(Clinical Chemistry. 1998;44:1073-1084.)
© 1998 American Association for Clinical Chemistry, Inc.
Standards of laboratory practice: antidepressant drug monitoring
Mark W. Linder1,a,
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.
a Author for correspondence. Fax 502-852-8299; e-mail mwlind01{at}homer.louisville.edu.
 |
Abstract
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Therapeutic drug monitoring (TDM) for certain tricyclic antidepressants
(TCAs) and lithium is supported on the basis of clearly defined
therapeutic ranges. TDM is of particular importance in individuals
whose pharmacokinetic behavior may differ from that of the general
population or is changing as the result of aging and maturation. Once
steady-state drug concentrations are achieved, serum or plasma
specimens should be collected during the terminal drug-elimination
phase and separated from cellular blood components immediately. Methods
of analysis must be specific for parent drug and active metabolites and
demonstrate imprecision (CVs) within 5–10% over the therapeutic
range. For support of overdose situations, semiquantitative values for
TCAs and quantitative measures of lithium should be available within
1 h, and routine TDM results should be reported within 24 h
of receipt in the laboratory. Standardized and rigorous laboratory
practices contribute to improved therapeutic
management.
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Introduction
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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)1
, 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 interindividual 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.
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TCAs and Lithium
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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 ß-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
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)(22)(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
).
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Indications for Monitoring
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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.
tcas
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
.
lithium
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
.
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Reporting Issues
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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 µg/L
(35)(36). In patients treated with
amitriptyline, the therapeutic range for amitriptyline plus
nortriptyline is 120–250 µg/L (37)(38)(39). Desipramine
(40)(41) has a therapeutic
threshold of 115 µg/L and an upper limit of efficacy of ~250
µg/L. The lower limit of the therapeutic range in patients treated
with imipramine is a combined plasma concentration of imipramine and
desipramine of 180 µg/L; the upper limit is in the range of 350
µg/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
µg/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 µg/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 µg/L (44). In addition, nonresponse and
toxicity have been associated with plasma hydroxybupropion
concentrations exceeding 1200 µg/L (45).
Toxicity of TCAs is primarily anticholinergic and cardiovascular. An
increased incidence of anticholinergic adverse effects is associated
with plasma TCA concentrations >500 µg/L and may be experienced at
lower plasma TCA concentrations (46). Lethal cardiotoxicity
has been associated with plasma TCA concentrations >1000 µg/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).
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TDM of Antidepressants in Specific Patient Groups
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tcas
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.
lithium
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).
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Analytical Issues
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methods and samples
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 °C, or for >1
year at -20 °C (75). An exception is bupropion, which is
degraded rapidly in specimens stored at temperatures >22 °C
(76) (Table 3
). Steady-state TCA concentrations
demonstrate modest intrapatient variation, and the imprecision of most
assays (±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 µg/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 C8,
C18, 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 
20 µg/L and linearity through
1000 µg/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 °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)(91)(92)(93),
ion-selective electrode (ISE) (94), and colorimetry
(95).
analytical interferences
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).
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In Vivo Drug–Drug Interactions
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tcas
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 in-hibits 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 steady-state 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.
lithium
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 semiquantitative 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.
|
Acknowledgments
|
|---|
We sincerely appreciate the significant contributions made by the
reviewers of this manuscript.
|
Footnotes
|
|---|
1 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. 
|
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Abstract
Introduction
