Therapeutic Uses of Lithium

The uses of lithium fall into two categories established and innovative. Among its established uses, lithium salts are used to treat acute mania and as a prophylactic measure to prevent the recurrence of bipolar manic-depressive illness. As an innovative agent, lithium salts have been used with certain success in the management of the following illnesses or conditions. 

In combination with tricyclic antidepressants, lithium is used in treating recurrent endogenous depression. In combination with neuroleptics, it is used in the management of schizoaffective disorders. In combination with neuroleptics, it is used to control schizophrenia. Lithium is also used in the case of patients with alcoholism associated with depression and has been used to correct the neutropenia that occurs during cancer chemotherapy. 

Lithium has been investigated for use in subduing aggressive behaviors in nonpsychotic but possibly brain-damaged patients. Its use has also been investigated in the management of inappropriate secretion of antidiuretic hormone. 

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Table 103.6 Therapeutic use of lithium salts in thyroid disorders...

The activity of a benzothiadiazine (XXXI) was gported as comparable to chlorpromazine in animal experiments. Initial clinical trials indicated promise that the imidazoline XXXII might be a worthwhile antidepressant, A review on the therapeutic use of lithium carbonate in the treatment of mania, excitement, epilepsy and premenstral tension has been given by Noyes. This compound has just been approved for introduction on the U.S, market (April, 1970). 

Whitworth P, Kendall DA Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D, receptor-mediated cyclic AMP formation by carbachol in rat brain slices. J Neurochem 53 536-541, 1989 Whybrow PC The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Acta Med Austriaca 21 44-47, 1994 Whybrow PC Update on thyroid axis approaches to treatment of rapid cycling bipolar disorder. Paper presented at the annual meeting of the New Clinical Drug Evaluations Unit (NCDEU), Boca Raton, EL, May 30, 1996... 

The first use of lithium for therapeutic purposes began in the mid-19th century to treat gout. Lithium had a relatively brief period of use as a substitute for sodium chloride in hypertensive patients in the 1940s, but it proved too toxic when available without monitoring and was banned. In 1949, Cade discovered that lithium was an effective treatment for bipolar disorder, engendering a series of controlled trials which confirmed its efficacy as monotherapy for the manic phase of bipolar disorder. 

Q3 Manic depressive disorder involves mood swings, and several agents can be used to stabilize mood lithium carbonate or citrate are often used. There appears to be little difference in the therapeutic usefulness of these two salts. Lithium salts are widely used mood stabilizers. They are useful prophylactically in treating both acute mania and bipolar conditions. 

Lithium salts have a narrow therapeutic index. Lithium levels should be monitored every 3 months. The long-term use of lithium is associated with thyroid disorders and mild cognitive and memory impairment. Thyroid and renal functions should be checked every 6-12 months,... 

Several processes in the immune response are affected by lithium in vivo and in vitro 139). The proliferative responses of hamster lymphoid cells to concanavalin A or phytohemagglutinin, which stimulate mitosis in T cells, were enhanced by lithium in a serum-free culture system. Proliferative stimulation also was obtained with lithium using the B cell mitogen lipopolysaccharide, but the B cell mitogens dextran sulfate and trypsin had no effect 140-143). Lithium increased the effects of suboptimal concentrations of stimulants, but had smaller effects on stimulation by optimal concentrations. With concanavalin A, the response to optimal stimulatory concentrations was inhibited 140). Paradoxical results such as these may be due to inhibitory effects of lithium on adenylate cyclase, or to effects on membrane transport systems 141). Most of these experiments used very high concentrations of lithium, considerably in excess of normal therapeutic doses (maximal inhibitory concentrations were 10 mM with hamster cells and 5 mM with human lymphocytes). At therapeutic levels of lithium, increased incorporation of [ H]thymidine was seen in human peripheral blood mononuclear cells. 

In conclusion, lithium is a moderate inhibitor of GSK-3, which in pre-clinical studies has been shown to influence pathophysiological mechanisms of Alzheimer s disease, i.e. both decreasing the hyperphosphorylation of tau and reducing the metabolism of beta amyloid. However, the action of lithium is complicated by the diverse actions associated with this compound. Due to the toxic effects associated with long-term use of lithium and therapeutically higher concentrations to decrease GSK-3 activity, it may not be considered as a prime candidate for treatment of Alzheimer s disease. 

Excess known secondary to use of lithium carbonate for treatment of mental disorders (low therapeutic index). 

In view of the influence of a complex matrix on the FD determination, e.g. in physiological fluids and tissues, and the importance of the use of lithium in medicine a further step was to exploit the utility of FDMS in combination w th signal accumulation and stable isotope dilution (internal standard) in this field. Lithium salts are used in the chemotherapy of manic-depressive psychoses . The transport phenomena of lithium through cell membranes and the mode of therapeutic action in elevated lithium levels are areas of biomedical research which are of special interest for the therapy of certain affective disorders. Concerning the accurate determination of very small lithium concentrations in the range of the normal physiological level, there is a special need for a reliable analytical technique, in particular, if only microliters of the sample are available. 

A large-scale retrospective study of the literature over the period 1966 to 1996 using the Medline database identified 41 cases of neurotoxic adverse effects in 41 patients with low therapeutic concentrations of lithium. Of these patients, 10 were taking haloperidol. ... 

If humans have a requirement for lithium, based on animal deprivation studies it is probably less than 25 pg day , which is much less than the usual dietary intake (see Table 3). Lithium is not a particularly toxic element, but the principal disadvantage in the use of lithium for psychiatric disorders is the narrow safety margin between therapeutic and toxic doses. About 500 mg lithium per day is needed to raise serum concentrations to be effective in these disorders this is close to the concentration where mild toxicity signs of gastrointestinal disturbances, muscular weakness, tremor, drowsiness, and a dazed feeling begin to appear. Severe toxicity results in coma, muscle tremor, convulsions, and even death. 

Lithium is therapeutically used in the prevention of major changes in mood which are characteristic of the affective disorders (Birch et al. 1994). The therapy can be... 

TABLE 36-5. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder... 

Detection of Li+ in artificial serum with a voltammetric Li-selective electrode in a flowthrough system was demonstrated [64], Lithium salts such as lithium carbonate have been extensively used for treatment of manic depressive and hyperthyroidism disorders. The therapeutic range of Li concentration is generally accepted to be 0.5-1.5mM in blood serum. The authors used normal pulse voltammetry in which a stripping potential was applied between pulses in order to renew the membrane surface and expel all of the extracted ions from the membrane, similar to galvanostatically controlled potentiometric sensors described above. Unfortunately, the insufficient selectivity... 

Lithium is commonly used for bipolar affective disorders. Lithium however has a narrow therapeutic index and high risk for toxicity (Groleau 1994). The use of loop diuretics or ACE-inhibitors significantly increases the risk of hospitalisation for lithium toxicity in the elderly (Juurlink et al. 2004). Treatment of elderly patients with lithium should be thoroughly monitored. 

Lithium, while not required for life, is used therapeutically in the form of lithium carbonate for the treatment of manic depression although its mechanism of action remains a mystery. Effective treatment requires attaining serum lithium concentrations of between 0.8 and 1.2 mmol/L. 

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