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/
"The effects of subchronic administration of the antidepressant fluoxetine (15 mg/kg i.p., 14 days) on thyroid hormone metabolism were investigated in 11 regions of the CNS and three peripheral tissues in the rat. Fluoxetine significantly enhanced the activity of the 5'II-deiodinase isoenzyme (5'D-II), which catalyzes the deiodination of the inactive prohormone thyroxine (T4) to the active compound triiodothyronine (T3) in areas of the cortex, the limbic forebrain and the striatum. The activity of the 5D-III deiodinase isoenzyme (5D-III), which catalyzes the further deiodination of T3 to the inactive metabolite 3,3'-T2, was inhibited in the first two of these areas. The areas affected were roughly the same as those with the highest density of 5-HT2 receptors in rat brain. Theoretically, the enhancement 5'D-II activity, together with a concomitant decrease in 5D-III activity, should lead to a rise in T3 concentrations." (NOTE: 5-HT2 receptors are coupled to Gq/11)
Bross R, Hoffer LJ - "Fluoxetine increases resting energy expenditure and basal body temperature in humans" Am J Clin Nutr 61(5):1020-5 (1995). doi: 10.1093/ajcn/61.4.1020
https://pubmed.ncbi.nlm.nih.gov/7733022/
Cornet M, Wu YW, Forquer H, et al. - "Maternal treatment with selective serotonin reuptake inhibitors during pregnancy and delayed neonatal adaptation: a population-based cohort study" Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online First: 29 November 2023. doi: 10.1136/archdischild-2023-326049
https://fn.bmj.com/content/early/2023/1 ... 023-326049
Crowe D, Collins JP, Rosse RB - "Thyroid hormone supplementation of fluoxetine treatment" J Clin Psychopharmacol 10(2):150-1 (1990) doi: 10.1097/00004714-199004000-00031
https://journals.lww.com/psychopharmaco ... ne.31.aspx
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). doi: 10.1089/thy.2008.0261
https://www.liebertpub.com/doi/10.1089/thy.2008.0261
"Patients with normal thyroid function who were treated with fluoxetine demonstrated a significant reduction of T3 after 15 and 30 days of treatment (p = 0.034 and p = 0.011) and a significant reduction of T4 throughout the intervention period (p = 0.04 after 15 days; p = 0.015 after 30 days; and p = 0.029 after 90 days)."
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) doi: 10.1017/S1461145709990769.
https://academic.oup.com/ijnp/article/13/5/553/629900
Gendall KA, Joyce PR, Mulder RT, Luty SE - "Thyroid indices and response to fluoxetine and nortriptyline in major depression" J Psychopharmacol. 17(4):431-7 (2003). doi: 10.1177/0269881103174001
https://journals.sagepub.com/doi/10.117 ... 1103174001
Golstein J, Schreiber S, Velkeniers B, Vanhaelst L - "Effect of fluoxetine, a serotonin reuptake inhibitor, on the pituitary-thyroid axis in rat" Eur J Pharmacol 91(2-3):239-43 (1983)
https://www.sciencedirect.com/science/a ... 9983904715
"The major effect of the drug seems to be stimulation of TSH synthesis and release via the inhibition of T4-mediated thyroid-pituitary feedback. Additionally, fluoxetine could exert a minor direct central stimulatory effect on TSH secretion."
Gupta S, Masand P, Tanquary JF - "Thyroid hormone supplementation of fluoxetine in the treatment of major depression" Br J Psychiatry 159:866-7 (1991). doi: 10.1192/bjp.159.6.866
https://www.cambridge.org/core/journals ... 3ECC385300
Hashemi SS, Jelodar GA, Rafati A - "Investigating the Effects of Fluoxetine on Cortisol and Thyroid Hormone Levels in Rats" J Arak Uni Med Sci 17(2):82-89 (2014)
http://jams.arakmu.ac.ir/article-1-2556-en.html
"Taking fluoxetine for 35 days significantly decreased the level in serum concentrations of Ft3, fT4, T4 and cortisol hormones compared to the control and sham groups."
Jackson IM, Luo LG - "Antidepressants inhibit the glucocorticoid stimulation of thyrotropin releasing hormone expression in cultured hypothalamic neurons" J Investig Med 46(9):470-4 (1998)
https://pubmed.ncbi.nlm.nih.gov/9861783/
Joffe RT - "Triiodothyronine potentiation of fluoxetine in depressed patients" Can J Psychiatry 37(1):48-50 (1992) doi: 10.1177/070674379203700111
https://journals.sagepub.com/doi/10.117 ... 9203700111
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). doi: 10.1097/WNF.0000000000000116
https://journals.lww.com/clinicalneurop ... _a.13.aspx
Liao H, Rosenthal DS, Kumar SC - "Abnormal Thyroid Function Laboratory Results Caused by Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressant Treatment" Case Rep Psychiatry 2023:7170564 (2023) doi: 10.1155/2023/7170564
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10195165/
(Results normalized after non-fluorinated serotonin reuptake inhibitor was substituted)
Lifschytz T, Segman R, Shalom G, Lerer B, Gur E, Golzer T, Newman ME - "Basic mechanisms of augmentation of antidepressant effects with thyroid hormone" Curr Drug Targets 7(2):203-10 (2006). doi: 10.2174/138945006775515482
https://www.eurekaselect.com/article/514
Lifschytz T, Gur E, Lerer B, Newman ME - "Effects of triiodothyronine and fluoxetine on 5-HT1A and 5-HT1B autoreceptor activity in rat brain: regional differences" J Neurosci Methods 140(1-2):133-9 (2004). doi: 10.1016/j.jneumeth.2004.03.028
https://linkinghub.elsevier.com/retriev ... 7004002900
Olivares EL, Silva-Almeida C, Pestana FM, Sonoda-Côrtes R, Araujo IG, Rodrigues NC, Mecawi AS, Côrtes WS, Marassi MP, Reis LC, Rocha FF - "Social stress-induced hypothyroidism is attenuated by antidepressant treatment in rats" Neuropharmacology 62(1):446-56 (2012). doi: 10.1016/j.neuropharm.2011.08.035
https://pubmed.ncbi.nlm.nih.gov/21903114/
Pavelka S - "Development of radiometric assays for quantification of enzyme activities of the key enzymes of thyroid hormones metabolism" Physiol Res 63(Suppl 1):S133-40 (2014). doi: 10.33549/physiolres.932621
https://www.biomed.cas.cz/physiolres/pdf/63/63_S133.pdf
Pavelka S - "125I-labelled iodothyronines: useful tools for studies of effects of an antidepressant drug fluoxetine in the rat" J Radioanal Nucl Chem 286: 867-871 (2010)
https://link.springer.com/article/10.10 ... 010-0799-7
"However, profound changes in enzyme activities were determined in case of IDs [deiodinases], especially in the pituitary and cerebellum of treated rats."
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). doi: 10.1016/0006-3223(93)90311-z
https://www.biologicalpsychiatryjournal ... 0311-Z/pdf
"There was a significant association between a decline in triiodothyronine (T3) levels and response to FLU but not DMI."
- Fluvoxamine/Fluoxetine
viewtopic.php?f=66&t=3810&p=4508&hilit=SSRI#p4508
Khan MF, Murphy CD - "Bacterial degradation of the anti-depressant drug fluoxetine produces trifluoroacetic acid and fluoride ion" Appl Microbiol Biotechnol 105(24):9359-9369 (2021) doi: 10.1007/s00253-021-11675-3
https://link.springer.com/article/10.10 ... 21-11675-3
Abstract
Fluoxetine (FLX) is a blockbuster drug with annual sales in the billions of dollars. Its widespread use has resulted in its detection in water courses, where it impacts aquatic life. Investigations on the biodegradation of FLX by microorganisms are important, since augmentation of secondary wastewater treatment by an effective degrader may be one method of improving the drug's removal. In this paper, we demonstrate that common environmental bacteria can use FLX as a sole carbon and energy source. Investigations into the metabolites formed using fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR) and gas chromatography-mass spectrometry indicated that the drug was initially hydrolysed to yield 4-(trifluoromethyl)phenol (TFMP) and 3-(methylamino)-1-phenylpropan-1-ol. Since the fluorometabolite accumulated, the bacteria presumably used the latter compound for carbon and energy. Further growth studies revealed that TFMP could also be used as a sole carbon and energy source and was most likely catabolised via meta-cleavage, since semialdehyde products were detected in culture supernatants. The final products of the degradation pathway were trifluoroacetate and fluoride ion; the former is a dead-end product and was not further catabolised. Fluoride ion most likely arises owing to spontaneous defluorination of the meta-cleavage products that were shown to be photolabile.Key points• Bacteria can use FLX and TFMP as sole carbon and energy sources for their growth.• Biodegradation produces fluorometabolites that were detected by 19F NMR and GC-MS.• Trifluoroacetic acid and fluoride ion were identified as end products.
Prozac & 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/
"We found significant changes as following: decreased G alpha Gq/11 for fluoxetine, low G alpha s for sertraline and both high G alpha q/11 and high G alpha s for citalopram."
MAPK/ERK (Gq/11)
Li B, Zhang S, Zhang H, Nu W, Cai L, Hertz L, Peng - "Fluoxetine-mediated 5-HT2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation" Psychopharmacology (Berl) 201(3):443-58 (2008) doi: 10.1007/s00213-008-1306-5. Epub 2008 Aug 29. PMID: 18758753.
https://pubmed.ncbi.nlm.nih.gov/18758753/
"Fluoxetine has relatively high affinity for Gq/11 protein-coupled 5-HT(2) receptors. Part of these receptors in brain are on astrocytes, where fluoxetine causes an increase in free cytosolic calcium concentration ([Ca(2+)](i)) and phosphorylation of extracellular regulated kinase 1 and 2 (ERK(1/2))."
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramaugé M, Courtin F, Pierre M - "MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes" J Mol Neurosci 24(2):207-16 (2004). doi: 10.1385/JMN:24:2:207
https://pubmed.ncbi.nlm.nih.gov/15456934/
Ogelman R, Gomez Wulschner LE, Hoelscher VM, Hwang IW, Chang VN, Oh WC - "Serotonin modulates excitatory synapse maturation in the developing prefrontal cortex" Nat Commun 15(1):1368 (2024). doi: 10.1038/s41467-024-45734-w.Abstract
Chronic treatments with antidepressants active on major depressive disorders influence pathways involved in cell survival and plasticity. As astrocytes seem to play a key role in the protection of brain cells, we investigated in these cells the rapid effects of the antidepressant fluoxetine (Prozac) on signaling cascades and gene induction, which probably play a role in neuroprotection. We show here that fluoxetine alone activates the extracellular signal-regulated-protein kinase (Erk) and p38 mitogen-associated protein (MAP) kinase cascades. RT-PCR revealed that genes, modulated in brain by long-term fluoxetine treatment, are rapidly induced by fluoxetine in cultured astrocytes: brain-derived nerve factor (BDNF) and its receptors, glial-derived nerve factor (GDNF) and deiodinase 3 (D3). Induction of D3 by fluoxetine is inhibited by U0126 and SB203580, suggesting that Erk and p38 MAP kinases are involved. Glial-derived nerve factor (GDNF) induction by fluoxetine is prevented by U0126, suggesting that Erk is implicated. Brain-derived nerve factor (BDNF) induction seems mediated by other signaling pathways. In conclusion, we show that fluoxetine alone rapidly activates mitogen activated protein (MAP) kinase cascades in rat astrocytes and that genes involved in neuroprotection are induced in a few hours in a MAP kinase-dependent or -independent manner.
https://www.nature.com/articles/s41467-024-45734-w
"5-HT2ARs are coupled to Gαq proteins and activate PKC, CaMKII, and many small molecules known to facilitate synaptic plasticity, often through concurrent Ca2+ influx. Stimulation of 5-HT7Rs initiates Gαs or Gα12 dependent cascades that can activate adenylyl cyclase, PKA, and voltage-gated Ca2+ channels, or small GTPases that are all critical for excitatory synapse development."
Toffoli LV, Rodrigues GM Jr, Oliveira JF, Silva AS, Moreira EG, Pelosi GG, Gomes MV - "Maternal exposure to fluoxetine during gestation and lactation affects the DNA methylation programming of rat's offspring: modulation by folic acid supplementation" Behav Brain Res 265:142-7 (2014) doi: 10.1016/j.bbr.2014.02.031. Epub 2014 Feb 28
https://www.sciencedirect.com/science/a ... 2814001065
- SEE: DNA Methylation - Thyroid & Fluoride
viewtopic.php?f=7&t=4649
Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD - "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential" Nat Commun 14(1):8221 (2023) doi: 10.1038/s41467-023-44016-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10724237/
"Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists."
Amelogenesis
Riksen EA, Stunes AK, Kalvik A, Gustafsson BI, Snead ML, Syversen U, Lyngstadaas SP, Reseland JE - "Serotonin and fluoxetine receptors are expressed in enamel organs and LS8 cells and modulate gene expression in LS8 cells" Eur J Oral Sci 118(6):566-73 (2010). doi: 10.1111/j.1600-0722.2010.00778.x.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422030/
Metamophosis
NOTE: All metamorphosis is regulated by T3.
Rogers E, Black M - "Effects of fluoxetine on development and metamophosis in Xenopus laevis" Fourth SETAC World Congress November 14-18, 2004, Portland, Oregon, USA; The Society of Environmental Toxicology and Chemistry (SETAC) (2004)
Serotonin and Thyroid DysfunctionABSTRACT- Pharmaceuticals detected at low concentrations in surface water may have the potential to affect aquatic organisms, including developing amphibians. Our research focuses on fluoxetine, a selective serotonin reuptake inhibitor and widely prescribed antidepressant. Mammalian research indicates that fluoxetine may inhibit the thyroid axis. In larval frogs, increasing levels of thyroid hormones are necessary for metamorphosis to occur, and the presence of fluoxetine in aquatic habitats has the potential to decrease thyroid hormone levels in tadpoles, thus delaying the completion of metamorphosis. To test this hypothesis, we exposed Xenopus laevis tadpoles individually in small aquaria to fluoxetine from early development until the completion of metamorphosis. We used the following measured concentrations of fluoxetine: 0.059, 0.295, 2.95, and 29.5 ppb, which overlap concentrations detected in effluent dominated streams. Ammonium perchlorate, a known inhibitor of the thyroid axis and anuran metamorphosis was used as a positive control at 10 ppb, and FETAX solution served as the negative control. Dates of completion of forelimb emergence and tail resorbtion and were recorded for each individual, and tadpoles were measured and staged at 10-day intervals. Severe malformations were observed at all concentrations of fluoxetine tested. Malformations appeared during metamorphic climax and included stunted forelimbs and primary rotation of the hind limbs. Tadpoles exposed to 50 ppb fluoxetine exhibited impaired balance and swimming behavior. These tadpoles floated upside down at the surface of the tank and swam in circles when prodded. As this research is on-going, final times to metamorphosis are not available, but our preliminary results indicate that fluoxetine impairs normal development in X. laevis tadpoles at concentrations that may occur in the environment.
Hassan WA, Aly MS, Rahman TA, Shahat AS - "Impact of experimental hypothyroidism on monoamines level in discrete brain regions and other peripheral tissues of young and adult male rats" Int J Dev Neurosci 31(4):225-33 (2013) doi: 10.1016/j.ijdevneu.2013.02.001
https://pubmed.ncbi.nlm.nih.gov/23411049/
"Hypothyroidism induced by daily oral administration of propylthiouracil (PTU, 5mg/kg body wt) caused a significant reduction in DA levels in most of the tissues examined of both young and adult rats after 21 and 28 days, in NE levels after all the time intervals studied in young rats, and after 21 and 28 days in adult rats. 5-HT exhibited a significant reduction in the selected brain regions and blood plasma after 21 and 28 days and in cardiac muscle after all the time intervals in the two age groups of animals."
Jin Z, Ling J, Yu J, He M, Ni P, Zhang F, Wang Y - "Serotonin 2A receptor function and depression-like behavior in rats model of hypothyroidism" Exp Brain Res 239(8):2435-2444 (2021) doi: 10.1007/s00221-021-06129-1
https://link.springer.com/article/10.10 ... 21-06129-1
"In conclusion, our results suggest that hypothyroidism induces depressive behaviors through the influence of the serotonin system, and the decreased expression of the 5-HT receptor is an important cause of the depressive behaviors in hypothyroidism."
Lee JH, Lee M, Park JA, Ryu YH, Lee KC, Kim KM, Choi JY - "Effects of hypothyroidism on serotonin 1A receptors in the rat brain" Psychopharmacology (Berl) 235(3):729-736 (2018) doi: 10.1007/s00213-017-4799-y.
https://pubmed.ncbi.nlm.nih.gov/29209734/
"Our results demonstrate that hypothyroidism elevates serotonin 1A receptor binding in the limbic system."
Yu D, Zhou H, Yang Y, Jiang Y, Wang T, Lv L, Zhou Q, Yang Y, Dong X, He J, Huang X, Chen J, Wu K, Xu L, Mao R - "The bidirectional effects of hypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats" Horm Behav 69:106-15 (2015) doi: 10.1016/j.yhbeh.2015.01.003
https://pubmed.ncbi.nlm.nih.gov/25623236/
"The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels."
Other (ADHD):
Umezu T, Kita T, Morita M - "Hyperactive behavioral phenotypes and an altered brain monoaminergic state in male offspring mice with perinatal hypothyroidism" Toxicol Rep 6:1031-1039 (2019). doi: 10.1016/j.toxrep.2019.10.005
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816216/