Lithium carbonate. Lithium is used for control of the manic phase of manic-depressive psychiatric illness. Peak levels are reached in 1-3 hours, and plasma half-life (in young adults) is about 24 hours (range, 8-35 hours). Time to steady state is about 5 days (range, 2-7 days). Most excretion is through the kidneys, where there is both excretion and reabsorption. Excretion is decreased (tending to increase half-life and blood levels) with poor renal function and also with sodium deficiency. Methyldopa also tends to delay lithium excretion. More rapid excretion occurs with salt loading or sodium retention. Interesting side effects are reversible hypothyroidism (about 5% of cases, with some thyroid-stimulating hormone elevation in up to 30% of cases) and neutrophilic leukocytosis. TDM assays are usually performed 12 hours after the last dose (before administration of the next dose). The usual laboratory method is flame photometry, although other methods are becoming available. The therapeutic range is somewhat narrow (approximately 0.5-1.5 mEq/L). Values higher than 2.0 mEq/L are usually considered to be in the toxic range. Maintenance therapy is customarily monitored once a month. Some interest has been shown in red blood cell (RBC) lithium analysis, especially when lack of patient compliance is suspected. RBC lithium levels are more stable over periods of time than serum lithium levels due to the relatively short half-life of serum lithium. Low RBC lithium levels in the presence of normal or elevated serum lithium levels suggest that the patient is noncompliant but took a lithium dose shortly before coming to have the specimen drawn.

Tricyclic antidepressants. The group name of these medications refers to their three-ring structure. They are widely used to treat unipolar psychiatric depression (i.e., depression without a manic phase). About 70% of these patients show some improvement. The tricyclics are thought to act through blocking one of the deactivation pathways of norepinephrine and serotonin at the brain nerve endings, thereby increasing the availability of these neurotransmitter agents in the synapse area. The different drugs differ in their effect on norepinephrine, serotonin, or both. Currently, the most commonly used tricyclics are imipramine (Tofranil), amitriptyline (Elavil), protrypyline (Vivactil), and doxepin (Sinequan). Of these, imipramine is metabolized to desipramine, and amitriptyline is metabolized to nortriptyline; in both cases the metabolites have pharmacologic activity and are actually marketed themselves under different trade names. Doxepin is also metabolized to the active compound desmethyldoxepin. If these parent compounds are assayed, their major metabolite must also be assayed as well as the parent. Other tricyclics are available, and still others are being introduced.

Oral doses are fairly completely absorbed from the GI tract. Once absorbed, there is 70%-96% binding to plasma proteins and considerable first-pass metabolism in the liver. By 6-8 days 60%-85% of the dose is excreted in the urine in the form of metabolites. Peak serum levels are generally attained 2-6 hours (range, 2-8 hours) after an oral dose. There is variation in peak level depending on the drug formula. There is considerable variation in metabolism between individuals, with variation fivefold to tenfold in steady-state levels being common and sometimes differences reported as great as thirtyfold. The half-life averages 20-30 hours (range, 15-93 hours), and steady state is reached on the average in about 7-10 days (range, 2-19 days). Imipramine has a somewhat shorter half-life (6-24 hours) and time to steady state (about 2-5 days) than the other tricyclics. However, there is variation between the various drugs and between individuals taking the same drug. It is reported that 30% or more patients have serum assay values outside the standard therapeutic range. African Americans may reach higher steady-state serum levels than Europeans.

Currently, high-performance liquid chromatography (HPLC) is considered the best assay method. Immunoassay (EMIT method) is also used but is not as specific. For example, thioridizine (Melloril) and possibly other phenothiazines may produce a reaction in the EMIT tricyclic test. When tricyclics are given once daily, TDM specimens are usually drawn 10-14 hours after the last dose (if the dose is given at bedtime, the specimen is drawn in the morning about 12 hours later). If the patient is on divided doses, the specimen should be drawn 4-6 hours after the last dose (this usually means that the specimen is drawn just before the next dose). The literature warns that some collection tube stoppers contain interfering substances and that certain serum separation devices using gels or filtration also might interfere. It is obviously necessary to select a collection and processing method that is known to be safe. Serum should be refrigerated rather than frozen. Quality control studies have shown variation within laboratories and between laboratories that is greater than the level of variation for routine chemistry tests.