Lithium dosing

Lithium reduces the kidney s ability to concentrate urine and may cause a nephrogenic diabetes insipidus with low urine specific gravity and low osmolality polyuria (urine volume greater than 3 L/day). This may be treated with loop diuretics, thiazide diuretics, or triamterene. If a thiazide diuretic is used, lithium doses should be decreased by 50% and lithium and potassium levels monitored. 

Absorption/Disthbution - Lithium is readily absorbed from the Gl tract. Peak serum levels occur in 0.5 to 3 hours and absorption is complete within 8 hours. Onset of action is slow (5 to 14 days). Until the desired therapeutic effect is attained, maintain a steady-state serum level of 0.8 to 1.4 mEq/L, then slowly decrease the lithium dose to a maintenance level. The therapeutic serum level range is from 0.4 to 1 mEq/L. 

Excretion - About 95% of the lithium dose is eliminated by the kidney. 

Nahorski SR, Jenkinson S, Chalhss RA Disruption of phosphoinositide signalling by lithium. Biochem Soc Trans 20 430-434, 1992 Naiman IP, Muniz DE, Stewart RB, et al Practicality of a lithium dosing guide. Am J Psychiatry 138 1369-1371, 1981... 

Possible use of indomethacin, with required lithium dose reduction (320, 321)... 

CNS adverse effects can be the result of toxic serum levels, which may result from accidental or intentional patient ingestion of lithium doses exceeding clinical needs (334). Patients with organic brain impairment are also at increased risk of neurotoxicity. Toxicity may also be caused by reduced clearance of lithium from the body. 

Early in the course of lithium therapy, exacerbations of psoriasis and acneiform eruptions as well as other skin reactions may occur. Possible mechanisms have included lithium s ability to decrease cAMP as well as to increase the number and activity of polymorphonuclear leukocytes. Those with a predisposition to skin disorders are most at risk for this complication, with women more likely than men to experience a dermatological reaction to lithium. These problems may clear spontaneously or may require lithium dose reduction, appropriate dermatological intervention, or lithium discontinuation ( 77). 

Zetin M, Garber D, De Antonio M, et al. Prediction of lithium dose a mathematical alternative to the test-dose method. J Clin Psychiatry 1986 47 175-178. 

Markoff RA, King M Jr. Does lithium dose prediction improve treatment efficiency Prospective evaluation of a mathematical method. J Clin Psychopharmacol 1992 12 305-308. 

Terao T, Okuno K, Okuno T, et al. A simple and more accurate equation to predict daily lithium dose. J Clin Psychopharmacol 1999 19 336-340. 

Cyr M, Guia MA, Laizure SC. Increased lithium dose requirement in a hyperglycemic patient. Ann Pharmacother 2002 36(3) 427-9. 

Lithium is not a drug of abuse or dependence, although when one bipolar alcohol abuser was prevented from drinking, he tried to get a buzz by increasing his lithium dose to the point of toxicity (serum concentration 3.0 mmol/1) (446). The only other suggestion of abuse appeared in 1977 when passing mention to the fairly recent (over the past 2 years or so) abuse of lithium by poly-drug abusers (447). 

The point of this case is that lithium toxicity can occur in a patient who has been taking a stable lithium dose during an episode that can be associated with nausea, vomiting, and diarrhea, which could reduce lithium excretion. 

For the expert, cautious addition of a diuretic (e.g., chlorothiazide 50 mg/day) while reducing lithium dose by 50% and monitoring plasma lithium levels may... 

Kilts CD. The ups and downs of oral lithium dosing. J Clin Psychiatry 1998 59(Suppl 6) 21-6. 

An equation to predict daily lithium dose has been suggested ... 

The polyuria which often accompanies lithium treatment is normally compensated for by drinking water, but when consciousness is impaired severe hypernatremia may develop. When any acute illness (particularly if associated with gastrointestinal symptoms) occurs or when new medication is given, lithium blood levels should be closely monitored, and the lithium dose adjusted. 

Reductions in lithium dose are required several weeks prior to delivery. 

Acutely manic patients require and tolerate higher lithium doses due to an increased lithium clearance. 

There are two stepwise multiple linear regression analyses that have derived a mathematical formula for determining a lithium dose based on a number of dependent variables. 

A patient who had taken amiodarone 400 mg daily for more than a year developed aeute manie depression. He was started on 600 mg of lithium daily [salt unknown], but within 2 weeks he developed elinieal signs of hypothyroidism, whieh were eonfirmed by clinical tests. He made a complete recovery within 3 weeks of stopping amiodarone while continuing lithium. Similarly, another patient rapidly developed hypothyroidism, when taking amiodarone with lithium [dose and salt unknown]. It resolved when the amiodarone was stopped. Both lithium and amiodarone on their own can cause hypothyroidism, (note that amiodarone ean also eause hyperthyroidism). In these two eases the effects appear to have been additive, and very rapid. 

An isolated report describes a diabetic patient receiving insulin who developed hypeiglycaemia when his serum-lithium levels were high, but not when the lithium dose was reduced. Lithium can raise blood glucose levels and in some instances this has been associated with the development of diabetes mellitus, but the association is unclear and there is little or no evidence that its use normally causes significant changes in diabetic controL... 

There seems to be no reason for avoiding concurrent use, but the outcome should be well monitored. Some have recommended that a reduction in the lithium dose should be considered, especially in patients maintained at relatively high serum-lithium levels. Patients taking lithium should be aware of the symptoms of lithium toxicity and told to report them immediately should they occur. This should be reinforced when they are given metronidazole. The authors of one of the reports also recommend frequent analysis of creatinine and electrol5fte levels and urine osmolality in order to detect any renal problems in patients on this eombination. ... 

In contrast to these reports, a study in 6 patients found that lithium (dosed to achieve plasma levels of 0.3 to 0.65 mmol/L) and fluvoxamine 100 to 150 mg daily (for between 3 and 23 weeks) was safe and effective, and no adverse interaction of any kind occurred. Another study in 6 depressed patients found that lithium did not affect the pharmacokinetics of fluvoxamine 100 mg daily and combined use was more effective than fluvoxamine alone. It would seem therefore that concurrent use can be valuable, but there is a clear need to monitor the outcome so that any problems can be quickly identified. 

A woman stable on lithium for several years developed marked psychosis and parkinsonism within a week of starting to take diltiazem 30 mg three times daily. An acute parkinsonism syndrome developed in a 58-year-old man within 4 days of adding 30 mg of diltiazem three times daily to his treatment with lithium and tiotixene. However, this report has been questioned as the symptoms may have been attributable to an adverse effect of the tiotixene, and, even if the lithium toxicity was genuine, it is thought to have been more likely due to recent increases in the lithium dose, or the patient s diuretic therapy than diltiazem. ... 

In a study of patients with essential hypertension, two doses of nifedipine 20 mg did not affect single-dose lithium clearance, but nifedipine 40 to 80 mg daily for 6 and 12 weeks was found to decrease single-dose lithium clearance by 30%.A man, on lithium carbonate 1.5 g daily with a level of 0.8 mmol/L, developed ataxia and dysarthria 7 days after starting nifedipine 30 mg daily for 48 hours, then 60 mg daily. His lithium dose was reduced by 40%, but his serum-lithium level first increased to 1.1 mmol/L (about 2 weeks after starting the nifedipine), before restabilising at 0.9 mmol/L. In contrast, a patient taking lithium, who developed dysarthria and ataxia after verapamil was added to her treatment (see fcj below), was subsequently well controlled on lithium and nifedipine 40 mg daily... 

Concurrent use under controlled conditions has been advocated for certain psychiatric conditions and for the control of lithium-induced nephrogenic diabetes insipidus. A successful case is described above. It has been suggested that a 40 to 70% reduction in the lithium dose would be needed with doses of 0.5 to 1 g of chlorothiazide, but it would seem sensible to base any dose adjustments on individual lithium levels. 

HimmeDioch IM, Poust RI, Mallinger AG, Hanin I, Neil JF. Adjustment of lithium dose during lithium-chlorothiazide therapy. Clin Pharmacol Ther (1977) 22, 225-7. 

A 47-year-old woman recently started on lithium was found to have blood-lithium levels of 0.4 mmol/L five days after an increment in her lithium dose and whilst also taking one teaspoonful ofispaghula husk twice daily. The ispaghula husk was stopped 3 days later and lithium levels measur 4 days later were found to be 0.76 mmol/L. ... 

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