Fluvoxamine/Fluoxetine

A forum investigating the similarities between COVID-19 and fluoride poisoning, thyroid dysfunction and Gq/11 pathways.
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Fluvoxamine/Fluoxetine

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Fluvoxamine
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Recently, fluvoxamine (Luvox) has been heralded as an effective treatment for COVID-19, reducing hospitalizations. Two new major studies have shown some benefits (Calusic et al., 2021; Reis et al., 2021). Similar benefits have been reported for fluoxetine (Prozac)(Hoertel et al., 2021). To us, this is particularly interesting and also concerning, as fluvoxamine and fluoxetine are fluorinated drugs known to interfere with thyroid hormone metabolism. [Thyroid dysfunction is now increasingly acknowledged to play a role in poor outcomes of COVID-19 (see: Damara et al. for recent review, also viewtopic.php?f=66&t=2040)]

Both drugs are "selective serotonin reuptake inhibitors" (SSRI). Serotonin (5-HT) receptors are coupled to Gq/11 proteins. Pathways activated by aberrant Gq/11 signaling are at the core of both COVID-19 and fluoride poisoning.

Interestingly, fluoxetine has been shown to reduce levels of Gq/11 in NK immunocytes (natural killer cells) (Kovárů et al., 2012, 2011).

  • SSRIs are among the most common medications prescribed worldwide. There are basically 6 SSRIs --> [Fluoxetine (Prozac), Paroxetine (Paxil), Citalopram (Celexa), Escitalopram (Lexapro), Fluvoxamine (Luvox), and Sertraline (Zooloft). All but Sertraline are fluorinated.

It will be interesting to find out if all SSRIs exhibit benefits in COVID-19 treatment. It is evident so far that fluvoxamine and fluoxetine benefit a small portion of those afflicted with COVID-19. Do they benefit patients who have hyperthyroidism, hypothyroidism, or those with normal thyroid function at admission?

Researchers have not yet considered effects on thyroid hormone metabolism, but focused on 5-HT, sphingomyelin, and sigma-1 receptors - all of which involve Gq/11 - while trying to explain the mechanism for the observed benefits of SSRIs.

When will someone consider targeted COVID-19 treatment employing T3, considering that low FT3 is now known as a predictor of COVID-19 severity?

More to come...


COVID-19

Calusic et al. reported that "no statistically significant differences between groups were observed regarding the number of days on ventilator support, duration of ICU or total hospital stay. However, overall mortality was lower in the fluvoxamine group, 58.8% (n=30/51), than in the control group, 76.5% (n=39/51), HR 0.58, 95%CI (0.36 - 0.94, p = 0.027)." (Calusic et al., 2021)

Reis et al. documented a decrease in hospitalizations - 11% as compared to 16% in the placebo or other treatment group (Reis et al., 2021).

Unfortunately, neither study investigated thyroid status.

Calusic M, Marcec R, Luksa L, Jurkovic I, Kovac N, Mihaljevic S, Likic R - "Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls" Br J Clin Pharmacol. 2021 Nov 1. doi: 10.1111/bcp.15126. Epub ahead of print. PMID: 34719789.
https://bpspubs.onlinelibrary.wiley.com ... /bcp.15126

Reis G, Dos Santos Moreira-Silva EA, Silva DCM, Thabane L, Milagres AC, Ferreira TS, Dos Santos CVQ, de Souza Campos VH, Nogueira AMR, de Almeida APFG, Callegari ED, de Figueiredo Neto AD, Savassi LCM, Simplicio MIC, Ribeiro LB, Oliveira R, Harari O, Forrest JI, Ruton H, Sprague S, McKay P, Glushchenko AV, Rayner CR, Lenze EJ, Reiersen AM, Guyatt GH, Mills EJ; TOGETHER investigators - "Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial" Lancet Glob Health. 2021 Oct 27:S2214-109X(21)00448-4. doi: 10.1016/S2214-109X(21)00448-4. Epub ahead of print. PMID: 34717820; PMCID: PMC8550952.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550952/

FLCCC Treatment Protocol
https://covid19criticalcare.com/wp-cont ... VID-19.pdf

American Psychiatric Association - "Antidepressants May Reduce Severity of COVID-19" (March 2021)
https://psychnews.psychiatryonline.org/ ... .2021.4.13

Hoertel N, Sánchez-Rico M, Vernet R, Beeker N, Jannot AS, Neuraz A, Salamanca E, Paris N, Daniel C, Gramfort A, Lemaitre G, Bernaux M, Bellamine A, Lemogne C, Airagnes G, Burgun A, Limosin F; AP-HP / Universities / INSERM COVID-19 Research Collaboration and AP-HP COVID CDR Initiative - "Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study" Mol Psychiatry. 2021 Feb 4. doi: 10.1038/s41380-021-01021-4. Epub ahead of print. PMID: 33536545
https://pubmed.ncbi.nlm.nih.gov/33536545/
(In this study 3 fluorinated SSRIs were shown to have benefit - fluoxetine, paroxetine, escitalopram)


Fluoride

Fluvoxamine and fluoxetine are organic fluoride compounds, all of which have been shown to interfere with thyroid hormone metabolism - just like inorganic fluorides.

Fluvoxamine chemical name: 2-[(E)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine
Formula: C15H21F3N2O2



Gq/11

Kovárů H, Kováru F, Lisá V - "Effect of fluoxetine and adenosine receptor NECA agonist on G alpha q/11 protein of C6 glioma cells" Neuro Endocrinol Lett 33(6):614-8 (2012)
https://pubmed.ncbi.nlm.nih.gov/23160219/
Fluoxetine reduced Gq/11.

Kovárů H, Kovaru F, Ondráčkova P, Lisá V, Fiserová - "Effect of fluoxetine or adenosine receptor NECA agonist on G-proteins of C6 glioma cells or NK immunocytes" Neuro Endocrinol Lett 32(3):274-8 (2011)
https://pubmed.ncbi.nlm.nih.gov/21712787/
"Significant reduction of G alpha q/11 subunits after acute administration of fluoxetine or NECA agonist was found."

Li B, Zhang S, Zhang H, Nu W, Cai L, Hertz L, Peng L - "Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation" Psychopharmacology (Berl) 201(3):443-58 (2008)
https://pubmed.ncbi.nlm.nih.gov/18758753/

Li Q, Hosaka T, Shikama Y, Bando Y, Kosugi C, Kataoka N, Nakaya Y, Funaki M - "Heparin-binding EGF-like growth factor (HB-EGF) mediates 5-HT-induced insulin resistance through activation of EGF receptor-ERK1/2-mTOR pathway" Endocrinology 153(1):56-68 (2012)
https://academic.oup.com/endo/article/153/1/56/2424270

Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, Rauly-Lestienne I - "Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells" Eur J Pharmacol 594(1-3):32-8 (2008)
https://pubmed.ncbi.nlm.nih.gov/18703043/

  • Gq/11 - S1R

    Hayashi T, Su TP - "Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival" Cell 131(3):596-610 (2007)
    https://www.cell.com/cell/fulltext/S009 ... 07)01099-9

    Gq/11 - Sphingomyelin

    Blankenbach KV, Claas RF, Aster NJ, Spohner AK, Trautmann S, Ferreirós N, Black JL, Tesmer JJG, Offermanns S, Wieland T, Meyer Zu Heringdorf D - "Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1" Cells 9(10):2201 (2020)
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599897/

    Pulli I, Asghar MY, Kemppainen K, Törnquist K - "Sphingolipid-mediated calcium signaling and its pathological effects" Biochim Biophys Acta Mol Cell Res 1865(11 Pt B):1668-1677 (2018)
    https://pubmed.ncbi.nlm.nih.gov/29704533/

Thyroid


- Fluvoxamine

de Carvalho GA, Bahls SC, Boeving A, Graf H - "Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function" Thyroid 19(7):691-7 (2009)
https://pubmed.ncbi.nlm.nih.gov/19583486/
"Results: Patients with normal thyroid function who were treated with fluoxetine demonstrated a significant reduction of T(3) after 15 and 30 days of treatment (p = 0.034 and p = 0.011) and a significant reduction of T(4) throughout the intervention period (p = 0.04 after 15 days; p = 0.015 after 30 days; and p = 0.029 after 90 days). However, all thyroid parameters remained within the euthyroid range. No changes were observed among hypothyroid patients on levothyroxine replacement therapy who were treated with either SSRI."

Brady KT, Lydiard RB, Kellner CH, Joffe R, Laird LK, Morton WA, Steele TE - "A comparison of the effects of imipramine and fluvoxamine on the thyroid axis" Biol Psychiatry 36(11):778-9 (1994)
(Slight elevation of TSH, change in T3/T4 ratio)

Abraham G, Milev R, Stuart Lawson J - "T3 augmentation of SSRI resistant depression" J Affect Disord 91(2-3):211-5 (2006)
https://pubmed.ncbi.nlm.nih.gov/16483669/
(Used T3 in addition to anti-depressants with significant benefit)

Kasper S, Vieira A, Schmidt R, Richter P - "Multiple hormone responses to stimulation with dl-fenfluramine in patients with major depression before and after antidepressive treatment" Pharmacopsychiatry 23(2):76-84 (1990)
https://pubmed.ncbi.nlm.nih.gov/2339181/
"Baseline and dl-FEN-stimulated cortisol values were significantly (P less than 0.001) lower and TSH values were significantly (P less than 0.01) higher in the condition after compared with the one before treatment."

De Mendonça Lima CA, Vandel S, Bonin B, Bechtel P, Carron R - "Maprotiline versus fluvoxamine: comparaison entre leurs actions sur l'axe hypothalamo-hypophyso-thyroïdien [Maprotiline versus fluvoxamine: comparison of their effects on the hypothalamo-hypophyseal-thyroid axis]. Encephale 23(1):48-55 (1997)
https://pubmed.ncbi.nlm.nih.gov/9172968/
(Basal TSH was ...decreased in the fluvoxamine group resulting in a significant difference (fluvoxamine: dTSH = 0.31 +/- 0.76 mUI/l.)

Moreau X, Azorin JM, Lejeune PJ, Jeanningros R - "Red blood cell triiodothyronine uptake in unipolar major depression: effect of a chronic antidepressant treatment" Prog Neuropsychopharmacol Biol Psychiatry 24(1):23-35 (2000)
https://pubmed.ncbi.nlm.nih.gov/10659981/
(As in Brady 1994, a slight increase in TSH after 28 days, disturbance in FT3/FT4 ratio)
T3 is accumulated in red blood cells (RBC), but not metabolized. "The RBC L-T3 uptake normalized after one month of fluvoxamine administration only in the patients who responded favorably to the treatment indicating that LT3 uptake alteration is associated with the depressive symptomatology."


- Fluoxetine

Several animal studies show that fluoxetine affects T3 production in various tissue, including brain (Eravci et al, 2000; Lin et al, 1999; Baumgartner et al, 1994; Shelton et al, 1993). Fluoxetine has been shown to interfere with deiodinase actvity in the brain (Evraci et al., 2000).

Baumgartner A, Dubeyko M, Campos-Barros A, Eravci M, Meinhold H - "Subchronic administration of fluoxetine to rats affects triiodothyronine production and deiodination in regions of the cortex and in the limbic forebrain" Brain Res 635(1-2):68-74 (1994)
https://pubmed.ncbi.nlm.nih.gov/8173980/
  • see also: Campos-Barros A, Musa A, Flechner A, Hessenius C, Gaio U, Meinhold H, Baumgartner A - "Evidence for circadian variations of thyroid hormone concentrations and type II 5'-iodothyronine deiodinase activity in the rat central nervous system" J Neurochem 68(2):795-803 (1997)
    https://pubmed.ncbi.nlm.nih.gov/9003071/
Eitan R, Landshut G, Lifschytz T, Einstein O, Ben-Hur T, Lerer B - "The thyroid hormone, triiodothyronine, enhances fluoxetine-induced neurogenesis in rats: possible role in antidepressant-augmenting properties" Int J Neuropsychopharmacol 13(5):553-61 (2010)
https://pubmed.ncbi.nlm.nih.gov/19835665/

Eravci M, Pinna G, Meinhold H, Baumgartner A - "Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain" Endocrinology 141(3):1027-40 (2000)
https://pubmed.ncbi.nlm.nih.gov/10698179/

Gitlin M, Altshuler LL, Frye MA, Suri R, Huynh EL, Fairbanks L, Bauer M, Korenman S - "Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors" J Psychiatry Neurosci 29(5):383-6 (2004)
https://pubmed.ncbi.nlm.nih.gov/15486607/

Lai J, Xu D, Peterson BS, Xu Y, Wei N, Zhang M, Hu S - "Reversible Fluoxetine-Induced Hyperthyroidism: A Case Report" Clin Neuropharmacol. 39(1):60-1 (2016)
https://pubmed.ncbi.nlm.nih.gov/26626429/

Lin X, Levitsky DA, King JM, Campbell TC - "The promotion effect of anorectic drugs on aflatoxin B(1)-induced hepatic preneoplastic foci" Carcinogenesis 20(9):1793-9 (1999)
https://pubmed.ncbi.nlm.nih.gov/10469626/

Martinez Ortiz JJ - "Hyperthyroidism secondary to antidepressive treatment with fluoxetine" An Med Interna 16(11):583-4 (1999) https://pubmed.ncbi.nlm.nih.gov/10638001/

Shelton RC, Winn S, Ekhatore N, Loosen PT - "The effects of antidepressants on the thyroid axis in depression." Biol Psychiatry 33(2):120-6 (1993)
https://pubmed.ncbi.nlm.nih.gov/8439600/

There are alert issues in some parts of the world after case reports that fluoxetine interfered with levothyronine (Synthroid), and caused elevated TSH levels.
Example: https://www.medsafe.govt.nz/safety/Aler ... roxine.asp

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SEE also: Old PFPC Website pages:
https://poisonfluoride.com/pfpc/html/organic_f-.html
https://poisonfluoride.com/pfpc/html/prozac.html
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