y et al. PLoS One. 2016 Jan 22; 11(1):e01467978.
  58. 58. Stahl SM. L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry. 20089 Sep;69(9):1352-3 Strategy: test for “MTHFR genotype.” References: www.genomind.com www.genesight.com
  59. 59. SEARCH: “n-acetyl cysteine schizophrenia” 05 13 2018
  60. 60. RELEVANT FACTS: •3600 mg NAC daily •52 week double blind, placebo controlled trials • NAC significantly improved PANSS total p<0.001 •No effects seen on brain morphology RELEVANT FACTS: •3600 mg NAC daily •52 week double blind, placebo controlled trials • NAC significantly improved PANSS total p<0.001 •No effects seen on brain morphology
  61. 61. Alan – the rest of the story October 25, 2014 http://cadywellness.com/a-shattered-mind-and-music-within/ Tip: www.youtube.com - type in Bethany Yeiser
  62. 62. Alan & Clozapine • Maximum benefit on meds and supplements reached. Still symptomatic. • Clozapine was suggested in 2016. • Started Clozapine March 3, 2017 • Seen on March 30th . Vastly better. Chuckled, “I’ve been paranoid for ten years.”
  63. 63. What it’s like from the inside- March 30, 2017 • Alan: “I am not as dizzy – still feel like I’m in a dreamlike state – but not as bad.” “There is a whole world of difference since taking this stuff. We’ve been going out more.” • “Clozaril® [sic] (Clozapine) has eliminated basically every paranoid thought I’ve had – I know they’re there. I noticed it the first day.” He notes that he has been “too sedated for them to hit me. It’s like the paranoid thoughts can’t catch up.” • Mother comments when he goes places, he is not troubled by voices.
  64. 64. March 30, 2017 • Clozapine – 100 mg a.m. + 175 mg pm • Olanzapine + Aripiprazole stopped • Nystatin1.5 million IU 2 – 3X/day • Topirimate • Lamotrigine • Duloxetine reduced • Liothyronine 5 ug 2x/day • D3 (2,000 iu) – one per day • ACES – one tablet twice daily (Vitamin A – 10,000 IU in 2 soft gels, Vitamin C 1000 mg in two capsules, Vitamin E 400 IU in two capsules , Calcium 119 mg in two capsules • Zinc 30 mg – one time per day (elevated from anti-dandruff shampoo) • Lithium Orotate (10 mg/day) • CoQ10 (200 mg.) • Fish Oil - Metagenics high potency EPA/DHA fish oil • Niacinamide – 500 mg three times daily recommended by Marci. • B5 (Pantothenic Acid) – 250 mg. twice daily • Manganese 15 mg twice daily • Chromium polynicotinate 200 mcg twice daily • Neuromag - two capsules before bedtime. – Marci has expressed interest in more magnesium using Epsom salts baths. • P-5-P 50 mg. 2x/day • Grapefruit Seed Extract – as recommended on the label (for yeast) – liquid form • Olive Leaf Extract – 1 per day (for yeast and bacterial overgrowth) – liquid form (with the grapefruit seed extract) • Enzymedica Digest + Probiotics – take 1 capsule at the beginning of each meal – Probiotic: Ther Biotic Complete from Klaire Labs – 1 capsule per day • Copper (1 mg./day) – added in a multivitamin (“Headache Free”) twice daily • Potassium was added 198 mEq twice daily (increased in September.) • Ferrochel added – one tablet per day. • Rubidium – 100 MICROgrams per day
  65. 65. April 14, 2017
  66. 66. Psychotherapy • 9,271 citations on “psychotherapy schizophrenia” May 16, 2018 – 243 citations on “psychoanalysis schizophrenia” • “Significant improvements were obtained in emotion recognition and most theory of mind [attributional style] variables” in schizophrenics vs. controls using an online self-training program in social cognition (e- Motional Training ®).” – Marono Souto Y, et al. Front. Psychiatry. 2018 Feb 6;9:40. doi: 10.3389/fpsyt.2018.00040.
  67. 67. So what the heck am I supposed to do with this stuff? Kitrick – the CWI “therapy baby” © Louis B. Cady, MD – image used with permission
  68. 68. Rational holistic considerations • Vitamin D • Omega 3 fatty acids • B-vitamins (full complex) • Antioxidants (and good diet!) • N-acetyl cysteine (high dose) ? • Assess for candida, and gluten, casein sensitivity • Assess MTHFR status • OPTIMIZE PHARMACOTHERAPY – Consider Clozapine • Do not discount the dyadic relationship.
  69. 69. Concluding thoughts • Just because someone has a classic “biological psychiatry” diagnosis doesn’t mean that there can’t/won’t be physiological or psychological impairments. • You may not be able to (totally) get rid of the main diagnosis, but you can improve the patient’s quality of life. (& perhaps decrease Rx) • Holistic medicine is of paramount importance in identifying root causes and helping the patient.
  70. 70. Perhaps the ability not only to acquire the confidence of the patient, but to deserve it, to see what the patient desires and needs, comes through the sixth sense we call intuition, which in turn comes from wide experience and deep sympathy for and devotion to the patient, giving to the possessor remarkable ability to achieve results. ...William J. Mayo, MD 1935
  71. 71. Louis B. Cady, MD Cady Wellness Institute 4727 Rosebud Lane – Suite F Newburgh, IN 47630 USA Office (812) 429-0772 info@cadywellness.com www.slideshare.net/lcadymd
  72. 72. APPENDIX: (These are slides that were not presented due to the inherent time limitations of a grand rounds talk.)
  73. 73. Schizophrenia Etiopathogeneses: some theories • Immuno-inflammatory response –From dysfunctions of brain-gut axis –Intestinal pathological processes. • Alterations in intestinal microbiome • Permeable intestine (leaky gut syndrome) • Hypersensitivity to food antigens – especially gluten and casein of cow’s milk.
  74. 74. As of May 13, 2018
  75. 75. Inflammation and the Mind
  76. 76. Gut bugs and brain • “Intestinal microbes in the gastrointestinal tract regulate peripheral immune responses, CNS function and behavior.” • Probiotics such as Bifidobacterium and Lactobacillus have potent anti- inflammatory properties that reduce behaviors associated with anxiety and depression. Fung TC, et al. Nat Neurosci. 2017;20(2):145-155.
  77. 77. Inflammation and schizophrenia • Short chain fatty acids (SCFAs) linked to a shortened lifespan with schizophrenia. Use of Mediterranean diet, omega 3 fatty acids, and probiotics may improve immune and cardiovascular outcomes. – SCFA derived from gut fermentation of fiber. • Evolving literature that short chain fatty acid can cross the blood brain barrier and target key inflammatory pathways. – Joseph J et al. Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids… Frontiers of Neurosceicne. 2017 Mar 27;11:155.
  78. 78. Immunoglobulin G genotypes and risk of schizophrenia • Assessment of highly polymorphic immunoglobulin GM (gamma marker) genes in schizophrenia. • N=798: 398 patients with schizophrenia, 400 controls • GM Alleles were determined by the TaqMan® genotyping assay. • GM 3/3;23-/23- genotype were over three times as likely to develop schizophrenia as those without the genotype [Odds Ratio 3.4] • Notably GM alleles have been implicated in gluten sensitivity Pandey JP et al. Human Genetics. 2016 Oct;135(10):1175-9.
  79. 79. “Bread and Other Edible Agents of Mental Disease” • Cereal grains – the world’s most abundant food source – can affect human behavior. • “Bread makes the gut more permeable and can thus encourage the migration of food particles to sites where they are not expected, prompting the immune system to attack both these particles and brain-relevant substances that resemble them.” • Causes release of opioid-like compounds • “A grain-free diet, although difficult to maintain… could improve the mental health of many and be a complete cure for others.” Bressan P, Kramer P. Frontiers of Human Neuroscience. 2016 Mar 29;10:130
  80. 80. Some current research • “Patients with schizophrenia have low plasma Vitamin D level.” (Does not appear to be associated with severity or type of antipsychotics used.) – Akindlade KS et al. Frontiers of Psychiatry June 2017 • “Average Vitamin D values were deficient for first episode of psychosis patients, especially those 22 with a final diagnosis of schizophrenia.” – Salavert J et al. Association between Vitamin D Status and Schizophrenia: A First Psychotic Episode Study. • Vitamin D Deficiency highlighted as potential environmental risk factor in multiple sclerosis, schizophrenia, and autism. – (Causation versus consumption duality reviewed.) – Kocovska E et al. Frontiers of Psychiatry 2017 Mar 27;8:47. – Link to full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366333/
  81. 81. More Vitamin D Research • Evaluation of 80 patients with chronic stable schizophrenia with residual symptoms and Vitamin D deficiency were recruited randomly and received 600,000 (!!) IU Vitamin D injection along with their antipsychotic regimen. – A negative but not significant correlation was found between serum Vitamin D level changes and PANSS []Positive and Negative Syndrome Scale] negative subscale score • Sheikhmoonesi F et al. Iran J Pharm Res. 2016 Gall;15(4):941-950 • Vitamin D deficiency in a psychiatric population: – 118 patients with bipolar disorder – 202 patients with schizophrenia or schizoaffective disorders. – Vitamin D levels were deficient in 30.3% – Vitamin D deficiency was 4.7 times more common among outpatients with bipolar disorder, schizophrenia, or schizoaffective disorder than among the Dutch general population. – “We believe that outpatients with bipolar disorder, schizophrenia, or schizoaffective disorder should be considered at risk of having low levels of Vitamin D.” • Boerman R et al. J Clin Psychopharmacol. 2016 Dec; 36 (6):588-592. • “In up to 16,125 individuals with measured serum 25 (OH)D, there was no clear evidence that genetic risk for schizophrenia causally lowers serum 25(OH) D).” • Taylor AE et al. Investigating causality in the association between 25(OH)D and schizophrenia. Sci Rep. 2016 May 24;6:26496.
  82. 82. Patients vs. professional staff • Naturalistic study – the Netherlands • Study: – Vitamin D levels measured in therapy-resistant schizophrenia in April, after the winter, and in patients and staff members in June after an exceptionally sunny spring. – Patients had HIGH rates of Vitamin D deficiency (79-90%) and lower levels of vitamin D than staff members (p<0.001). • Conclusions: “The vitamin D deficiency of therapy-resistant schizophrenia patients is pronounced and cannot be explained by differences in skin pigmentation, or by an inactive, indoor lifestyle on the ward.” – (“Even theoretically sufficient exposure of the patients to daylight did not ameliorate the low vitamin D levels”) – Bogers, JPAM et al. Low levels of vitamin D poorly responsive to daylight exposure in patients with therapy-resistant schizophrenia. Nord J Psychiatry. 2016;70(4):262-6
  83. 83. “The movers and shapers in immune privilege of the CNS.”
  84. 84. BioPsychoSocial – the “ACT” model •A ssertive •C ommunity •T reatment • Help with finding jobs, integrating into society. Multiple touch-points throughout the week.
  85. 85. Normal colon vs. pseudomembranous colitis
  86. 86. • HPHPA found in higher concentration in urine samples of children with autism compared to controls. • Highest value ever measured was 300X the median normal adult value, in a patient with acute schizophrenia during an acute psychotic episode. • HPHPA source – appears to be from multiple species of the Clostridium genus. • Appears to be a metabolic of 3-hydroxyphenylalanine – a tyrosine analog which depletes brain catecholamines and causes symptoms of autism in experimental animals.
  87. 87. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies • Autoantibodies against folate receptor alpha at the choroid plexus that block methyltetrahydrofolate (MTHF) transfer into the brain found in catatonic schizophrenia. . – Acoustic hallucinations disappeared following folinic acid treatment. • Study examines patients with schizophrenia unresponsive to conventional treatment. – had normal levels of homocysteine, folate, and B12. – But had positive FR Autoantibodies of the blocking type. • Conclusion: assessment of FR auto-antibodies in serum is recommended for schizophrenia patients. Ramaekers VT et al. Mol. Genet Metabolism. 2014 Dec; 113(4):307-14.
  88. 88. Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Joseph J et al. Front Neurosci. 2017;11:155 • Multiple immune pathways that accompany systemic inflammation are dysregulated in schizophrenia. • “The presence of inflammatory markers indicates that a tissue injury mechanism is active.” • Dysregulated reward circuitry leads to unhealthy dietary intake. – [hyperdopaminergic mesolimbic pathway combined with poor cognitive control] Link to full text article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366345/
  89. 89. Modified Mediterranean Diet for Enrichment of Short Chain Fatty Acids: Potential Adjunctive Therapeutic to Target Immune and Metabolic Dysfunction in Schizophrenia? Joseph J et al. Front Neurosci. 2017;11:155 INTERVENTION STRATEGIES • Gluten free diets. – Celiac disease and non-celiac gluten sensitivity is higher in schizophrenia than the general population. • Psychotic symptoms can be triggered by gluten in those with a gluten intolerance [Lionetti et al, 2015] • Omega 3 fatty acid supplementation (especially docosohexanoic acid) • Ketogenic diets • Colonic generation of short chain fatty acids and transport (via probiotics, if necessary.) • Mediterranean style diets – Have already been shown to reduce overall heart disease risk. – Adherence reduces c-reactive protein and TNF-alpha. Link to full text article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366345/
  90. 90. • Case reports of two patients with schizoaffective disorder • Both had failed clozapine – 1 patient failed 12 Rx. – 1 patient failed 17 Rx. • Ketogenic diet tried by female patient for weight loss. – All delusions resolved (and she lost 10 lbs) • Also tried by 322 lb male, who lost 104 lbs during a year. – Coincidentally, his PANSS scores dropped from 98 to only 49.
  91. 91. www.cadywellness.com

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