The Moral Imperative of Integrative Medicine 2024

This presentation was given by Dr. Cady on June 22, 2024, to the nationwide virtual conference on Psychiatry Refined.

In it, he reviews MTHFR polymoprhisms, and simple nutrient interventions that can work better than some psychiatric medications. Four clinical cases are reviewed. Avoidance of overly-reliance on typical psychiatric medication is carefully REVIEWED.

Multiple references are provided.

1. The Moral Imperative of Integrative Medicine Louis B. Cady, MD, LFAPA CEO, Founder – Cady Wellness Institute Presented for Psychiatry Redefined – June, 2024

2. “The beginning of wisdom is the definition of terms.” Socrates Moral [mores (L) = HABITS]: “A person’s standards of behavior or beliefs concerning what is and is not acceptable for them to do.” Imperative: “Of vital importance; crucial.” “An essential or urgent thing.” Integrative: “Serving or intending to unify separate things.” Medicine: “The science or practice of the diagnosis, treatment , and prevention of disease.”

3. Organization of this presentation Illustration of need for optimum range of focus in diagnosis & treatment of ALL psychiatric disorders CAVEATS: Can’t cover every hormonal intervention and dosing. Some of the fine points will clarify for you over time, and with practice.  Please review this multiple times and “check the literature.” The purpose is to expose you to the concepts. Further study will be required to master this material.

4. Orientation “Tell me the facts and I’ll learn. Tell me the truth and I’ll believe. But tell me a story and it will live in my heart forever.” - Native American Proverb

5. Three objectives, and three stories 1) Never miss an MTHFR polymorphism again, and be a hero in your own time. (And get your patients WELL). Always take a TARGETED medical hx, minimum , to identify potential causes for trouble. Always take a precise and inclusive past psychiatric hx of “failed treatments.” 2) Never consider a case “hardcore biological psychiatry that needs more antipsychotic” and neglect the functional, integrative aspects. 3) Never underestimate the importance and significance of functional, integrative medicine techniques.

6. The first story… 12 year old 7 th grader. Intake Nov 15, 2019. “Worried about food being contaminated and that he is going to have a heart attack.” “Worried about the lead in his pencils hurting him.” Things “getting stuck in his head – like tunes, sports, good stuff.” Holding saliva in his mouth constantly. Admits to “getting bored sometimes.” Math teacher comments about “careless errors.” Already started on Escitalopram 10 mg by pediatrician Oct 26. Increased to 20 mg Nov. 4.

7. On exam: From intake: “Alert, pleasant, remarkably poised, self-confident, mature and communicative. He is a straight-talking, ‘put it all out on the table’ kind of kid. He is extremely refreshing. He clearly wants to get better.” Childhood depression inventory relevant positives: “I worry that bad things will happen to me.” “Many bad things are my fault.” “I cannot make up my mind about things.” “There are some bad things about my looks.” “I have to push myself all the time to do my schoolwork.” “I worry about aches and pains many times.” “I can never be as good as other kids.”

8. DSM5 review (at intake) Anxiety Constant worry Repetitive, senseless thoughts Fearful feelings Keyed up/on edge Trouble concentrating Depression: Sad/depressed/down in the dumps Lack of/loss of interest in things Decrease in appetite and weight (due to obsessionality) Trouble concentrating Frequent thoughts of death. Of suicide, he says, “Oh, no. I don’t want to do that.” Miscellaneous Feeling life is not worth living Fear of dying Frequent crying or weeping

9. Questions Diagnoses: Psychotic disorder? AD(H)D? Mixed depression/anxiety? Other? What to do? (already on max adult dose of escitalopram) Add antipsychotic? Add concomitant antidepressant? Add ADD medication? Refer for even more intense psychotherapy? How long do you think it will take to get him better?

10. Differential/case management ideas: OCD Mixed depression/anxiety Features of mild ADHD Doubt psychotic disorder Potential MTHFR polymorphism as a fundamental weakness Possible cytochrome p450 2D6 hypermetabolic genotype (“SSRI pathway”) Tx: Leave escitalopram alone L-methylfolate 800 ug – ½ q am x 3-5 d, then 1 q am 5-HTP 50 mg + P5P supplement before bedtime. Haloperidol 0.1 mg – ½ or 1 before bedtime, or ½ - 1 twice daily ONLY AS NEEDED FOR SEVERE OCD SYMPTOMS. DO NOT FILL FOR ONE WEEK UNLESS NEEDED. LABS – cheek swab for pharmacogenomic testing FOLLOW UP – one month.

11. The follow up – Dec 13, 2019 Miscellaneous Feeling life is not worth living Fear of dying Frequent crying or weeping Only 2 symptoms remained: “a tiny bit” of constant worry Increase in appetite (which was HEALTHY) Current Rx : Escitalopram 20 mg L-methylfolate – 800 ug daily 5HTP with P5P before bedtime. NO HALOPERIDOL WAS USED.

12. RELEVANT LABS & Status GENE SLC6A4 (SERT) S/S SSRI’s don’t work well MTHFR C677T A1298C C/C C/C Perfect. This is the major gene. Worst POSSIBLE genotype at minor gene = needs L-MF (This minor gene is OMITTED by Genesight and checked for on GENOMIND) COMT Val/met The best genotype “right down the middle.” Cyp 2D6 2/4 NORMAL SSRI metabolizer (escitalopram) Cyp 2B6 1/1 Bupropion would work if ever needed. OPRM1 – a “lagniappe” G/G Worst POSSIBLE genotype – opioids will not work for pain (if ever needed). This gene is also omitted by one of the major players in gene testing.

13. YES, IT’S PUBLISHED Methylenetetrahydofolate reductase A1298c and major depressive disorder. Cho K et al. Cureus . 2017 Oct; 9(10): e1734 Most of the focus has been placed on C677T “Another polymorphism, MTHFR A1298C, has often taken the back set to MTHFR C677T in respect to research focus.” “Current findings on C677T are conflicting.” Metanalysis review: A1298C “C/C” genotype assoc with MDD and bipolar. Implicated in homocysteine metabolism.

14. STATUS – 12/13/2019 Fully resolved “OCD + mixed depression/anxiety ”*** MTHFR polymorphism – “homozygous at the A1298C gene” Poor SLC6A4 – might not even need escitalopram in the future. Plan is taper the escitalopram as able and see back in four months. *** More like: MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION

15. June 24, 2022 “Tell’em my name is LB.” (mom approved) No psychiatric symptoms. NONE. Finished freshman year of high school. Playing soccer. Will be studying pre-calc and normal English, AP Euro Hx, AP Bio, and Literature. Exercising and weight lifting. Failed escitalopram taper (?!) Note discussion point: gene testing is not an infallible fortune-teller. Will try again in future.

16. “If you just know the names of the terms you absolutely know nothing, and nothing about it.” - Richard P. Feynman, Ph.D.

17. Stahl SM. L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry. 2009 Sep;69(9):1352-3 Strategy: test for “MTHFR genotype.” References: www.genomind.com www.genesight.com

18. Let’s take it again – new case May 28 th , 2022 “ANGIE”: 16-year-old high school junior. Ref by pediatrician. Chief complaint: “I’m depressed. I’m anxious. I’m having a rough time with life, and I don’t always feel like I want to be here anymore. My mood is up and down.” [for three years] Mother: “Major depression, anxiety to the point of having panic attacks and missing school every week.” PREVIOUS LABS REVIEWED: TFT’s – wnl, low Vitamin D. Normal CBC.

19. More granular review Leading up to 6 th grade: hard to focus. (continued as straight A student, however.) 6 th grade: depressed. Thoughts of “I don’t want to be here anymore.” Anxious and tired. No reasons for depression . Good psychosocial baseline. Current: “I have a hard time with daily things – like getting out of bed. Hard to find words in conversation. Varying moods. “Racing thoughts” “I feel like crying all the time.”

20. Previous FAILED Rx history Jan 2020 – 10 mg of fluoxetine. Worked for three weeks, then stopped. Nov 2020 –fluoxetine increased to 20 mg . “It was helpful for a short time, and then it wasn’t.” Mother: “It always seemed to appear on the outside that it would work for a while, but then it wouldn’t be effective.” 2021 –fluoxetine increased to 40 mg – did absolutely nothing. Nov 2021 – saw the “medication specialist” at Riley. Fluoxetine d/c’ed – Bupropion started.

21. Bad Rx, continued Bupropion – 100 mg SR daily. Worked a couple of weeks, then stopped. Dec 2021 – Trazodone added for sleep. Worked for a while, then stopped. Jan 2022 – Bupropion increased to 100 mg SR twice daily. Worked for a couple of weeks and then stopped. March 2022 – nothing working. Aripiprazole was added. Worked for a while, then stopped. April 2022: “I’m not good. I’m depressed. I don’t want to be here anymore.” So… .Aripiprazole increased to 5 mg daily. (of course!) Made her faint and dizzy at school. (of course!) Cut to ½ tablet. Father noted his championship soccer-playing daughter was now “Clumsy on the field.”

22. Targeted psych/med family hx: Psych: Mother – post-partum depression . Numerous relatives with ADHD Father – anxiety/depression . Medical: PGM – five miscarriages . MGM – had at least one miscarriage . Maternal great aunt – never had kids, though married .

23. Childhood Depression Inventory, a FEW of the relevant responses. I am sad all the time. Nothing will ever work out for me. I do many things wrong. Nothing is fun at all. I am sure that terrible things will happen to me. I hate myself (frustrated that she hasn’t been able to get through this). Many bad things are my fault. I think about killing myself but would not do it. (She ASSURES me and her mother that she would not act on this.)

24. CDI – just a FEW more I feel like crying every day. Things bother me all the time. I do not like being with people many times. I cannot make up my mind about things. I look ugly. I have to push myself all the time to do my schoolwork. I have trouble sleeping many nights. I am tired all the time. + eight more symptoms.

25. Previous testing by “Rx Specialist” SLC6A4 (SERT) L/S decreased SSRI effect HTR2A G/G increased sensitivity ADRA2a C/C moderately reduced response HLA A 3101 and HLA B 1502 - optimum = decreased risk for skin reactions from medications Pharmacokinetic genes Cyp 2D6 (fluoxetine) 1/1 NORMAL Cyp 2 B6 (bupropion) 1/1 perfect, normal Cyp 3A4 1/1 NORMAL MTHFR not checked –????

26. Diagnoses: Unspecified mood disorder. Possible mild ADD – masked by intelligence. POSSIBLE bipolar disorder type II. Hormone imbalance - with delayed menarche and very irregular periods. Failed menstrual cycles. MTHFR polymorphism until proven otherwise – no previous MTHFR testing (and this was not ordered/not done on the Genesight testing).

27. If in doubt, stop digging yourself deeper… Cut Aripiprazole to 1/4/ tablet x 3-4 days, then stop Continue Bupropion at 100 mg SR twice daily (with plans to taper) Start Lamotrigine 25 mg -1/2 tablet daily x 7, then one tablet daily x 14, then two tablets. NO further antidepressants, nor stimulant, nor atypical antipsychotics. START: L-methylfolate at 800 ug,& then 1600 ug (Omega 3’s planned later) Plan on using a medical food with L-MF, fish oil, and co-factor if favorable response. Continue on MVI and 2000 IU D3 for now. GENOMIND testing ordered.

28. Follow-up testing reviewed (6/6/2022) TFT’s TSH 1.73 {0.27 – 4.2} Free T4 1.46 (0.86-1.76) Free T3 4.00 {2.3 – 5.0} REV T3 25.9 (!!} {10 – 24} ADRENALS: A.m cortisol 6.6 {6.0 – 18.4} Aldosterone 12.1 {4.0 – 31.0}

29. Reference smorgasbord Mech AW, Farah A. correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism. J Clin Psychiatry 2016;77:668-671. Randomized, placebo-controlled, double blind. n = 330 Active (LM-F) treated patients: 12-point reduction on MADRS by week 8. Homocysteinemia as well as MTHFR reductase polymorphism are associated with affective psychosis. Reif A et al. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1162-1168 . Analysis of genetic polymorphisms of BDNF and MTHFR in depressed patients in a Slovak (Caucasian) population. Evinova A. et al. Gen Physiol. Biophs . 2012;31:415-422 . Increased OR of 2.38 with C/C genotype for A1298C “This study shows that CC genotype of the MTHFR A1298C is associated with higher risk of MDD in Slovak population.”

30. June 25, 2022 Med and supplements changes: Off Aripiprazole. Clumsiness gone. Couldn’t tolerate Lamotrigine On Bupropion 100 mg SR bid Supplements: Vitamin D3 1000 IU twice daily MVI for teen 1600 ug of l-methylfolate per day. STATUS: Subtly better. Changes: Move to 15 mg of l-methylfolate Increase Bupropion to 300 mg XL Low dose Trazodone (sleep) Start Rhodiola for COMT Start adrenal supplementation Spironolactone 50 mg for acne REFER: workup of menstrual irregularities

31. PAUSE… What have we learned so far? How do you think this case is going to turn out? Why didn’t the “medication specialist” get this one right? How much better can this teen get?

32. “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”

33. 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 * “On Being Therapeutic” - Stanley Greben, MD [Canadian Psychiatric Association Journal. Vol. 22(1977) 371-380].

34. So what happened to the teen?? (8/26/2022) SYMPTOMS: “Mood is a lot better.” But DID decide to give up soccer…. “I still get down in those slumps every once in a while. Usually they would last 4 – 5 days. Now I just have one for one or two days.” “My period is still being weird.” Shaky and unsettled two days before a test. MEDS & SUPPLEMENTS: the same Notably, on adrenal supplementation… “It’s working. I have more energy. I don’t really take naps after school.” MOM REPORT: “There have been some really big changes. Now she comes home and then goes out to games with her friends.”

35. 8/26/2022 Surprises/ Strategies PROFOUND family hx of ADHD discovered and reviewed. Profound dislike of body image. “Star” sister - with a photo wall…. ?! HOLISTIC Strategies: Trial of Viloxazine SR (new branded ADHD Rx) Refer for photoshoot with super-competent photographer. Start her OWN photo wall in the family home.  Continue – all prescriptions and supplements as is.

36. Fatigue Severity Scale - (Scores of 36 or more on this standardized and normed questionnaire suggest significant fatigue. Patient's score is: 24 - 6/25/2022 15 - 8/26/2022 Epworth Sleepiness Scale - scores over 10 are considered to indicate that the patient may be suffering from excess daytime sleepiness: 17 - 6/25/2022 (she had been sleepy for two years.) 8 - 8/26/2022 CDI (# of abnormal responses) 24 - 5/28/2022 23 - 6/25/2022 13 - 8/26/2022

37. “Cady 0 – 10,” and Stahl hobbies (depression) “0 – 10 scale, where 0 is ‘rather be dead,’ and 10 is deliriously happy, where are you?” Angie: “7 – 8 as a child.” “2 - 3” in the midst of recent problems. “7 – 8” now – August 26, 2022 Stephen Stahl, MD, Ph.D. What are your top three favorite hobbies? Are you doing them? REMISSION is when they are.

38. SEPTEMBER 10, 2022 (telephone check with Mom.  ) RX: Mood improved. Weight up on 1/16 th mg of Risperidone (off-label) All other Rx as is. Great school functioning – missed one week due to death of beloved PGF. Grades are good. No concentration issues. No trial of Viloxazine SR. Patient was doing well. Told her parents: “You know, I think I’m going back to soccer.” Mom: “We about fell off our chairs!”

39. THE REFERENCES AND THE MEAT “Show me da money.”

40. MTHFR polymorphism (5,980 citations on PubMed as of June 19, 2024) MTHFR polymorphisms “significantly related to schizophrenia and major depression in the overall population.” Homozygous C677T with TT genotype –linked to increase risk of bipolar model. Zhang, Yu-Xin. Association between variants of MTHFR genes and psychiatric disorders: a meta analysis. Front Psychiatry. 2022 Aug 18;13:976428

41. MTHFR polymorphisms and pregnancy loss

42. MTHFR polymorphisms and pregnancy loss 90 women with two or more consecutive pregnancy losses with MTHFR polymorphisms. Age 18 – 35. NINE FOLD increased risk in unexplained pregnancy loss with ONE C677T (major gene) MTHFR polymorphism . C677T + A1298C changes may have synergistic effect. Ngoc, NN et al. Evaluating the association between genetic polymorphisms related to homocysteine metabolism and unexplained recurrent pregnancy loss in women. Appl Clin Genet. 2002;15:55-62.

43. MTHFR polymorphisms may keep men from getting their wives pregnant CAUSE: elevated homocysteine. (Known to be detrimental to spermatogenesis) Clément A et al. MTHFR SNP’s C677T and A1298C prevalence and serum homocysteine levels in >2100 hypofertile Caucasian male patients. Biomolecules 2002 Aug 7;12(8:1086

44. Case #3 THYROID

45. Depression 50-year-old MWF. Seen since April 1, 2002. Menopausal No hx of depression prior to 1985. At that time, she underwent TAH but not BSO. Told that her ovaries “quit working” after the procedure. Therefore, surgical menopause at 33 yoa . Medication failures: Started on standard HRT including “Provera shots” + Estradiol oral. Bupropion 450 mg XL in a.m. without success. Amitriptyline and lithium left her feeling “doped up.” Effexor 75 mg XR twice daily. Made her swell. More recently – citalopram at 20 mg and later raised to 40 mg. Still depressed. Trazodone 25 mg HS. Terazosin 1 mg – for hyperhidrosis. Feb 2007. No better. Recommended removing all IgG-sensitive foods (dairy, wheat, soy).

46. Oct 2007 – an “estradiol pill” was added by other HCP. I added Thyrolar ® (synthetic T4 and T3). Changed to Armour ® April 2008 – doing better (on Thyrolar ). Other Rx the same. Started HRT.

47. 12/18/2024 12/2015 – she elected to go OFF of BHRT (after 13 years!) Informed consent discussion reviewed: BOTH ways. November 2016 – Thyroid HRT changed to Naturethroid. October 2017 – Husband has brain cancer. Brother “Drinking himself to death.” April 2018 – Husband is fading. “I haven’t been eating good because he don’t want me to fix anything.” October 2018 – Husband is getting erratic. June 8 th 2019 – Husband passes.

48. Aftermath of husband’s death 10/1/2019: “It’s been horrible. He’s just gone and I’m so lonely.” “I can’t hardly even get to church.” RX: Now on Armour thyroid 90 mg in a.m. Same baseline antidepressant Rx (Bupropion and Escitalopram – both at max doses.) 4/6/2020: “I haven’t been doing really good. I don’t do good. I still cry a lot.” Gabapentin added. 10/9/2020 - Gabapentin causing weight gain and sedation

49. Thyroid Rx change responses in the past: 10/7/2021: “I don’t cry as much because of ___ (deceased husband) and I’m staying busier.” Rx essentially the same. Thyroid changed to NP Thyroid (90 mg). 4/7/2022: non-specific symptoms “There’s nothing new going on. I just can’t seem to get myself going.” This has been going on for three months. “I just have no interest in anything.” “It’s not a depression thing. It’s not like that. It’s just…. I’m tired, and I don’t want to do anything. But it’s not a depression.” She notes that, “I am like that when I’m depressed.” NP Thyroid increased from 90 to 120 mg (2 grains). Now it’s not working. She is gaining weight. Other Rx remain stable.

50. 3/13/2023 – change in thyroid Rx NP Thyroid (120mg) stopped. Note NP has T4:T3 ratio of 4:1. (May inflate Rev T3). New RX: Levothyroxine 100 ug – 1 – 1 ½ tablets in the a.m. Liothyronine 25 ug – one up to three times daily as directed. (This is a change in ratio possibly up to 2:1 T4 to T3 (a doubling of the relevant amount of T3) Call when self-adjustment ends.

51. What happened after the thyroid switch 9/11/2023: “Doing a lot better. The new thyroid medication is doing good. It took me about 3 months to where I could take it.” She notes that she gets headaches, but “You cannot believe the difference going on in my mind. It’s not that dark stuff.” She recalls previously going to bed and waking up in a “dark place.” She has been at the full dose for three months and in that time, she has not had any of the “darkness.” States her “brain has improved.” TFT’s (on 150 ug T4 + 37.5 ug T3) on 9/8/2023 TSH 0.01 (L) {0.27 – 4.2} Free T4 1.27 {0.8 – 1.76} Free T3 3.1 {2.3 – 4.4} Rev T3 16.4 {8 – 25}

52. Response to thyroid 3/4/2024 Re: Thyroid Rx: “It’s great for my mind. It’s just clear. I still have nervousness, but not that dread. Once these thyroid pills got in my system, it was like a calm came over. All that other darkness was gone. Now I hardly ever have a bad day.” Mental Status Examination: “I feel good! I cannot tell you the difference in my brain. Just don’t know what it’s like to wake up in the a.m. and not have that gloom hanging over your head.” Plan: see back in six months with TFT labs, Vitamin D, and CMP

53. Conclusions: When you’re at full bore bupropion and escitalopram doses and the patient doesn’t feel well, is still depressed, and is having classic symptoms of subclinical hypothyroidism (with suboptimal thyroid levels), it’s time to dial in the thyroid dosing. Two options: Find an endocrinologist who truly knows what she/he is doing. or: Learn how to do it yourself. Don’t blindly trust a colleague to do it the right way.

54. Other techniques! Lithium at LOW doses (e.g. lithium orotate 10 mg) Amino acid precursor loading (433 results of Pub Med as of 6/9/2024.) Studied in ADHD and depression. Tryptophan loading (4 g / day) may reverse tolerance to opiate analgesics in humans. Hosobunchi Y, et al. Pain. 1980 Oct;9(2):161-169 Tyrosine for ADHD McConnell, H. Med Hypotheses. 1995 Aug;174 Note – multiple conflicting papers. (Some show deterioration of effectiveness after 6 – 12 weeks.)

55. Putative role of trace element deficiencies in mental disorders Diagnosis Relevant elements Depression: Zn,Cr, Se, Fe, Co, I PMDD, binge eating Cr Schizophrenia Zn, Se, (and, per other articles, Li.) Cognitive deterioration/ dementia B, Zn, Fe, Mn, Co (Se) Autism Zn, Mn, Cu, Co Attention deficit disorder Fe (check FERRITIN and Fe) Excess quantity (overexposure, genetic error) can also lead to mental disturbances. Janka Z. Ideggyogy Sz. 2019 Nov 30;72(11-12):367-379.

56. April 15, 2013 - Alan Low dose Lithium orotate started

57. Repeat testing 13 months later – May 21, 2014 (after lithium orotate)

58. Gut microbiota Both the gut microbiota and immune system are implicated in the etiopathogenesis/manifestation of …autism spectrum disorder, depression, Alzheimer’s disease. Microbes influence activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity, and neurogenesis. Fung TC et al. Nat. Neurosci . 2017 Feb;20(2):145- 155.

59. Schizophrenia About as “biological” as a psychiatric disorder can get Follow ups from previous lectures

60. “ 1/3 rd of people with schizophrenia have elevated IgG antibodies to Gliadin & increased inflammation.” Glutamate ionotropic receptor (NMDA type) has similar protein structure to gliadin – representing a potential target for cross-reactivity. “Mimicry through the process of cross-reactivity between and gliadin and the glutamate ionotropic receptor might disrupt the functions of the glutamate system and relate to illness pathophysiology.”

61. 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)

62. Candida & schizophrenia (10 papers on PubMed June 9, 2024)

63. Probiotic normalization of candida albicans in schizophrenia . Severance, EG Brain Behav . Immun. 2017 May:62:41-45. The gut microbiome in schizophrenia and the potential benefits of prebiotic and probiotic treatment. Liu, J C W et al. Nutrients. 2021 Mar 31;13(4):1152. Correlation of depression and microbiota-gut-brain connections. “Restoration of intestinal microbiota …using probiotics… improves mental disorders.” (1 billion CFU) Jach , ME. The role of probiotics and their metabolites in the Treatment of Depression. Molecules. 2023 Apr 4:28(7):3213

64. 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 on yeast Ericson E et al. PLoS Genet. 2008 Aug 8;4(8):e1000151. doi: 10.1371/journal.pgen.1000151. on

65. Treatment mashup on schizophrenia from the literature TBL – don’t just be thinking “Antipsychotic therapy” “MTHFR deficiency schizophrenia” – 8 citations “Vitamin D deficiency schizophrenia” – 175 “B12 deficiency schizophrenia” – 52 “B-vitamin deficiency schizophrenia” - 118 “PUFA deficiency schizophrenia” – 21 “omega 3 deficiency schizophrenia” – 56 “lithium deficiency schizophrenia” – 30 PubMed Search – June 10, 2024

66. November 18, 2012 Mild elevation – probiotic started The “Alan” case

67. What happened to Alan on Clozapine & integrative medicine therapy? May 21, 2024 “I’m doing great. The electronic things…but it’s getting way better. Every year is better and better. I almost feel like I’m going to be ready to go out and get a job.” No TRACE of psychosis or paranoia. Euthymic. RX: Clozapine 300 mg at night. 10 mg Trintellix daily (added in last few years). From PCP: Atenolol and rosuvastatin Supplements: Coenzyme Q10, Vitamin D Dietary restrictions: dairy and gluten.

68. With the Rx pad: Clozapine is the single best agent for schizophrenia. Docs are afraid to use it. (REMS program, etc.) “The Laitman protocol” – Robert S. Laitman , MD The idea: Deliberately prescribe microdoses of fluvoxamine to commit a drug-drug interaction with clozapine. Monitor /modify dosing carefully. Pre-emptively begin an anticonvulsant due to possibility of excessively high levels of clozapine. Result: INCREASED clozapine level and DECREASED norclozapine level. ( Norclozapine is where the side effects reside).

69. October 25, 2014 Used with permission Google: “Bethany Yeiser TEDx”

70. “The glory of medicine is that it is constantly moving forward, that there is always more to learn.” William J. Mayo, MD [ in: The Preliminary Education of the Clinical Specialist. Collect. Papers Mayo Clinic. 1931. “Medicine can be used only as people are educated to its accomplishments.” Charles H. Mayo [International medical Progess . Collect. Papers Mayo Clin & Mayo Foundation 23;1020-1024, 1931]

71. Louis B. Cady, MD Cady Wellness Institute 4727 Rosebud Lane – Suite F Newburgh, IN 47630 USA Office [phone] www.cadywellness.com www.facebook.com/cadywellness Instagram: cadywellnessinstitute TikTok: cadywellnessinstitute Follow us on social media: Link to slides: