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The Integrative Medicine Approach to
the Treatment of Schizophrenia
Louis B. Cady, MD
“Streaking”, or…..
Better Buckle Up!!!
• Definition: Streaking is the act of taking off
one's clothes and running naked th...
Attention class!!
www.slideshare.net/lcadymd
Cady Wellness Institute app – Apple
“app” store (currently pending re-
approv...
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...
Schizophrenia
heterogeneities:
• Etiopathogenesis
• Course
• Effective agents
• Treatment response
“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.
Multiple pathways for Alzheimer’s
Disease…
Schizophrenia Etiopathogeneses:
some theories
• Immuno-inflammatory response
– From dysfunctions of brain-gut axis
– Intes...
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 and...
• 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 e...
Clinical course through July
2007• Continued in treatment with me every 1 – 3
month appointments. Still isolated.
• Seemed...
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) – defi...
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 i...
November 18, 2012
January 2010 to present
• November 2012 – high IgG allergies to dairy and
wheat. Diet again emphasized.
• August 2014 – el...
August 31, 2014
Fungal markers went up; Nystatin
started.
April 15, 2013
Low dose Lithium orotate started
Repeat testing 13 months later – May 21, 2014
Schizophrenia & candida
As of October 4, 2017
Candida – what is it?
• “C. albicans is a diploid, polymorphic
yeast residing in mucosal surfaces of
the human respiratory...
Antimicrob. Agents Chemother. October 2009 vol. 53
Caspofungin
The only four papers in the
literature
• 1. Clozapine found to inhibit yeast budding to
hyphal transition. This and other ...
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...
• HPHPA found in higher concentration in urine samples of
children with autism compared to controls.
• Highest value ever ...
Normal colon vs.
pseudomembranous colitis
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 September 24, 2017
Patient “Alan”
Another recent schizophrenic patient for comparison
Differential antibody responses to gliadin-
derived indigestible peptides in patients
with schizophrenia
• IgG and IgA ant...
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...
Schizophrenia & Vitamin D
*
*
As of September 24, 2017
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-resi...
Anti-inflammatory strategies
Vitamin D & Omega 3 fatty acids –
relevance for SCHIZOPHRENIA
“VITAMIN D & marine omega 3 fatty acid intake may help preve...
As of October 8, 2017
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...
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
m...
Stahl SM. L-methylfolate: a vitamin for your monoamines. J
Clin Psychiatry. 20089 Sep;69(9):1352-3
Strategy: test for “MTH...
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...
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
• Clozapine – 100 mg a.m.
+ 125 mg pm
• Nystatin 1.5 million IU 2 –
3X/day
• OFF OF:
– Olanzapine
– Aripipr...
Concluding thoughts
• Just because someone has a classic “biological
psychiatry” diagnosis doesn’t mean that there
can’t/w...
Louis B. Cady, MD
Cady Wellness Institute
4727 Rosebud Lane – Suite F
Newburgh, IN 47630 USA
Office (812) 429-0772
info@ca...
Appendix – one slide
“The movers and shapers in immune
privilege of the CNS.”
The Integrative Medicine Treatment of Schizophrenia
The Integrative Medicine Treatment of Schizophrenia
The Integrative Medicine Treatment of Schizophrenia
The Integrative Medicine Treatment of Schizophrenia
The Integrative Medicine Treatment of Schizophrenia
The Integrative Medicine Treatment of Schizophrenia
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The Integrative Medicine Treatment of Schizophrenia

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This is the third of three lectures that Dr. Cady did in Sao Paulo, Brazil, for Laboratorio Great Plains. Dr. Cady dispenses with the "Dopamine hypothesis of schizophrenia" quickly, and notes that the most powerful drug for schizophrenia, clozapine, is actually only a weak blocker at that receptor. Using the concepts of Dale Bredesen, MD, Dr. Cady advances the idea that there is no "one magic bullet" approach to the treatment of schizophrenia, but that, rather, multiple possibile causes of schizophrenia exist, multiple nutritional laboratory values exist, multiple other physiological perturbations exist (including gluten sensitivyt), and that the thoughtful practitioner's approach should be to attempt to identify, integrate, and address all possible causes and exacerbating influences on the causes, and treatments of schizophrenia. Obviously, this is not a comprehensive treatment on the subject - which would take days - but does scratch the surface at other ways to look at schizophrenia and approach its treatment.

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The Integrative Medicine Treatment of Schizophrenia

  1. 1. The Integrative Medicine Approach to the Treatment of Schizophrenia Louis B. Cady, MD
  2. 2. “Streaking”, or….. Better Buckle Up!!! • Definition: Streaking is the act of taking off one's clothes and running naked through a public place. [ref: http://en.wikipedia.org/wiki/Streaking - accessed 09 02 2013] • “In 1973, what the press called a ‘streaking epidemic’ hit Stephen F. Austin State University in Nacogdoches, TX, with streakers being seen in residence halls, at football games and at various other on-campus locations and events, including Spring graduation.(Harvard-Yale game, 2006)
  3. 3. Attention class!! www.slideshare.net/lcadymd Cady Wellness Institute app – Apple “app” store (currently pending re- approval) or Google Android store Resources for you to master this material: Louis B. Cady, MD
  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. Schizophrenia heterogeneities: • Etiopathogenesis • Course • Effective agents • Treatment response
  7. 7. “Dopamine hypothesis of schizophrenia” From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  8. 8. How much D2 blockade is enough? From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  9. 9. Clozapine – a problem with the D2 blockade theory From Stahl’s Essential Psychopharmacology, 4rth edition, 2013.
  10. 10. Multiple pathways for Alzheimer’s Disease…
  11. 11. 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.
  12. 12. 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.
  13. 13. 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.”
  14. 14. • 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
  15. 15. 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.”
  16. 16. 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
  17. 17. 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.”
  18. 18. 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 mg / day – Modafanil – 100 mg daily – 5HTP 100 mg in the a.m. INTEGRATIVE MEDICINE TESTING finally ordered!
  19. 19. 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.
  20. 20. 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
  21. 21. 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 Alex 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.
  22. 22. November 18, 2012
  23. 23. January 2010 to present • November 2012 – high IgG allergies to dairy and wheat. Diet again emphasized. • 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.
  24. 24. August 31, 2014 Fungal markers went up; Nystatin started.
  25. 25. April 15, 2013 Low dose Lithium orotate started
  26. 26. Repeat testing 13 months later – May 21, 2014
  27. 27. Schizophrenia & candida As of October 4, 2017
  28. 28. 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.
  29. 29. Antimicrob. Agents Chemother. October 2009 vol. 53 Caspofungin
  30. 30. The only four papers in the literature • 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.
  31. 31. 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/
  32. 32. 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.
  33. 33. • 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.
  34. 34. Normal colon vs. pseudomembranous colitis
  35. 35. 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
  36. 36. 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
  37. 37. Schizophrenia and Gluten
  38. 38. As of September 24, 2017
  39. 39. Patient “Alan”
  40. 40. Another recent schizophrenic patient for comparison
  41. 41. Differential antibody responses to gliadin- derived indigestible peptides in patients with schizophrenia • 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.
  42. 42. 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.
  43. 43. “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
  44. 44. Schizophrenia & Vitamin D
  45. 45. * * As of September 24, 2017
  46. 46. 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/
  47. 47. 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. • 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.
  48. 48. 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”)
  49. 49. Anti-inflammatory strategies
  50. 50. 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
  51. 51. As of October 8, 2017
  52. 52. Inflammation and the Mind
  53. 53. 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.
  54. 54. 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.
  55. 55. 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 Enhance apoptotic d4ath B3 – Niacin Positive benefits on lipids Dampens inflammation Inhibits NF-kB activity Historically used by Abraham 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
  56. 56. 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 were 3 times lower than age-matched controls. Zhang Y et al. PLoS One. 2016 Jan 22; 11(1):e01467978.
  57. 57. 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.comn
  58. 58. 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.
  59. 59. 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/
  60. 60. 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/
  61. 61. • 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.
  62. 62. 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
  63. 63. 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.
  64. 64. 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® (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.
  65. 65. 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
  66. 66. April 14, 2017 • Clozapine – 100 mg a.m. + 125 mg pm • Nystatin 1.5 million IU 2 – 3X/day • OFF OF: – Olanzapine – Aripiprazole – Topirimate – Lamotrigine – Duloxetine – Liothyronine 5 ug /day – Rosuvastatin • DIET: Still casein free/gluten free
  67. 67. Concluding thoughts • Just because someone has a classic “biological psychiatry” diagnosis doesn’t mean that there can’t/won’t be functional (or medical) impairments. [e.g., obstructive sleep apnea, hypothyroidism, vitamin deficiency, gluten sensitivity, intestinal candidiasis etc. ] • You may not be able to get rid of the main diagnosis, but you can improve the patient’s quality of life. • You MAY be able to get rid of a phenotypic diagnosis if there is an underlying physiological problem that can be addressed. • Integrative medicine is of paramount importance in identifying root causes and helping the patient.
  68. 68. Louis B. Cady, MD Cady Wellness Institute 4727 Rosebud Lane – Suite F Newburgh, IN 47630 USA Office (812) 429-0772 info@cadywellness.com Available on Apple “app store” and Google Android store. www.slideshare.net/lcadymd Louis B. Cady, MD
  69. 69. Appendix – one slide
  70. 70. “The movers and shapers in immune privilege of the CNS.”

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