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Standards of laboratory practice: antidepressant drug monitoring.

Depression is a common and major psychiatric disorder affecting as many as 20% of individuals within their lifetime and occurring almost twice as frequently in women as in men (1, 2). The diagnosis of major depression can be defined as persistently depressed mood and markedly diminished interest or pleasure in all or most activities for at least 2 weeks in combination with at least three of the following symptoms: significant change in weight or appetite, sleep disturbances, feeling or being restless or very slowed down, fatigue, feelings of worthlessness, inability to concentrate and make decisions, and recurrent thoughts of death or suicide (3).

A wide variety of pharmaceuticals are available for treating depression, including tricyclic antidepressants (TCAs) [3], atypical antidepressants, monoamine oxidase inhibitors, selective serotonin-reuptake inhibitors, and lithium. A list of antidepressant medications is included in Table 1. Although clearly defined therapeutic ranges have not been established for the majority of antidepressant medications, therapeutic drug monitoring for certain TCAs and lithium has been well documented to improve the use of these agents for therapeutic management of depression or mood stabilization and has become the "standard of care" in psychiatry. The relationship between TCA dose and antidepressant response is poorly delineated, in part because of the wide range of inter-individual variability in metabolism and elimination. Fewer than 40-50% of patients treated with standard doses of TCAs will achieve optimal plasma concentrations. The antidepressant response to therapy with TCAs and lithium is improved two- to three-fold with the application of appropriate therapeutic drug monitoring (4). Improved response rates translate into improved safety and cost-effectiveness of antidepressant therapy (5). The poor dose-response relationship and narrow therapeutic index of the TCAs and lithium make these drugs excellent candidates for improved therapeutic efficacy through therapeutic drug monitoring. As a result of intensive work illustrating the benefits of therapeutic drug monitoring (TDM) of antidepressant medications, the American Psychiatric Association task force on the use of laboratory tests in psychiatry recommended the clinical use of monitoring plasma concentrations of the TCAs imipramine, desipramine, and nortriptyline (6). Therapeutic monitoring of amitriptyline is also accepted, based in part on its metabolism to nortriptyline. Additionally, evidence for plasma concentration vs response relationships for doxepin (7), clomipramine (8, 9), and bupropion (10,11) has been reported. Therapeutic ranges for the antidepressants maprotiline, amoxapine, trazodone, and alprazolam have also been suggested (7,12). However, no general consensus has been achieved.

This document will focus on standards of laboratory practice for those antidepressants for which a clearly defined therapeutic range is established (Tables 2-4). However, monitoring the blood concentration of other antidepressants may be of value in establishing compliance, monitoring the effects of drug-drug interactions on steady-state blood concentrations, and establishing for future reference the target concentrations attained in patients during periods of successful therapy.

TCAs and Lithium

TCAs contain a characteristic three-ringed nucleus structure that is the basis for the name of this group of drugs. In addition to the treatment of various forms of depression, TCAs also have efficacy in the treatment of anxiety disorders, eating disorders, attention deficit hyperactivity disorder, and enuresis in children and as an adjunct to analgesics for certain chronic and neuropathic pain syndromes. Clomipramine has been shown to be superior to other antidepressants in the treatment of obsessive compulsive disorder (13), although its therapeutic range in this disorder appears to be somewhat higher than the range recommended for treating depression (14). Lithium, an alkali metal, is classified as a thymoleptic or mood-stabilizing drug along with carbamazepine and valproic acid. Lithium is indicated for the management of acute manic episodes and bipolar disorder, in addition to depression. This document will address TDM of lithium in addition to the antidepressants. Guidelines for TDM of carbamazepine and valproic acid can be found in the antiepileptic drug section of this report. The therapeutic applications of the TCAs and lithium are outlined in Table 2.

The pharmacological basis for the antidepressant effects of the TCAs and lithium is not completely understood. Acute administration of TCAs produces increased synaptic concentrations of neurotransmitters, including serotonin, norepinephrine, and (or) dopamine, in the central nervous system. However, whereas neurotransmitter concentrations are increased immediately, resolution of depressive symptoms often requires 4 to 6 weeks of chronic TCA dosing. Chronic TCA administration has generally been associated with a decrease in ([beta]-adrenergic and serotonin type 2 receptor density (15,16) and functional changes in neuronal second-messenger systems, specifically a decrease in norepinephrine-stimulated cAMP production (2,17). The correlation between these delayed effects and the typical time course of antidepressant response implicates their involvement in the mechanism of therapeutic response. However, the precise mechanisms of antidepressant response remain to be elucidated (18).

The adverse pharmacological effects of TCAs largely occur through blockade of cholinergic, histaminic, and [[alpha].sub.1]-adrenergic receptors. Anticholinergic activity of TCAs produces dry mouth, blurred vision, constipation, urinary retention, and decreased sweating. In addition, TCAs and their metabolites produce adverse effects by acting directly on cardiac tissue and eliciting effects similar to class IA antiarrhythmics. In patients with preexisting abnormalities in cardiac conduction, TCA-induced prolongation of cardiac conduction can increase the risk of developing atrioventricular heart block (19) (Table 2).

Although lithium shares many of the physiochemical properties of sodium, potassium, calcium, and magnesium, its mechanism of action does not appear to involve partial substitution of lithium for these physiological cations. Consistent with the dysregulation hypothesis of depression, lithium may augment homeostasis by enhancing the function of a secondary system, e.g., cAMP and cGMP second-messenger systems (20). Lithium-dependent uncoupling of external cell surface receptors from the cyclase enzyme complex (21-23) may alter cation transport across the cell membrane in nerve and muscle cells and influence the reuptake of synaptic neurotransmitters. This mechanism may also be linked to the polyuria and hypothyroidism associated with lithium use (6,24) (Table 2).

Indications for Monitoring

In general, therapeutic monitoring of the TCAs and lithium is instrumental in the evaluation of compliance, potential for toxicity, and effects of drug-drug interactions on steady-state concentrations and in verifying therapeutic concentrations or establishing individual target concentrations in patients who are responding well to therapy.


TDM of the TCAs and lithium should be initiated once steady-state is achieved. The TCAs may display a wide range of half-lives across patients; however, the mean half-life for the TCAs is ~24 h. Thus, in most cases, steady-state is achieved after ~5 days of continual dosing. For routine monitoring, samples should be collected during the terminal elimination phase, 1-14 h after the last dose for once-daily dosing and 4-6 h after the last dose for divided daily dosing (25). Imipramine, amitriptyline, clomipramine, and doxepin are tertiary amines. Monodemethylation of the tertiary amines yields the respective secondary amines desipramine, nortriptyline, desmethylclomipramine, and desmethyldoxepin. When patients are treated with the tertiary amines, the secondary amine metabolites should be measured as well, given their substantial contribution to pharmacological activity. The secondary amines desipramine and nortriptyline have slightly different receptor affinities (26) and, in many instances, are used as the primary therapeutic agent to diminish side effects associated with treatment with the tertiary amines. The secondary amine TCAs are further metabolized to hydroxy metabolites, which are monitored only in specific cases of renal impairment, where these metabolites may be contributing to toxicity. Appropriate specimen type, specimen stability, and drug metabolites to monitor for the TCAs are outlined in Table 3.


The currently recognized standard draw time for lithium serum concentrations is at least 10 to 12 h after the evening dose on a twice-daily dosing regime. Concentrations measured before 10 to 12 h postdose may still be in the absorption and distribution phases (27). Lithium dosage adjustments should be based on serum concentrations determined on a biweekly or weekly basis until a serum concentration of 0.4-1.5 mmol/L is obtained (28, 29). Once steady-state concentrations and symptom remission are achieved, the lithium concentration should be monitored every 1 to 3 months (30).

In addition to serum and plasma concentration, several reports have advocated the clinical utility of lithium determinations in erythrocytes (RBCs) and the RBC/ plasma ratio as a better indicator of therapeutic response and potential for neurotoxicity (31). However, due in part to wide inter- and intraindividual variations (32, 33), the clinical use of RBC lithium concentrations has not become routine. Appropriate specimens for lithium monitoring and specimen storage requirements are outlined in Table 3.

Reporting Issues

Therapeutic ranges for the TCAs and for lithium have been determined through multiple clinical studies and years of experience (1, 34) and are listed in Table 4 along with important pharmacokinetic parameters. The therapeutic range for nortriptyline is 50-150 [micro]g/L (35, 36). In patients treated with amitriptyline, the therapeutic range for amitriptyline plus nortriptyline is 120-250 [micro]g/L (37-39). Desipramine (40,41) has a therapeutic threshold of 115 [micro]g/L and an upper limit of efficacy of ~250 [micro]g/L. The lower limit of the therapeutic range in patients treated with imipramine is a combined plasma concentration of imipramine and desipramine of 180 [micro]g/L; the upper limit is in the range of 350 [micro]g/L. The therapeutic response to doxepin is best associated with the serum concentrations of doxepin and its desmethyl metabolite. Combined concentrations of doxepin plus desmethyldoxepin between 150 and 250 [micro]g/L appear to be associated with optimal antidepressant response (7). Although not as well characterized, a therapeutic range for antidepressant response to clomipramine is a combined concentration of clomipramine plus desmethylclomipramine of 160-400 [micro]g/L (42). In addition, clomipramine has been demonstrated to be superior to other antidepressants in treating obsessive compulsive disorder (43). Plasma concentrations producing antiobsessional effects tend to be higher than typically required for antidepressant response (13). Studies investigating the plasma concentration-response relationship for bupropion demonstrate antidepressant response when plasma bupropion concentrations are between 25 and 100 [micro]g/L (44). In addition, nonresponse and toxicity have been associated with plasma hydroxybupropion concentrations exceeding 1200 [micro]g/L (45).

Toxicity of TCAs is primarily anticholinergic and cardiovascular. An increased incidence of anticholinergic adverse effects is associated with plasma TCA concentrations >500 [micro]g/L and may be experienced at lower plasma TCA concentrations (46). Lethal cardiotoxicity has been associated with plasma TCA concentrations >1000 [micro]g/L and a QRS duration of >100 ms (47, 48). The generally accepted therapeutic range of lithium is 0.4-1.5 mmol/L. However, this range depends on both the stage of therapy and the patient population. Acute management of manic episodes tend to require steady-state lithium concentrations in the upper end of the therapeutic range (e.g., 0.8-1.5 mmol/L), whereas maintenance therapy may be achieved with lower steady-state concentrations (e.g., 0.6-1.2 mmol/L) (49). Toxic effects of lithium, which begin at concentrations of 1.5 mmol/L or more (50), include fine tremors of the limbs, gastrointestinal disturbances, muscle weakness, and fatigue and, less commonly, confusion, agitation, memory impairment, delirium, increased deep tendon reflexes, and seizures (51, 52). Lithium concentrations >2.5 mmol/L are associated with severe toxicity, including coarse tremors, delirium, basal ganglia dysfunction, seizures, coma, respiratory complication, and death (53). Toxicity in chronic lithium therapy may be more severe and may occur at lower lithium concentrations (54).

In addition to TDM, other laboratory tests are useful for monitoring therapy with the TCAs and lithium. In overdose, the TCAs can cause life-threatening cardiotoxicity. The most sensitive indicator of potential cardiotoxicity is a prolonged QRS interval >100 ms. In addition to electrocardiograph and ongoing cardiac monitoring, ancillary monitoring of the complete blood count, blood pressure, and heart rate is indicated in patients treated with TCAs (55). The physiological and toxic effects of lithium require monitoring electrocardiograms, fluid status, serum electrolytes, thyroid status, serum creatinine, and renal function when toxicity is suspected or when serum concentrations exceed 1.5 mmol/L (56).

TDM of Antidepressants in Specific Patient Groups


An increased need for TDM of the TCAs is indicated for specific populations such as the elderly, children, and adolescents and other patients in whom pharmacokinetic parameters may be considerably different from those for the average individual or may be changing as a consequence of maturation or disease (57). One basis for dramatic interindividual differences in the pharmacokinetics of TCAs is variation in the activity or expression of the principal hepatic enzyme involved in the metabolism of these drugs (cytochrome P4502D6/debrisoquine hydroxylase). Germline genetic variations in the structural gene CYP2D6, including single and multiple basepair variants, CYP2D6 gene deletion, and amplification, give rise to discrete drug metabolism phenotypes. Subjects with more than one inactive CYP2D6 allele (i.e., including basepair variants and gene deletion) demonstrate a poor metabolizer phenotype and will develop greater plasma TCA concentrations than will extensive metabolizers when treated with standard doses. Between 5-10% of Caucasians and 2-5% of individuals of other ethnic groups are poor metabolizers with regard to CYP2D6 substrates. Individuals with more than two active CYP2D6 alleles demonstrate an ultraextensive metabolizer phenotype, characterized by subtherapeutic plasma TCA concentrations when treated with standard doses. The prevalence of ultraextensive metabolizers among Caucasians is ~7%. Taken together, as many as 17% of Caucasian subjects will require individualization in TCA dosage because of genetic variation in CYP2D6 alone. Cytochrome P4502D6 drug metabolism phenotype may be measured directly through administration of a test substrate or "probe drug," followed by determination of parent drug-to-metabolite ratios in blood or urine. Alternatively, with recent advances in characterization of the most common variant CYP2D6 alleles, the drug metabolism phenotype can be reliably predicted through rapid genotyping techniques (58) and can provide a cost-effective approach to avoiding toxicity or therapeutic failure (59). However, such methods are currently underutilized in clinical practice.

Pharmacokinetic parameters are also subject to age-related changes. For example, in geriatric patients, decreased metabolic capacity of the liver, decreased hepatic blood flow, and possible changes in the volume of distribution (60) can all contribute to increased TCA blood concentrations under standard dosing conditions. Because not all elderly patients show the same degree of age-related changes, this population displays a high degree of variability (61). In addition, decreased renal clearance of unconjugated hydroxy metabolites can lead to accumulation in situations of chronic dosing and thus contribute to toxicity (6). In children, increased metabolism of TCAs (62) may require divided daily doses rather than once-daily dosing, to minimize the peak-to-trough fluctuations in plasma concentration. Children may also display wide interindividual variation in elimination rates, associated with differing rates of maturation. Children and adolescents may be at risk of sudden death associated with TCA-induced atrioventricular conduction delay. These differences in metabolism and resulting increased risks of severe toxicity increase the need for TDM in children and adolescents to optimize dose titration.

Various disease states are associated with altered pharmacokinetics of antidepressants. Hepatic cirrhosis causes considerable portocaval shunting, leading to increased drug concentrations (63); thus, lowering of the usual dose of TCAs is recommended for patients with significant hepatic dysfunction. Chronic renal failure has little or no effect on disposition of parent compounds and demethylated metabolites. Conjugated and unconjugated hydroxy metabolites, however, can be markedly increased in patients with impaired renal function (64, 65). Monitoring of hydroxy metabolites is not routine and has not been demonstrated to improve the correlation between desired response or toxicity and measured concentrations of parent drug and active metabolite (66). In patients with congestive heart failure or other causes of decreased left ventricular function, decreased cardiac output (resulting in decreased hepatic blood flow) can increase the bioavailability of some TCAs and require dose reduction to maintain therapeutic drug concentrations.


The principal elimination route of lithium is via renal excretion, >95% of a lithium dose being recovered in the urine. In acute renal failure, use of lithium is contraindicated. However, with careful patient selection and frequent laboratory monitoring, lithium therapy may be successful in patients with chronic renal failure (67). Lithium itself is nephrotoxic and can lead to a reduction of its own renal elimination, producing increased serum lithium concentrations. Renal excretion of lithium tends to be increased in children, and therefore, higher doses per body weight may be necessary to achieve concentrations similar to those seen in adults (68). In elderly subjects, alterations in lithium distribution and clearance can lead to increased elimination half-lives and require longer intervals to achieve steady-state. As a result, geriatric patients may require smaller dosages to achieve therapeutic concentrations; the time between dosage adjustments also may need to be longer than in younger patients (69). Lithium is potentially teratogenic during the first trimester and should be used in pregnant women only after careful evaluation of the potential risks and benefits with the patient (70). Lithium clearance also increases during pregnancy because of increased renal blood flow and glomerular filtration rate, so dosages commonly need to be increased in the last trimester of pregnancy to maintain therapeutic lithium plasma concentrations. To adjust for a return to prepregnancy renal elimination of lithium, Shafey has suggested that therapy should be discontinued several days before the anticipated delivery date and then resumed several days postpartum at the prepregnancy dose (71).

Analytical Issues


TCAs. Acceptable specimens for monitoring TCAs are serum or plasma (EDTA) (72). Specimens should be collected 10-14 h after the last dose for once-daily therapy and 4-6 h after the last dose for patients receiving divided doses. Initially, blood collected into heparin-containing tubes was preferred because more plasma than serum could be obtained from the same volume of blood. However, use of heparin tubes has been argued to cause a decrease in the measured plasma drug concentration (73). With the advent of improved sample preparation techniques that allow greater recovery, serum is now the preferred specimen; it allows greater ease of extraction and involves no fibrin clots, which may clog pipet tips or extraction cartridges. The serum concentration of TCAs is stable for 1 week at room temperature (74), up to 4 weeks at 4 [degrees]C, or for >1 year at -20 [degrees]C (75). An exception is bupropion, which is degraded rapidly in specimens stored at temperatures >22 [degrees]C (76) (Table 3). Steady-state TCA concentrations demonstrate modest intrapatient variation, and the imprecision of most assays ([+ or -] 5-10% CV) allows for medically reliable monitoring with single measurements (77).

Because tubes containing a gel for separation of blood cells from serum have been demonstrated to lower the measured blood concentration of TCAs, it is recommended that the use of gel separator tubes be avoided (78). In addition, tris-2-butoxyethylphosphate, once a component of blood-collection tube stoppers, had been shown to decrease measured concentrations of TCAs. Although the interference of this compound from the stoppers has been eliminated, analysts should be cautious when exposing specimens to materials that have not been evaluated for their effects on measured TCA concentrations. Hemolyzed specimens also should be avoided for the determination of serum TCA concentrations because of the potential for variable effects on measured concentrations.

The American Psychiatric Association task force on the use of laboratory tests in psychiatry recommends that the method chosen for TDM of TCAs be specific and capable of measuring the antidepressant drug itself as well as any active metabolites without interference from other metabolites or drugs that may be administered concurrently. The assay of choice must be sufficiently sensitive to measure concentrations as low as 10-20 [micro]g/L in 1- to 2-mL samples. The assay should have an interassay imprecision of 5-10% or less over the therapeutic range and results should be available within 24 h after the specimens are received in the laboratory (55). Methods for quantitative analysis of TCAs include: immunoassay (79), HPLC (80), and gas-liquid chromatography (81, 82). Detailed reviews of these methods have been previously published (83, 84).

For TDM purposes, two immunoassay formats are available, including individual methods for amitriptyline, nortriptyline, imipramine, and desipramine based on the enzyme-multiplied immunoassay technique (Emit) technology, and a "total tricyclics" method based on fluorescence polarization immunoassay (FPIA) technology, which utilizes a polyclonal antibody and is calibrated against imipramine. The Emit (79) assays include a solid-phase sample extraction followed by analysis with monoclonal antibodies directed against amitriptyline and imipramine; for nortriptyline and desipramine, sheep polyclonal antibodies are used. The tertiary amines and their secondary amine metabolites can be measured from the same extract by using the individual assays. These methods have a dynamic range consistent with therapeutic concentrations of the respective drugs and give results that correlate with those by HPLC, the slope of the regression line ranging from 0.94 to 1.04 and the y-intercept ranging from -3.56 to 6.79 mg/L. A shortcoming of these assays is the considerable cross-reactivity of the tertiary and secondary amines. Therapeutic concentrations of imipramine cross-react in the amitriptyine assay, and the converse is also true. Likewise, therapeutic concentrations of desipramine will cross-react in the assay for nortriptyline and vice versa. Many structurally related drugs, including clomipramine, cyclobenzaprine, doxepin, and chlorpromazine also cross-react in more than one of the assays. Thus, although these assays appear to provide accurate results in patients treated with monotherapy, the potential for cross-reactivity dictates that the patient's medication history be considered before these assays are used (83). Emit assays for doxepin, bupropion, and clomipramine are not available.

The FPIA total tricyclics assay (85) was originally designed for toxicology screening and has been subsequently adapted to TDM. An advantage of this assay is that no extraction of the serum samples is involved. In patients' samples, the assay demonstrates a 15-20% negative bias for the estimate of amitriptyline plus nortriptyline and a 35-40% negative bias for the estimate of imipramine plus desipramine, compared with results by gas-liquid chromatography (85). A review of proficiency testing results for 1997 demonstrated a recovery of amitriptyline plus nortriptyline and of imipramine plus desipramine equal to 90%. The difference in accuracy between analyses of patients' samples and analyses of proficiency specimens should be carefully weighed before determining the acceptability of an assay. For analysis of doxepin by the FPIA total tricyclics assay, no significant overall bias was observed for the estimate of doxepin plus metabolites vs HPLC. In individual patient's samples, however, both positive and negative biases as great as 100% may be observed, which could noticeably affect patient care (85). As with the Emit assay, the FPIA is subject to substantial cross-reactivity with multiple antidepressant and neuroleptic drugs, and therefore, a complete medication history must be available for interpretation of results. The inability to determine parent drug-to-metabolite ratios or to assess the presence of more than one drug, in addition to cross-reactivity with drugs highly likely to be coadministered, must be considered when utilizing immunoassay methods for routine TDM.

HPLC with absorbance detection is the most common method for quantitative analysis of TCAs reported on CAP proficiency testing surveys. The majority of reversed-phase methods use [C.sub.8], [C.sub.18], CN, or phenyl columns and permit simultaneous determination of tertiary and secondary amines. These methods are also adaptable to monitoring other antidepressants, e.g., amoxapine, maprotiline, and fluoxetine (83, 84). HPLC methods typically offer detection limits [less than or equal to] 20 [micro]g/L and linearity through [greater than or equal to] 1000 [micro]g/L. Normal-phase chromatography and fluorescence or electrochemical detection methods are also available (86).

Gas-liquid chromatography is another highly sensitive and specific method for the quantitation of TCAs. For gas-liquid chromatographic techniques, the samples are extracted, concentrated, and in some methods derivatized. Derivatization is not absolutely required for all tricyclics; however, it generally improves the chromatographic performance. The most commonly used detection modes are nitrogen-phosphorus and mass spectrometer detectors (84).

Lithium. The recommended specimens for monitoring lithium therapy are serum and plasma (Na-heparin) collected at a standard time from the last dose once steady-state is achieved, preferably 10-12 h. Serum samples for the analysis of lithium are stable for extended periods at 4 [degrees]C and room temperature. However, specimen stability may be method-dependent and should be determined on an individual basis (87). A summary of sample requirements is listed in Table 3. Free drug measurements are not of concern, given the absence of protein binding of lithium. Serum and plasma should be immediately separated from RBCs. Hemolyzed specimens or plasma specimens collected in Li-heparin tubes should be rejected for analysis of lithium; they result in falsely decreased or increased measurements, respectively (88, 89). Analytical methods for quantitation of lithium include flame emission photometry (FEP), atomic absorption spectroscopy (AAS) (90-93), ion-selective electrode (ISE) (94), and colorimetry (95).


TCAs. Multiple therapeutic drugs bear structural similarity to the TCAs and interfere with the analytical measurement. Table 5 includes a list of the most common interferents in various assay formats. For example, immunoassays for the TCAs may give false-positive readings in the presence of commonly used drugs, including diphenhydramine, thioridizine, chlorpromazine, alimenazine, carbamazepine, cyclobenzaprine, and perphenazine (96). In addition, cross-reactivity by TCAs between immunoassays designed to monitor the individual drugs has been demonstrated, leading to cause for concern when monitoring patients treated with more than one TCA at a time or during periods of transition between medications. Multiple analytical interferences are also noted in various HPLC assays for the TCAs; e.g., cyclobenzaprine, a muscle relaxant, and its desmethyl metabolite norcyclobenzaprine may be indistinguishable from imipramine and desipramine (97); methadone and methadone metabolite interfere with the quantitation of nortriptyline and doxepin, respectively; and propoxyphene may interfere with quantitation of amitriptyline in certain HPLC methods (98). Interferences in HPLC and gas-chromatographic techniques depend on the sample preparation, the chemistry of the analytical column, and the mode of detection (83). Therefore, each method should be carefully evaluated for these and other interferences individually. Careful attention to relative retention time limits and use of multichromatic detection techniques are helpful in avoiding misinterpretation of HPLC results (99). The use of a mass spectrometer provides the most specific detection technique for gas-chromatographic analysis (83).

Lithium. Because of their conveniences of automation and testing consolidation, ISEs have become the predominant methodology for measuring serum lithium. However, various drugs, including carbamazepine quinidine, procainamide, N-acetylprocainamide, lidocaine, and valproic acid can introduce a positive bias in lithium determination by ISE (87). Quinidine and procainamide introduce a negative interference with the colorimetric method and an ISE method (100). These interferences are concentration dependent and typically introduce clinically significant error only in combination or at toxic concentrations. Moreover, one ISE method has been shown to be affected by a silicone surfactant clot activator in plastic Vacutainer Tubes, introducing a positive bias in the determination of plasma lithium (101). High calcium concentrations (>8.9 mmol/L) introduce a substantial positive bias in some ISE methods for lithium. Although they require dedicated or partially dedicated equipment, AAS and FEP methods demonstrate the least interferences and excellent precision and accuracy (87).

In Vivo Drug-Drug Interactions


The clearance of TCAs is almost exclusively by hepatic metabolism (102) involving the cytochrome P450 mixed-function monooxygenase system. The major metabolic pathways of TCAs are N-demethylation and ring hydroxylation with subsequent glucuronide conjugation. The major demethylation pathways of the tertiary amines, imipramine and presumably amitriptyline, are catalyzed by P4501A and P4503A isoenzyme systems (103). The major hydroxylation pathways of many TCAs are catalyzed by the cytochrome P4502D6 system. Carbamazepine, phenobarbital, phenytoin, rifampin, and tobacco smoke induce the metabolism of cytochrome P450 substrates in general (104), and this inductive effect can increase the clearance of psychotropic drugs by as much as 10-fold (105). Maximal induction may require more than 2 weeks of therapy with the inducing agent and have a delayed effect on steady-state plasma concentrations (106). Consequently, after the introduction of an enzyme-inducing agent, TCAs should be monitored for about twice the time expected to achieve the maximal induction effect to ensure stabilization of steady-state concentrations. Certain drugs, e.g., haloperidol and quinidine, inhibit cytochrome P4502D6 activity but are not substrates for the enzyme (107, 108).

Combined treatment with TCAs and selective serotonin-reuptake inhibitors may be undertaken in some depressed patients who fail monotherapy. The selective serotonin-reuptake inhibitors fluoxetine (109), paroxetine (110), and sertraline (111, 112) inhibit the metabolism of TCAs and may lead to increases in their plasma concentrations (113). Fluvoxamine inhibits demethylation and not hydroxylation (114) and therefore has a greater effect on the tertiary amines. Other psychotropics that may be coadministered with TCAs also reportedly increase the plasma TCA concentrations, such as alprazolam, methylphenidate (115), and antipsychotics (116). Cimetidine inhibits many cytochrome P450 isoenzymes through interaction with the heme iron complex. This inhibition may increase the bioavailability and plasma drug concentrations of TCAs by as much as twofold (117). Therefore, it is recommended that the TCA dose be lowered when these agents are used concomitantly. Table 6 outlines several pharmacokinetic and pharmacodynamic drug-drug interactions involving the TCAs and lithium.

Pharmacodynamic interactions are also of concern in patients treated with TCA in combination with other medication. Amitriptyline and imipramine may decrease or reverse effects of clonidine and guanethidine and may increase the effects of central nervous system depressants, adrenergic agents, and anticholinergic agents. When TCAs are administered with monoamine oxygenase inhibitors, fever, tachycardia, hypertension, seizures, and death may occur. Use of TCAs in combination with monoamine oxidase inhibitors should generally be avoided (118).

For patients treated with drug combinations, clinicians should be made aware of these interactions and adjust dosages accordingly. Lower doses should be used in the presence of a drug that inhibits TCA metabolism; increased doses may be required to maintain therapeutic drug concentrations in patients treated with a cytochrome P450-inducing agent. We emphasize: TDM becomes increasingly important for monitoring changes in steadystate plasma concentrations of TCAs when interacting drugs are added or deleted from a treatment protocol. The potential for polypharmacy underscores the importance of analytical methods that provide a high degree of specificity in monitoring blood concentrations of TCAs.


As previously mentioned, >95% of lithium elimination occurs through the kidney; as a result, therapeutics that are potentially nephrotoxic or modulate renal function have the greatest effect on blood lithium concentrations. Diuretics that act on the proximal tubule can affect lithium clearance. The sodium and volume depletion induced by thiazide diuretics acting on the distal tubule initiate compensatory mechanisms that increase sodium and lithium reabsorption at the proximal tubule (119). Theophylline enhances the renal elimination of lithium and requires careful monitoring of lithium concentration and dose adjustment when these drugs are combined (120). Nonsteroidal antiinflammatory drugs decrease lithium clearance by decreasing renal blood flow secondary to prostaglandin inhibition (121). Concomitant use of lithium with nonsteroidal antiinflammatory drugs or acetylcholinesterase inhibitors may also decrease renal excretion and enhance lithium toxicity (122). Captopril and ketorolac can cause increases of lithium concentrations.

In addition to pharmacokinetic drug-drug interactions, some medications also influence the pharmacodynamics of lithium. Several phenothiazines, verapamil, and piroxicam can potentiate adverse neurologic effects of lithium. The selective serotonin-reuptake inhibitors fluoxetine (123), sertraline (124), and fluvoxamine (125) can sometimes cause a serotonergic hyperarousal syndrome when taken with lithium, and carbamazepine can exacerbate lithium-induced neurotoxicity (126). Lithium may, in rare instances, increase the severity of extrapyramidal reactions (127) and neurotoxic reactions to antipsychotic agents (128), leading to irreversible brain damage. The incidence of this neurotoxic reaction may be increased with haloperidol (129) (Table 6).

Reporting Issues

Because of the potential for dire consequences of overdose, TCA and lithium concentrations after an overdose should be reported as soon as possible. In suspected overdose, a semi quantitative screen for TCA intoxication or quantitative analysis of lithium should be reported within 1 h. Specific quantitative analysis of TCAs and lithium for therapeutic drug monitoring purposes should be available within 24 h for inpatients. The laboratory personnel should contact the hospital unit to report critical values for inpatients and should contact the treating physician for critical outpatient values. Subtherapeutic values can be handled routinely. Whenever possible, information pertaining to the time of last dose, time of sampling, duration of dosage regimen (i.e., has steady-state been achieved?), and concomitant medications should be included with the overall report to aid in interpretation.

We sincerely appreciate the significant contributions made by the reviewers of this manuscript.

Received September 2, 1997; revision accepted December 4, 1997.


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MARK W. LINDER [1]* and PAUL E. KECK, JR. [2]

[1] Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY 40292.

[2] Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45221.

* Author for correspondence. Fax 502-852-8299; e-mail

[3] Nonstandard abbreviations: TCA, tricyclic antidepressant; TDM, therapeutic drug monitoring; RBC, erythrocyte; Emit, enzyme-multiplied immunoassay technique; FPIA, fluorescence polarization immunoassay; FEP, flame emission photometry; AAS, atomic absorbance spectrometry; and ISE, ion-selective electrode.
Table 1. Drugs used for treatment of depression.

Tricyclic antidepressants


Selective serotonin-reuptake inhibitors

Fluvoxam ine

Monoamine oxidase inhibitors





Table 2. Antidepressant drugs that are typically monitored:
general information.

Drug Conditions treated

Amitriptyline Various forms of depression, (a)
 including A, D, D, I, and N.
Clomipramine Depression, obsessive compulsive
Bupropion Depression

Lithium Acute manic episodes, bipolar

Drug Most common side effects

Amitriptyline Anticholinergic: dry mouth, constipation

Clomipramine Urinary retention, blurred vision, sinus
 tachycardia, and cognitive dysfunction
Bupropion Agitation, dry mouth, constipation, tremor,
 insomnia, and nausea
Lithium Sedation, lethargy, dysarthria, polyuria,

Drug Major toxic effects

Amitriptyline Cardiac conduction, prolonged
 QRS duration
Clomipramine Seizures, cardiac conduction,
 prolonged QRS duration
Bupropion Seizures

Lithium Coarse tremors, seizures

(a) In addition to depression, the drugs listed are used to treat
anxiety disorders, eating disorders, attention deficit
hyperactivity disorder, and enuresis in children and as an
analgesic for certain chronic neuropathic pain.

Table 3. Samples for therapeutic monitoring.

Drug Sample timing

TCAs and At SS (a): 10-14 h after the
 bupropion last dose in once-daily dosing;
 4-6 h after the last dose for
 divided daily dosing

Lithium 6-12 h after last dose

Drug Sample type

TCAs and Serum or plasma (EDTA)
 bupropion Avoid stoppers containing TBEP or
 materials not tested for potential
 interfering substances
 Separate from cellular components
 as soon as possible
 Avoid gel tubes or other devices
 for separation of serum or
 plasma from cellular
 Specimens should be free of
Lithium Serum or plasma (Na-heparin);
 avoid Li-heparin tubes

Drug Sample stability Metabolite monitoring

TCAs and 24 h at RT; 4 wks at 4 Secondary amine metabolites,
 bupropion [degrees]C; >1 yr at -20 10-hydroxy-bupropion
 Bupropion degrades rapidly
 in specimens stored at
 >22 [degrees]C

Lithium Extended periods at all None
 storage temperatures

(a) SS, steady-state; TBEP, tris-2-butoxyethylphosphate; and RT, room

Table 4. Pharmacokinetic information.

 Days to [V.sub.d],
Drug Half-life, h steady-state L/kg

Amitriptyline 9-46 3-8 8-36
Bupropion 14 2-5 27-63
Clomipramine 20-30 4-6 7-20
Desipramine 12-28 3-6 24-60
Doxepin 8-36 2-8 15-20
Nortriptyline 18-56 4-11 15-23
Imipramine 6-28 2-5 9-23
Lithium 8-24 4-6 0.7-1

 Protein Therapeutic range, concentration,
Drug binding, % [micro] g/L [micro] g/L

Amitriptyline >90 120-250 (a) >500
Bupropion 75-90 20-100 >1200 (b)
Clomipramine >90 160-400 (a,c) >500
Desipramine >90 115-250 >500
Doxepin >80 150-250 (a) >500
Nortriptyline >90 50-150 >500
Imipramine 80-90 180-350 (a) >500
Lithium None 0.6-1.2 (d) >1.5 (d)

(a) Ranges include the concentration of parent drug and active
desmethyl metabolite.

(b) Ranges include 10-hydroxy-bupropion.

(c) Ranges tend to be higher for the treatment of obsessive compulsive

(d) mmol/L.

SS, steady-state.

Table 5. Analytical issues in monitoring.

 Analytical precision
Drug required (CV, %)

TCAs [+ or -] 10

Lithium [+ or -] 5

Drug Analytical interferences Comments

TCAs Immunoassays:
 Alimenazine, General interferents in
 diphenhydramine, doxepin, immunoassays
 perfenazine, thioridizine

 Amitriptyline and Emit assays for imipramine
 nortriptyline and desipramine, respectively
 Imipramine and desipramine Emit assays for amitriptyline
 and nortriptyline,
 Cyclobenzaprine Interferes with desipramine
 Methadone Interferes with nortriptyline
 Methadone metabolite Interferes with doxepin
 Propoxyphene Interferes with amitriptyline
Lithium ISE:
 Carbamazepine, Introduce a positive bias at
 N-acetylprocainamide, high concentrations
 procainamide, quinidine
 Quinidine, procainamide Introduce a negative bias
 Calcium Introduce a positive bias
 Silicone surfactant clot Introduce a positive bias
 Quinidine, procainamide Introduce a negative bias

Table 6. In vivo drug interferences.

Drug Interacting drug Mechanism of action

TCAs Pharmacokinetic
 Carbamazepine, Induce metabolism of TCAs
 phenytoin, rifampin,
 tobacco smoke
 SSRIs, (a) Inhibit metabolism of TCAs
 cimetidine, quinidine,
 Amitriptyline and Decrease or reverse effects
 imipramine of clonidine and
 guanethidine; increase
 effects of CNS depressants;
 increase effects of
 adrenergic and
 anticholinergic agents
 Monoamine oxidase Effects on serotonin result
 inhibitors in fever, tachycardia,
 hypertension, seizures, and
Lithium Pharmacokinetic
 Thiazide diuretics Increased reabsorption in
 the proximal tubule
 NSAIDs Reduced renal elimination
 Theophylline Increased renal elimination
 Phenothiazines, Potentiate adverse neurologic
 verapamil, piroxicam effects of lithium
 Fluoxetine, fluvoxamine, Induce a serotonergic
 sertraline hyperarousal syndrome
 Carbamazepine Exacerbate lithium neurotoxicity
 Lithium Increase severity of
 extrapyridimal reactions
 and neurotoxic reactions to
 antipsychotic agents, e.g.,

(a) SSRI, selective serotonin-reuptake inhibitor; CNS, central
nervous system; and NSAIDs, nonsteroidal antiinflammatory drugs.
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Title Annotation:NACB Symposium
Author:Linder, Mark W.; Keck Jr., Paul E.
Publication:Clinical Chemistry
Date:May 1, 1998
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