Dosing of lithium
Dose-response relationships of lithium and other proposed mood-stabilizing agents have not been investigated extensively. Most studies have considered the daily minimum or trough serum levels of lithium (ca. 12 hrs after the last dose), which were introduced initially to provide protection from overdosing with this agent of very low therapeutic index (only about 3-fold ratio of toxic to therapeutic levels). Levels of about 0.50-1.25 mEq/L cover the therapeutic range; levels below 0.5 mEq/L are less effective, while levels above 1.0 mEq/L probably provide limited additional benefit but increase side effects and are best reserved for acute mania, rapid cycling, or treatment-resistant cases. Tolerability and compliance may be enhanced by long-term use of relatively moderate doses of lithium (providing levels at 0.6–0.8 mEq/L), as is standard in European clinical practice. Based on animal experimentation and limited and inconsistent clinical data, it has been suggested that once or twice daily dosing with ordinary lithium carbonate may reduce renal side effects, particularly polyuria and nocturia, and increase compliance; however, in view of the narrow margin of safety of his agent, and the risk of CNS intoxication with high peak plasma concentrations (which can be at least 2-3x trough levels), especially in elderly patients, and the limited risk of significant, irreversible, nephrotoxicity of lithium, as well as trivial average reductions in 24-hour urine volumes, once-daily dosing is not recommended as a routine practice. Sustained-release lithium carbonate may limit CNS intoxication risks but can increase GI distress. Many patients are now reluctant to accept lithium treatment owing to popular views of its alleged toxicity or lack of efficacy, as well as issues of stigmatization and denial of illness. Moreover, adherence to long-term lithium treatment is often variable, and requires constant encouragement in order to maximize protective benefits.
Antidepressants
Adverse effects of lithium
Adverse effects of lithium include frequent initial polyuria and thirst and 10%-20% risk of later persistent (but usually reversible), clinically significant diabetes insipidus, associated with elevated circulating levels of antidiuretic hormone (ADH) and unresponsiveness to exogenous synthetic antidiuretic peptides (such as desmopressin). High 24-hr urine volumes (5 L) have been associated with elevated risk of histopathological changes in renal biopsies suggestive of chronic granulomatous, nephron-distorting, inflammation. Nevertheless, irreversible azotemic renal failure due to lithium treatment is rare and is sensitively and simply detected by quarterly or semiannual monitoring of serum creatinine concentrations, watching for gradually rising trends rather than any single abnormal value.
Weight-gain and dermatological disorders (severe acne, worsening of psoriasis, mild alopecia) are common reasons for discontinuing lithium. However, subtle neurological or cognitive effects are among leading reasons to resist or discontinue long-term lithium therapy. These include a high risk of mild resting tremor and impaired handwriting (often responsive to reduced dose or use of propranolol), as well as varying degrees of subjective cognitive impairment, mild mental confusion and even low-grade delirium, which can occur even at trough plasma concentrations in a nominally therapeutic range, particularly in elderly or neurologically impaired patients.
Clinical myxedema is unusual during lithium therapy, diffuse, nontoxic, and non-precancerous goiter can occur, sometimes with a lowering of serum thyroid hormone indices into the low-normal or subnormal range, with elevated TSH as an early harbinger; some clinicians believe that adding supplemental thyroid hormone not only can reduce goiter, but may also contribute to minimizing depression and slowing rapid cycling.
There probably is moderately increased risk of major cardiovascular malformations during the first trimester of pregnancy during lithium use (most commonly, Ebstein’s tricuspid/septal malformations, at 2-5 times above the spontaneous base rate of ca. 1/20,000 live births). Lithium can also induce hypotonia in the newborn, and elimination and tolerance of lithium typically decrease sharply soon after delivery. These risks have strongly encouraged avoiding pregnancy during lithium treatment. Nevertheless, recurrence risks in pregnancy, and especially the neonatal period, are high when lithium is discontinued early in pregnancy (similar to that in nonpregnant women), and particularly rapidly. Sudden discontinuation of lithium (eg, due to pregnancy or other medical contraindications), even in patients who have been euthymic for several years, carries a high risk of early relapse which can be minimized by slowly tapered dosing (over at least one month). While mood-stabilizing anticonvulsants can not be considered safe during pregnancy (mainly owing to spina bifida in >1/100 cases), cautious use of neuroleptics or antidepressants in low-effective doses can be considered when necessary, and ECT is safe and effective in mania or depression during pregnancy. For some high-risk patients, lithium is being used in middle or late pregnancy and the neonatal period to avoid potentially dangerous and life-threatening (suicide, infanticide) recurrences of manic-depressive illness (as many cases of “post-partum psychosis” probably are).
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