Is impulsivity in part a lithium deficiency state?

Lithium mechanisms of action are related to the function of many enzymes, hormones, vitamins, and growth factors. In humans, lithium treatment has been associated with humoral and structural evidence of neuroprotection, such as increased expression of antiapoptotic genes, inhibition of cellular oxidative stress, synthesis of brain-derived neurotrophic factor, cortical thickening, increased grey matter density, and hippocampal enlargement. Lithium, in pharmacological doses, has been used successfully in treating bipolar disorders, and has been shown to decrease suicidality and violent crime in this situation. The guidelines of major psychiatric association name lithium as a first-line therapy for bipolar disorder. From the other hand, impulsivity is a core feature of bipolar disorder. Increased levels of this dimensional trait are present not only during acute phases of the illness but also during euthymia. Increased impulsivity worsens clinical prognosis of bipolar disorder due to its association with several severity indices, such as substance abuse or dependence, suicidal behavior, and poorer functional outcome. A wide range of intracellular responses may be secondary to the inhibition of glycogen synthase kinase-3 beta (GSK3ß) by lithium, while genetic variability at GSK3ß gene was found to be associated with increased impulsivity in bipolar patients. Although impulsivity has been traditionally linked to dysregulation of serotonergic and dopaminergic systems, some authors have proposed that lithium could reduce impulsivity levels by means of its capacity to regulate the aforementioned neurotransmitter systems. Moreover, lithium in trace amounts, as occurs in drinking water, has been inversely related to suicidal mortality, aggression and homicidal violence. These findings pose the question of whether the prospect of adding lithium to drinking water is realistic, weighing the benefits and potential risks. It seems also that in the competition for survival, those entities that best minimized lithium toxicity and maximized the benefits of lithium action had an edge in the competition to survive and reproduce. Finally, lithium has been reported to increase the volume of the prefrontal cortex and anterior cingulate gyrus. Evidence from both basic and clinical researches support that lithium may decrease impulsivity and may at least partially, exert its antisuicidal effect via reinforcing "top-down brakes" of impulsive action. Considering the research data, we may suggest that even natural lithium level intake can influence impulsivity, a possible core factor that mediate to the manifestation of both suicidality and aggressiveness, or even criminality. Moreover, we may suggest that a lithium deficiency state may precipitate these situations.

Evaluation of lithium serum level in multiple sclerosis patients: A neuroprotective element.

INTRODUCTION: It has been claimed that continuous and high production of nitric oxide (NO) and its metabolites may be involved in the pathogenesis of several neurological disorders such as multiple sclerosis. A number of studies have demonstrated that lithium regulates NO levels in disorders of the central nervous system. The aim of this study was to investigate whether NO as a marker of disease activity is correlated with lithium deficiency in relapsing remitting multiple sclerosis (RR-MS). METHODS: This case-controlled study comprised 44 patients with RR-MS and 43 healthy subjects matched by age, gender, smoking status, and body mass index. The Griess reaction was used to measure the NO metabolites, nitrite and nitrate in serum. In addition serum lithium levels were measured using atomic absorption spectrometry method. The mean serum NO concentrations in the groups RR-MS and the control were 18.5 ± 3.1µM and 15.5 ± 2.9µM, respectively. Data analysis showed a statistically significant difference between subjects with RR-MS and the control group (p < 0.05). Furthermore, serum lithium concentrations in RR-MS (0.57 ± 0.2) were remarkably lower in RR-MS patients than the controls (2.29 ± 0.7) (p < 0.05). CONCLUSION: The present findings suggest that lithium deficiency may upregulates NO production in RR-MS. Further studies with larger samples are needed to confirm the effects of lithium treatment on NO pathway and its association with synaptic plasticity in RR-MS patients.

Is violence in part a lithium deficiency state?

Violence, particularly firearm violence, leading to suicide and homicide is a significant problem worldwide. A majority of suicidal and homicidal violence involves males; homicidal violence is prevalent among young men and suicide is the leading cause of violence worldwide. Lithium, in pharmacological doses, has been used successfully for decades in treating bipolar disorders, and has been shown to decrease violent crime in this situation. Interestingly, lithium, in trace amounts, as occurs in some drinking water, has been inversely related to aggression, and suicidal and homicidal violence. Lithium is naturally found in vegetables, grains and drinking water, and dietary intake varies from nearly zero to 3mg daily. Elemental lithium, in trace doses, has been shown to improve mood in weeks. Moreover, lithium, in trace amounts, has no toxicity. In order to ensure adequate dietary intakes of elemental lithium daily for the purpose of decreasing aggression and violence, we propose considering the fortification of cereal grain products with lithium and also the addition of lithium to vitamin preparations for adults. Importantly, randomized trials in various populations are needed to test this hypothesis.

Essential elements in depression and anxiety. Part I.

Essential elements are very important for the proper functioning of the human body. They are required for fundamental life processes such as cell division and differentiation and protein synthesis. Thus a deficiency of these essential elements is associated with an enormous health risk that can ultimately lead to death. In recent years, studies have provided valuable information on the involvement of essential elements in psychiatric disorders, in particular depression and anxiety. There is strong evidence indicating that deficiency of essential elements can lead to the development of depressive and/or anxiogenic behaviour and supplementation can enhance therapeutic effect of antidepressants and anxiolytics. This review presents the most important results from preclinical and clinical studies showing involvement of essential elements such as zinc, magnesium, lithium, iron, calcium and chromium in depression and anxiety. From these studies it is evident that different types of depression and anxiety respond to treatment at different receptors indicating that the underlying mechanisms are slightly different. Furthermore, administration of low dose antidepressants supplemented with an element is effective and can reduce unwanted side effects in different types of depression/anxiety.

[Side effects of low serum lithium concentrations on renal, thyroid, and sexual functions in male and female rats]. / Effets secondaires de faibles concentrations de lithium sur les fonctions rénales, thyroïdiennes et sexuelles chez des rats matures mâles et femelles.

The present study, carried out in rats, is a contribution to explore physiological mechanisms underlying lithium toxicity. Male and female mature rats were divided into three groups and fed on commercial pellets: group (C) was control, group (Li1) was given 2000 mg lithium carbonate/kg of food, and group (Li2) was given 4000 mg lithium carbonate/kg of food. If we take into account the BW of the rats and the quantity of food they eat every day, we can estimate that the quantities of lithium carbonate ingested per day and kilogram of BW are, respectively, for the groups Li1 and Li2, of 212 mg (5,738 mmol Li) and 323 mg (8,742 mmol Li) for the males, and about 190 mg (5,142 mmol Li) and 289 mg (7,822 mmol Li) for the females. After 7, 14, 21 and 28 days, serum concentrations of lithium, creatinine, free triiodothyronine (FT3) and thyroxine (FT4), testosterone and estradiol were measured. Attention was also paid to growth rate and a histological examination of testes or vaginal mucosa was carried out. In treated rats, a dose-dependent loss of appetite and a decrease in growth rate were observed together with polydipsia, polyuria, and diarrhoea. Lithium serum concentrations were found to increase from 0.44 mM (day 7) to 1.34 mM (day 28) in Li1 rats and from 0.66 to 1.45 mM (day 14) in Li2 rats. Treatment was stopped at day 14 in Li2 rats because of a high mortality. The significant increase of creatinine that appeared, respectively, at day 7 and 14 in Li2 and Li1 rats shows that serum lithium concentrations ranging from 0.62 to 0.75 mM were able to induce renal insufficiency, secondarily leading to a time-dependent rise in lithium serum concentrations. A significant decrease of serum thyroxine (FT4) and triiodothyronine (FT3) levels was observed for lithium concentrations ranging from: 0.66 to 0.75 mmol l(-1) (Li2 rats) to 1.27 mmol l(-1) (Li1 rats). This effect was more pronounced for FT3, suggesting a defect of FT4/FT3 conversion. Under lithium treatment, the testosterone level decreased and spermatogenesis was stopped. By contrast, in treated female rats, estradiol level was found to be increased in a dose-dependent manner and animals were blocked in the diestrus phase at day 28. These results show that lithium can rapidly induce toxic effects in the rat at concentrations used for the treatment of bipolar disorders in human.

Lithium: occurrence, dietary intakes, nutritional essentiality.

Lithium is found in variable amounts in foods; primary food sources are grains and vegetables; in some areas, the drinking water also provides significant amounts of the element. Human dietary lithium intakes depend on location and the type of foods consumed and vary over a wide range. Traces of lithium were detected in human organs and fetal tissues already in the late 19th century, leading to early suggestions as to possible specific functions in the organism. However, it took another century until evidence for the essentiality of lithium became available. In studies conducted from the 1970s to the 1990s, rats and goats maintained on low-lithium rations were shown to exhibit higher mortalities as well as reproductive and behavioral abnormalities. In humans defined lithium deficiency diseases have not been characterized, but low lithium intakes from water supplies were associated with increased rates of suicides, homicides and the arrest rates for drug use and other crimes. Lithium appears to play an especially important role during the early fetal development as evidenced by the high lithium contents of the embryo during the early gestational period. The biochemical mechanisms of action of lithium appear to be multifactorial and are intercorrelated with the functions of several enzymes, hormones and vitamins, as well as with growth and transforming factors. The available experimental evidence now appears to be sufficient to accept lithium as essential; a provisional RDA for a 70 kg adult of 1,000 microg/day is suggested.

Effects of lithium deficiency in some insulin-sensitive tissues of diabetic Chinese hamsters.

In this work, we report the effect of low-dose lithium carbonate on blood glucose levels and tissue lithium content in hereditary spontaneous diabetic Chinese hamsters (HSDCHs). Hepatic lithium levels are significantly lower in diabetic hamsters when compared to healthy controls: 2.05 +/- 0.26 and 3.04 +/- 0.11 micrograms/g, respectively. The same trend was observed in kidney and muscle: 18.26 +/- 0.24 vs 20.23 +/- 1.10 micrograms/g and 4.66 +/- 0.17 vs 5.95 +/- 0.67 micrograms/g, respectively. The significance level was p < 0.05 in all cases. Supplementation with lithium carbonate eliminated tissue lithium deficiency, and had a normalizing effect on blood glucose and glycosylated serum protein levels. The insulin sensitivity index (ISI) increased, thus reducing insulin resistance. Our results suggest that lithium deficiency in certain insulin-sensitive tissues may be associated with blood glucose imbalance resulting from insulin resistance.

Lithium deficiency reduces thymus weight and alters differential blood count in rats.

Effects of lithium (Li) deficiency and/or immobilization stress on the thymus weight and differential blood count of rats were studied. The thymus weight of the rats fed a low Li diet were lighter than those of rats fed a Li supplemented diet, whether the rats were exposed to stress or not. Of the rats not exposed to stress, those in the low Li diet group showed a significant decrease in the ratios of neutrophils and T helper lymphocytes. However, there was an increase in the total number of lymphocytes in the low Li dietary group. It was shown that Li deficiency altered the responses to stress in rats.

Effects of nutritional lithium deficiency on behavior in rats.

To demonstrate whether nutritional lithium deficiency is associated with behavioral changes, male Sprague-Dawley rats were placed on a lithium-deficient diet (Li content < .01 ppm). A lithium-deprived group, receiving drinking water containing 31 microM NaCl, were compared to a control group receiving drinking water containing 31 microM LiCl. Growth and general appearance were the same in both groups. However, lithium-deficient animals demonstrated decreased aggression in social interactions with other rats and also in response to handling. The phase of wheel-running activity was delayed by 0.8 h and exhibited decreased amplitude (p < .05). Other behaviors, including acquisition and retention of a passive avoidance response, were unaffected by lithium deprivation.

[Effects of lithium deficient diet on avoidance behavior].

To determine whether lithium deficiency has an effect on lever-press avoidance behavior, low lithium diets were given to mice and the effects of these diets on conditioned lever press avoidance response were compared with that of a commercial diet containing 110 ng Li/g diet. Three low-lithium diets were prepared in this experiment and the lithium contents of the diets were 6.6, 36.6 and 76.6 ng Li/g diet. The mice used in this experiment had been maintained on a practical diet and trained by Sidman's situation previously. After checking that the conditioned response was established, they were divided into four groups. Three groups of mice each were given one of the low lithium diets, indicated above, and these were assigned into the lithium-deficient groups. Some mice were given the practical diet and this group was used as controls. The avoidance behavior was analyzed by the method reported previously by the authors. After changing the diet to a low-lithium one, the avoidance behavior was significantly suppressed in lithium-deficient groups and this appeared to be proportional to the level of lithium deficiency in the diet. Furthermore, this suppression in the avoidance behavior was recovered by lithium supplementation in the same experimental diet. These findings suggest that low-lithium intake may suppress acquired avoidance behavior in mice.