individuals on chronic lithium therapy, a condition called lithium-induced nephrogenic diabetes insipidus. continued use of lithium can lead to more serious kidney damage in an aggravated form of diabetes insipidus. chronic kidney disease caused by lithium has not been proven with various contradicting results presented by a 2018 review. in rare cases, some forms of lithium-caused kidney damage may be progressive and lead to end-stage kidney failure with a reported incidence of 0.2% to 0.7%. hyperparathyroidism lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia. interactions lithium plasma concentrations are known to be increased with concurrent use of diuretics—especially loop diuretics (such as furosemide) and thiazides—and non-steroidal anti-inflammatory drugs (nsaids) such as ibuprofen. lithium concentrations can also be increased with concurrent use of ace inhibitors such as captopril, enalapril, and lisinopril. lithium is primarily cleared from the body through glomerular filtration, but some is then reabsorbed together with sodium through the proximal tubule. its levels are therefore sensitive to water and electrolyte balance. diuretics act by lowering water and sodium levels; this causes more reabsorption of lithium in the proximal tubules so that the removal of lithium from the body is less, leading to increased blood levels of lithium. ace inhibitors have also been shown in a retrospective case-control study to increase lithium concentrations. this is likely due to constriction of the afferent arteriole of the glomerulus, resulting in decreased glomerular filtration rate and clearance. another possible mechanism is that ace inhibitors can lead to a decrease in sodium and water. this will increase lithium reabsorption and its concentrations in the body. there are also drugs that can increase the clearance of lithium from the body, which can result in decreased lithium levels in the blood. these drugs include theophylline, caffeine, and acetazolamide. additionally, increasing dietary sodium intake may also reduce lithium levels by prompting the kidneys to excrete more lithium. lithium is known to be a potential precipitant of serotonin syndrome in people concurrently on serotonergic medications such as antidepressants, buspirone and certain opioids such as pethidine (meperidine), tramadol, oxycodone, fentanyl and others. lithium co-treatment is also a risk factor for neuroleptic malignant syndrome in people on antipsychotics and other antidopaminergic medications. high doses of haloperidol, fluphenazine, or flupenthixol may be hazardous when used with lithium; irreversible toxic encephalopathy has been reported. indeed, these and other antipsychotics have been associated with increased risk of lithium neurotoxicity, even with low therapeutic lithium doses. overdose main article: lithium toxicity lithium toxicity, which is also called lithium overdose and lithium poisoning, is the condition of having too much lithium in the blood. this condition also happens in persons that are taking lithium in which the lithium levels are affected by drug interactions in the body. in acute toxicity, people have primarily gastrointestinal symptoms such as vomiting and diarrhea, which may result in volume depletion. during acute toxicity, lithium distributes later into the central nervous system resulting in mild neurological symptoms, such as dizziness. in chronic toxicity, people have primarily neurological symptoms which include nystagmus, tremor, hyperreflexia, ataxia, and change in mental status. during chronic toxicity, the gastrointestinal symptoms seen in acute toxicity are less prominent. the symptoms are often vague and nonspecific. if the lithium toxicity is mild or moderate, lithium dosage is reduced or stopped entirely. if the toxicity is severe, lithium may need to be removed from the body. mechanism of action the specific biochemical mechanism of lithium action in stabilizing mood is unknown. upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis. unlike many other psychoactive drugs, li+ typically produces no obvious psychotropic effects (such as euphoria) in normal individuals at therapeutic concentrations. lithium may also increase the release of serotonin by neurons in the brain. in vitro studies performed on serotonergic neurons from rat raphe nuclei have shown that when these neurons are treated with lithium, serotonin release is enhanced during a depolarization compared to no lithium treatment and the same depolarization. lithium both directly and indirectly inhibits gsk3β (glycogen synthase kinase 3β) which results in the activation of mtor. this leads to an increase in neuroprotective mechanisms by facilitating the akt signaling pathway. gsk-3β is a downstream target of monoamine systems. as such, it is directly implicated in cognition and mood regulation. during mania, gsk-3β is activated via dopamine overactivity. gsk-3β inhibits the transcription factors β-catenin and cyclic amp (camp) response element binding protein (creb), by phosphorylation. this results in a decrease in the transcription of important genes encoding for neurotrophins. in addition, several authors proposed that pap-phosphatase could be one of the therapeutic targets of lithium. this hypothesis was supported by the low ki of lithium for human pap-phosphatase compatible within the range of therapeutic concentrations of lithium in the plasma of people (0.8–1 mm). the ki of human pap-phosphatase is ten times lower than that of gsk3β (glycogen synthase kinase 3β). inhibition of pap-phosphatase by lithium leads to increased levels of pap (3′-5′ phosphoadenosine phosphate), which was shown to inhibit parp-1. another mechanism proposed in 2007 is that lithium may interact with nitric oxide (no) signalling pathway in the central nervous system, which plays a crucial role in neural plasticity. the no system could be involved in the antidepressant effect of lithium in the porsolt forced swimming test in mice. it was also reported that nmda receptor blockage augments antidepressant-like effects of lithium in the mouse forced swimming test, indicating the possible involvement of nmda receptor/no signaling in the action of lithium in this animal model of learned helplessness. lithium possesses neuroprotective properties by preventing apoptosis and increasing cell longevity. although the search for a novel lithium-specific receptor is ongoing, the high concentration of lithium compounds required to elicit a significant pharmacological effect leads mainstream researchers to believe that the existence of such a receptor is unlikely. oxidative metabolism evidence suggests that mitochondrial dysfunction is present in patients with bipolar disorder. oxidative stress and reduced levels of anti-oxidants (such as glutathione) lead to cell death. lithium may protect against oxidative stress by up-regulating complex i and ii of the mitochondrial electron transport chain. dopamine and g-protein coupling during mania, there is an increase in neurotransmission of dopamine that causes a secondary homeostatic down-regulation, resulting in decreased neurotransmission of dopamine, which can cause depression. additionally, the post-synaptic actions of dopamine are mediated through g-protein coupled receptors. once dopamine is coupled to the g-protein receptors, it stimulates other secondary messenger systems that modulate neurotransmission. studies found that in autopsies (which do not necessarily reflect living people), people with bipolar disorder had increased g-protein coupling compared to people without bipolar disorder. lithium treatment alters the function of certain subunits of the dopamine associated g-protein, which may be part of its mechanism of action. glutamate and nmda receptors glutamate levels are observed to be elevated during mania. lithium is thought to provide long-term mood stabilization and have anti-manic properties by modulating glutamate levels. it is proposed that lithium competes with magnesium for binding to nmda glutamate receptor, increasing the availability of glutamate in post-synaptic neurons, leading to a homeostatic increase in glutamate re-uptake which reduces glutamatergic transmission. the nmda receptor is also affected by other neurotransmitters such as serotonin and dopamine. effects observed appear exclusive to lithium and have not been observed by other monovalent ions such as rubidium and caesium. gaba receptors gaba is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. it was found that patients with bipolar disorder had lower gaba levels, which results in excitotoxicity and can cause apoptosis (cell loss). lithium has been shown to increase the level of gaba in plasma and cerebral spinal fluid. lithium counteracts these degrading processes by decreasing pro-apoptotic proteins and stimulating release of neuroprotective proteins. lithium's regulation of both excitatory dopaminergic and glutamatergic systems through gaba may play a role in its mood stabilizing effects. cyclic amp secondary messengers lithium's therapeutic effects are thought to be partially attributable to its interactions with several signal transduction mechanisms. the cyclic amp secondary messenger system is shown to be modulated by lithium. lithium was found to increase the basal levels of cyclic amp but impair receptor coupled stimulation of cyclic amp production. it is hypothesized that the dual effects of lithium are due to the inhibition of g-proteins that mediate cyclic amp production. over a long period of lithium treatment, cyclic amp and adenylate cyclase levels are further changed by gene transcription factors. inositol depletion hypothesis lithium treatment has been found to inhibit the enzyme inositol monophosphatase, involved in degrading inositol monophosphate to inositol required in pip2 synthesis. this leads to lower levels of inositol triphosphate, created by decomposition of pip2. this effect has been suggested to be further enhanced with an inositol triphosphate reuptake inhibitor. inositol disruptions have been linked to memory impairment and depression. it is known with good certainty that signals from the receptors coupled to the phosphoinositide signal transduction are affected by lithium. myo-inositol is also regulated by the high affinity sodium mi transport system (smit). lithium is hypothesized to inhibit mi entering the cells and mitigating the function of smit. reductions of cellular levels of myo-inositol results in the inhibition of the phosphoinositide cycle. neurotrophic factors various neurotrophic factors such as bdnf and mesencephalic astrocyte-derived neurotrophic factor have been shown to be modulated by various mood stabilizers. history lithium was first used in the 19th century as a treatment for gout after scientists discovered that, at least in the laboratory, lithium could dissolve uric acid crystals isolated from the kidneys. the levels of lithium needed to dissolve urate in the body, however, were toxic. because of prevalent theories linking excess uric acid to a range of disorders, including depressive and manic disorders, carl lange in denmark and william alexander hammond in new york city used lithium to treat mania from the 1870s onwards. by the turn of the 20th century, as theory regarding mood disorders evolved and so-called "brain gout" disappeared as a medical entity, the use of lithium in psychiatry was largely abandoned; however, a number of lithium preparations were still produced for the control of renal calculi and uric acid diathesis. as accumulating knowledge indicated a role for excess sodium intake in hypertension and heart disease, lithium salts were prescribed to patients for use as a replacement for dietary table salt (sodium chloride). this practice and the sale of lithium itself were both banned in the united states in february 1949, following publication of reports detailing side effects and deaths. also in 1949, the australian psychiatrist john cade and australian biochemist shirley andrews rediscovered the usefulness of lithium salts in treating mania while working at the royal park psychiatric hospital in victoria. they were injecting rodents with urine extracts taken from manic patients in an attempt to isolate a metabolic compound which might be causing mental symptoms. since uric acid in gout was known to be psychoactive, (adenosine receptors on neurons are stimulated by it; caffeine blocks them), they needed soluble urate for a control. they used lithium urate, already known to be the most soluble urate compound, and observed that it caused the rodents to become tranquil. cade and andrews traced the effect to the lithium ion itself, and after cade ingested lithium himself to ensure its safety in humans, he proposed lithium salts as tranquilizers. he soon succeeded in controlling mania in chronically hospitalized patients with them. this was one of the first successful applications of a drug to treat mental illness, and it opened the door for the development of medicines for other mental problems in the next decades. the rest of the world was slow to adopt this treatment, largely because of deaths which resulted from even relatively minor overdosing, including those reported from use of lithium chloride as a substitute for table salt. largely through the research and other efforts of denmark's mogens schou and paul baastrup in europe, and samuel gershon and baron shopsin in the u.s., this resistance was slowly overcome. following the recommendation of the apa lithium task force (william bunney, irvin cohen (chair),