Predictors of lithium prophylaxis effectiveness
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Lithium carbonate
Comparative experimental study of the known antimanic drug lithium carbonate and the original compound lithium oxybutyrate that possesses a neurotropic activity similar to that of lithium carbonate has shown lithium oxybutyrate to elicit a more prolonged and more pronounced central depressant action, and a significantly less toxicity. Lithium oxybutyrate is well soluble that makes it possible to use it as injections required for rapid arrest of manic conditions.
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Lithium carbonate is the treatment of choice in the prevention of recurrences of bipolar mood disorders. The aim of this study is the evaluation of the pharmacokinetics of a new lithium compound to be administered "once a day", with a half-life of 32.4 hours. The present study investigates plasma lithium levels in patients treated with the novel vs. standard preparation of lithium carbonate to assess whether the new preparation may be associated with lithium plasma accumulation. The authors studied twenty-two bipolar patients whose standard lithium treatment was replaced by the new one. The total duration of the new treatment was 57 days. During this period, lithium plasma levels were monitored 7 times, 12 hours post-lithium administration. Lithium plasma level 24 hours following administration was evaluated in seven patients. The average dose of "once a day" lithium was 821 (+/- 250) mg/day, the corresponding plasma level was 0.45 (+/- 0.11) mEq/L, and the dose (g) to plasma level ratio was 1.96 (+/- 0.66). Differences between average lithium plasma levels at time T1 and successive times were not statistically significantly. Moreover, the average lithium level at 12 hours after lithium administration was not different from that after 24 hours (0.45 +/- 0.11 and 0.47 +/- 0.0.29 respectively). These results demonstrate that the new preparation, "once a day", maintains steady lithium plasma levels during our times of observation without accumulation in body fluids and tissues. "Once a day" lithium carbonate appears to be a useful alternative to the standard preparation, and may potentially improve treatment compliance by simplifying patients' medication.
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The need for a practical screening test to predict whether or not an individual patient will benefit from lithium carbonate therapy grows more urgent with each claim for lithium's use. Serry has suggested that the “Lithium Excretion Test” (LET) (measurement of the amount of lithium excreted in the urine over the 4 hours after a 1200-mg loading dose of lithium) answers this need; he reported that patients who are “lithium retainers” responded to lithium therapy and that “lithium excretors” did not. In a study of a mixed group of 52 subjects, we found that lithium excretion during the LET did not, predict subsequent response to lithium therapy. The LET is therefore useless as a screening test since it would exclude many patients who would benefit from lithium therapy. Our results also differed markedly from Serry's in that lithium excretion in this population fell into a normal distribution with very few “retainers” according to his criteria. It is suggested that the high percentage of “retainers” which he found may be an artifact due to delayed absorption of the lithium carbonate preparation which he administered. The rate of absorption will need to be monitored and controlled in future studies of short-term lithium balance.
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Twenty-one patients with recurrent endogenous depressions were treated with lithium carbonate for periods up to two and a half years. Although depressions did not recur in six of eight patients with non-periodic disorders who were on lithium, the treatment did not reduce the frequency of exacerbation in eleven of thirteen periodic disorders. Urinary measurements of sodium, potassium 17-ketosteroids, hydroxy-steroids and lithium in several of the patients did not help to differentiate them by their reaction to lithium. It is concluded that the notion of lithium as an effective prophylactic agent against recurrent depressions, based on decreased frequency or increased interval between episodes, is not supported by this study.
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Chronic neurotoxicity caused by lithium salts can be reversible or irreversible and may appear after years of treatment, even at serum levels considered within the usual therapeutic range. The authors present the case of a patient with bipolar disorder who developed dementia at the age of 54 after being treated with lithium carbonate at therapeutic levels for 4 years. Nevertheless, lithium treatment was continued. At age 56, the patient presented with an acute encephalopathy caused by toxic lithium levels, which resolved only after lithium carbonate was discontinued. Full recovery from the dementia, which had started 2 years earlier, occurred only after cessation of lithium. The authors conclude that when patients treated with lithium develop subacute cognitive impairment, the possibility of lithium toxicity should be considered, even if the serum levels are considered within the therapeutic range. A long duration of neurotoxicity associated with lithium treatment does not necessarily indicate an irreversible prognosis. (Journal of Psychiatric Practice 2015;21:154–159)
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In the beginning of 1960s, initial reports appeared pointing to a possibility of preventing depressive and manic recurrences in affective illness by means of long-term administration of lithium salts. Subsequent several years of controlled studies confirmed such prophylactic effect of lithium in affective illness beyond any doubt. Some patients in whom lithium administration was started in the beginning of 1970s may, by now, have received lithium for more than twenty years. The patient reported in the present paper, had began lithium treatment on April 1, 1971, after her third depressive episode since 1965. During 25 years of uninterrupted lithium carbonate administration in daily dose 1000 mg (for 5 years-750 mg) and with mean serum lithium concentration 0.6 mmol/l, the recurrences have not been observed, mental status was normal and professional (physician-ophthalmologist) and family functioning was good. Either somatic or mental side-effects have not occurred. Twenty five years of the patient's lithium treatment, was paralleled by important events for lithium therapy such as, i.a., autobiographies of prominent persons receiving lithium for porphylactic purposes, definition of a new category of psychotropic drugs (normothymic) with lithium as a prototype, establishing some mechanism of lithium action on intracellular transmission, discovery of antiviral and immunomodulatory effect of lithium as well as finding of decreased mortality of patients receiving long-term lithium therapy.
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57% of a group of 35 patients treated with Lithium Carbonate at dosages predicted by the nomogram suggested by Cooper et al (1973) failed to reach therapeutic levels of serum lithium. This finding casts serious doubts on the usefulness of the claim by Cooper et al (1973 & 1976) that 24 hour serum lithium level after a test dose of 600 mg. lithium can predict the daily lithium dose.
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In a cross‐over study in 10 subjects, rapidly dissolving coated lithium carbonate tablets and medium‐slow‐release lithium sulphate tablets were compared. Both preparations were administered twice a day. They gave similar post‐absorptive concentrations of lithium in plasma and similar standard deviations of these concentrations. The medium‐slow‐release tablets gave smaller increases of lithium in plasma, and postponed the absorption peaks. They also gave less interindividual variation of lithium in plasma during the first few hours after administration.
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