Lithium: downside ?
rwac 26 Jul 2010
Chronic lithium treatment affects rat brain and serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) levels.
Maayan R, Shaltiel G, Poyurovsky M, Ramadan E, Morad O, Nechmad A, Weizman A, Agam G.
Laboratory of Biological Psychiatry, Felsentein Medical Research Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abstract
Lithium (Li) is an established effective treatment for bipolar disorder. However, the molecular mechanism of its action is still unknown. Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are adrenal hormones also synthesized de novo in the brain as neurosteroids. Recent studies have suggested that DHEA has mood-elevating properties and may demonstrate antidepressant effects. 3(2)-Phosphoadenosine 5-phosphate (PAP) phosphatase is a novel Li-inhibitable enzyme involved in sulphation processes. In the present study we examined the impact of 10 d Li treatment on serum and brain DHEA and DHEA-S levels in rats. Our results show that Li administration lowered frontal cortex and hippocampus DHEA and DHEA-S levels, in line with our hypothesis assuming that Lis inhibition of PAP phosphatase leads to elevated PAP levels resulting in inhibition of sulphation and reduction in brain DHEA-S levels. Future studies should address the involvement of neurosteroids in the mechanism of Lis mood stabilization.
PMID: 14725722 [PubMed - indexed for MEDLINE]
Lithium: evidence for reduction in circulating testosterone levels in mice following chronic administration.
Collins TJ, Chatterjee S, LeGate LS, Banerji TK.
Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston 77550.
Abstract
Lithium, the widely-used antipsychotic drug, is known to exert adverse effects on a number of endocrine organs. In the present investigations, the effects of chronic lithium administration on circulating levels of testosterone and plasma and pituitary levels of luteinizing hormone (LH) were evaluated in order to examine whether or not the pituitary-gonadal axis is a probable target of lithium action. Adult male C57BL/6 mice, maintained on a fixed photoperiodism (LD 14:10), were administered lithium orally, by being fed on a specially prepared chow containing 0.4% lithium chloride for 15 or 30 days, while their matched controls were maintained on standard laboratory chow. At the termination of the respective experimental schedules, the animals were decapitated, their blood collected, and plasma was separated and stored frozen. Pituitaries were quickly removed, weighed, homogenized, centrifuged and their supernatants were stored frozen. Testosterone in plasma and LH in pituitary and plasma were quantitated by standard RIA methods. Plasma Li concentration was determined by using flame photometric methods. A significant suppression in testosterone levels was noted after both 15 (p less than .01) and 30 (p less than .05) days of lithium treatment, but both pituitary and plasma LH levels remained unchanged at both the periods. It is, therefore, suggested that lithium exerts its effect directly at the level of the Leydig cells rather than through the pituitary-gonadal axis. Since the noted lithium-induced reduction of testosterone was manifested when the plasma lithium levels were within (or around) the therapeutic range, these results may have important clinical implications.
PMID: 2848165 [PubMed - indexed for MEDLINE]
Anyone know how to estimate elemental Li for these studies. Both studies have used dosage as per kg food.
Additionally, we know that brain concentration of LiOrotate is higher than carbonate. Will this apply to the testes as well ?
markymark 26 Jul 2010
to extrapolite about DHEA(S) from rodent studies to man is slippery......
Moreover,
I found this (the authors below, of course, did not check for neurosteroids in the brains of the volunteers):
Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):937-50.
Effects of lithium carbonate on reproductive hormones in healthy men: relationship with body weight regulation--a pilot study.
Baptista T, Alastre T, Contreras Q, Martinez JL, Araujo de Baptista E, Burguera JL, de Burguera M, Hernández L.
Laboratory of Behavioral Physiology, Medical School, Universidad de Los Andes, Mérida, Venezuela.
Abstract
1. To test the hypothesis that lithium-induced body weight gain is related to an unbalance in the reproductive hormones, lithium carbonate (900 mg/day) or placebo was administered to healthy men for 1 month. 2. Body weight, skin folds and the serum levels of thyrotropic hormone, tetraiodothyroxine, prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone (T5), dehydroepiandrosterone sulfate (DHEAS), estradiol (E2), cortisol, the ratios E2/T5 and T5/DHEA-S, and blood lipids were evaluated before and during treatment. 3. Body weight, skin folds, hormones and lipids serum levels were not significantly affected by the treatment with Li. These results agree with previous reports of lack of effects of 1 month-Li administration on appetite and body weight in normal male subjects (Chen et al., 1992), and question the appropriateness of studying Li-induced obesity in healthy volunteers, given the short-term administration and low doses of Li that must be used.
ajnast4r 26 Jul 2010
900mg lithium carbonate is ~170mg elemental lithium... significantly higher than the doses(1,5,10mg) used by most people here.
turn off the sirens, lithium is safe
Happy Gringo 26 Jul 2010
chrono 30 Jul 2010
In that other thread, I think we determined that this was only the case with a single injected dose. The study I posted using chronic oral dosing showed no difference in brain levels.Additionally, we know that brain concentration of LiOrotate is higher than carbonate.
Edited by chrono, 31 July 2010 - 05:25 AM.
rwac 30 Jul 2010
You forgot to normalize for weight. The average mouse weighs 20-25g. so multiply by 75000, divide by 25 = multiply by 3000 to normalize to human weight. That's ~600mg of lithium, fairly large.C57BL/6 mice eat about 4g of food per day [1]. At 0.4%, that's .016g LiCl/day, or .0026g elemental Li. Divide this by 12.3 to get an equivalent human dose according to BSA values.
In that other thread, I think we determined that this was only the case with a single injected dose. The study I posted using chronic oral dosing showed no difference in brain levels.
I still wonder why we notice strong effects from 5mg of the orotate, when the typical pharmacological dose is much larger. (~100-200 mg)
Edited by rwac, 30 July 2010 - 12:47 PM.
Logan 30 Jul 2010
I still wonder why we notice strong effects from 5mg of the orotate, when the typical pharmacological dose is much larger. (~100-200 mg)
Because the typical pharmacological dose is used to treat people who have a much more active manic brain chemistry. Bipolar patients in the middle of some type of mania simply are not sensitive to lower doses of lithium. They may feel the effects of lower doses, it is just not enough to take them out of their manic state. People that are not bipolar obviously have a different chemistry and are in a different state that would be more sensitive to lower doses of lithium. Even someone that has a predisposition toward developing bipolar manic states but has not developed manic symptoms may be more sensitive to low doses of lithium. I have read about several people with bipolar, that were experiencing milder symptoms, having success treating those symptoms with taking just a few 5mg lithium orotate tablets/capsules a day.
chrono 31 Jul 2010
You forgot to normalize for weight. The average mouse weighs 20-25g. so multiply by 75000, divide by 25 = multiply by 3000 to normalize to human weight. That's ~600mg of lithium, fairly large.C57BL/6 mice eat about 4g of food per day [1]. At 0.4%, that's .016g LiCl/day, or .0026g elemental Li. Divide this by 12.3 to get an equivalent human dose according to BSA values.
See this thread for an explanation of how body surface area (BSA) is used to estimate human equivalent dosages: Converting dosages from animal studies. There's enough studies on lithium serum measurements that I'm sure a more accurate conversion is possible, but BSA values are probably still in the ballpark (unless lithium acts much differently than other pharmaceuticals).
I think morganator is right about the LiOr issue. A dose we 'feel' doesn't necessarily equate to a dose which would successfully treat a psychiatric problem. 300mg lithium carbonate (~55mg Li) is the smallest dose available, I believe. There have been a few papers suggesting that lower dosages than this might be efficacious for certain disorders, and would avoid some concerns about toxicity.
Edited by chrono, 31 July 2010 - 05:26 AM.
rwac 31 Jul 2010
So mouse dose in mg/kg and human dose in mg/kg are related by a factor.I don't think that's necessary when converting from animal studies; most rat/mouse dosages are already 6-12x what a human would take to get similar effects.
See this thread for an explanation of how body surface area (BSA) is used to estimate human equivalent dosages: Converting dosages from animal studies. There's enough studies on lithium serum measurements that I'm sure a more accurate conversion is possible, but BSA values are probably still in the ballpark (unless lithium acts much differently than other pharmaceuticals).
But you still need to account for the relative weights of humans and mice to calculate human dose.
Or,
(Human dose)=(BSA factor)*(Mouse dose)*(Human weight)/(Mouse weight)
chrono 31 Jul 2010
So, in that study, the equivalent human doses would be 8.4-10.5mg/kg, which is a medium-high therapeutic dose.
The study in post #2 showing no change in human DHEA-S/T5 levels used ~170mg/day elemental Li.
Edited by chrono, 31 July 2010 - 05:40 AM.
Sillewater 31 Jul 2010
e Volution 31 Jul 2010
Maybe I'm just too lazy as cutting up that stupid little pill got too cumbersome
Edited by e Volution, 31 July 2010 - 05:42 AM.
chrono 31 Jul 2010
5mg is pretty arbitrary, but as a psychiatric dose, seems pretty safe. Unfortunately, there's a dearth of papers which deal with this dosage range (between drinking water and 'therapeutic'), and they don't support any firm conclusions, except perhaps that in it's much less toxic than even lowest therapeutic dosages.
levianthan 31 May 2013
Serum luteinizing hormone and testosterone were determined weekly during the course of a comparison of the effects of lithium versus placebo on impulsive aggressive behavior in 16-24 year-old male prisoners. The duration of drug treatment for each individual was up to 3 months. A significant reduction of serious agressive behavioral incidents occurred in the third month on lithium and was accompanied by a significant rise in serum luteinizing hormone, with no change in serum testosterone.
Edited by levianthan, 31 May 2013 - 12:50 PM.
spookytooth 01 Jun 2013
orotate form.
Edited by spookytooth, 01 June 2013 - 08:57 PM.