The document summarizes a presentation on the holistic medicine approach to treating schizophrenia. It discusses the multiple domains affected by schizophrenia, including positive and negative symptoms, cognitive dysfunction, and social deficits. It reviews the etiology and pathogenesis of schizophrenia. It then presents a case study of a patient with schizophrenia who was treated holistically over many years with integrative testing to identify deficiencies and allergies, dietary changes, supplements, low dose lithium, and antifungals. The patient showed significant improvement with this approach.

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. “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. 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. 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. 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. 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

8. Multiple pathways for Alzheimer’s
Disease…

9. “Dopamine hypothesis of
schizophrenia”
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.

10. How much D2 blockade is enough?
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.

11. Clozapine – a problem with the D2 blockade
theory
From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.

12. Holistic Treatment of Schizophrenia
•Psychodynamic
•Biological
•Holistic

13. 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

14. “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”

15. 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].

16. 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
*

17. 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.

18. 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.

19. 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?”

20. • 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

21. 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.”

22. 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

23. 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.”

24. 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!

25. 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.

26. 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

28. 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.

29. November 18, 2012

30. 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.

31. April 15, 2013
Low dose Lithium orotate started

32. August 31, 2014Fungal markers went up; Nystatin
started.

34. May 16, 2018

35. 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

36. Repeat testing 13 months later – May 21, 2014

37. As of May 16, 2018

38. 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.

40. 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.

41. 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/

42. 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.

43. 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

44. Note for posted slide deck: This and the next slide show functional testing first, and
conventional testing, second. Conventional testing is useful.

46. 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

47. 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

48. 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

49. Schizophrenia and Gluten

50. As of May 13, 2018

51. 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.

52. 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
)

53. Patient “Alan”

54. Another recent schizophrenic patient for comparison

55. Note for posted slide deck: This and the next slide show functional testing first, and
conventional testing, second. Conventional testing is useful.

57. Schizophrenia & Vitamin D

58. *
*
As of May 13, 2018

59. Feb 2018 – latest article as
of May 13, 2018

60. Anti-inflammatory strategies

61. 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

62. 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

63. 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.

65. 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

67. SEARCH: “n-acetyl cysteine schizophrenia” 05 13 2018

68. 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

69. 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

70. 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.”

71. 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.

72. 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

73. April 14, 2017

74. 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.

75. 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

76. 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.

77. 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.

78. 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

79. 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

80. APPENDIX:
(These are slides that were not
presented due to the inherent
time limitations of a grand
rounds talk.)

81. 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.

82. As of May 13, 2018

83. Inflammation and the Mind

84. 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.

85. 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.

86. 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.

87. “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

88. 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/

89. 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.

90. 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

91. “The movers and shapers in immune
privilege of the CNS.”

92. BioPsychoSocial – the “ACT” model
•A ssertive
•C ommunity
•T reatment
• Help with finding jobs, integrating
into society. Multiple touch-points
throughout the week.

94. Normal colon vs.
pseudomembranous colitis

96. • 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.

97. 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.

98. 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/

99. 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/

100. • 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.

101. www.cadywellness.com