Effect of cyclobenzaprine on tricyclic antidepressant assays

OBJECTIVE: To evaluate cyclobenzaprine interference on tricyclic antidepressant assays. DATA SOURCES: Literature was identified through a MEDLINE search (1966-August 2004) using the search terms cyclobenzaprine, tricyclic antidepressant, toxicology, and assay. DATA SYNTHESIS: Cyclobenzaprine is structurally similar to tricyclic antidepressants and is often identified as a tricyclic antidepressant on toxicology assays. Older chromatographic assays demonstrate retention time differences of only seconds and nearly identical color stains between cyclobenzaprine and individual tricyclic antidepressants. In comparison, ultraviolet absorption ratios of 4.18 for amitriptyline and 1.85 for cyclobenzaprine are easily distinguished. Spectroscopy also consistently identifies cyclobenzaprine's unique mass-to-charge ratio peaks of 275 and 215 compared with those of amitriptyline. Available bioanalytic techniques are reviewed for their ability to correctly identify cyclobenzaprine and differentiate the drug from tricyclic antidepressants. CONCLUSIONS: When assays are positive for tricyclic antidepressants without a history of their use, an attempt should be made to identify confounders, such as cyclobenzaprine. Newer bioanalytic techniques, such as ultraviolet absorption and mass spectroscopy, accurately identify cyclobenzaprine in such instances.     

Issues in methodology and applications for therapeutic monitoring of antidepressant drugs

Measurement of antidepressant drugs in serum provides a useful indicator of optimal dosage and can enable the clinician, in certain circumstances, to easily adjust dosages for individual differences in drug metabolism, alterations in the concentration in serum owing to drug interactions, or failure to achieve an adequate concentration in serum because of noncompliance. Practical therapeutic monitoring of antidepressants, however, is still complicated by a lack of suitable reference methodology or established assay-performance criteria and the diversity of analytical techniques. We review here several contemporary methods of analysis for the tricyclic antidepressant drugs--including gas chromatography with a nitrogen-specific detector, HPLC, and immunoassays--that are available for toxicology screening or for quantifying the most widely monitored tricyclic drugs. We also present an overview of current laboratory issues and practical considerations facing those who analyze for antidepressant drugs.     

Compliance during tricyclic antidepressant therapy: pharmacokinetic and analytical issues

Information on steady-state concentrations of parent tricyclic antidepressants (TCAs) and their major metabolites in plasma is useful in ascertaining compliance, for possible pharmacokinetic changes during longer treatment, and for prospective individualized dosing procedures. Adequate response can be maintained when there are relatively small fluctuations in drug concentration from visit to visit, but large fluctuations increase the liklihood of relapses during the acute-treatment phase and recurrences afterwards. Changes in the individualized in dosage regimens complicate measurement of concentrations in plasma at steady state. Longitudinal examinations of concentration/dosage (L/D) values in our three-year imipramine (IMI) maintenance study reveal that patients having large intra-individual fluctuations can be classified as noncompliers, likely to have recurrences. The time course and magnitude of L/D values reflect higher accumulation of both components, IMI and desipramine (DMI), in plasma. Evidently, dose-dependent kinetics lead to higher steady-state concentrations in plasma than previously observed with similar dosages in shorter-term treatment. With amitriptyline (AMI), in a 12-month study, the mean total concentrations of both AMI and nortriptyline (NT) progressively increased, by 22% and 33%, respectively. The pharmacokinetic linearity of AMI and (or) NT, i.e., (L/D)high/(L/D)low, is maintained over much wider dosage and age range than with IMI or DMI. We advocate concurrent use of the L/D method and co-administration of riboflavin for identification of noncompliers. We describe our current experience with various analytical procedures in this regard, concluding that high-performance liquid-chromatographic methods, with appropriate selection among ultraviolet, enhanced fluorescence, and electrochemical detectors for each TCA under specified therapeutic conditions, are most suitable and versatile, having superior analytical parameters. A suitable alternative procedure is gas-chromatography (N/P mode). Although immunoassays (EMIT, radiochemical) are most convenient for toxicological screens, their significant cross reactivities with several phenothiazines and the detection limits, requiring higher concentrations for EMIT, restrict their usage during research and (or) clinical monitoring.     

Measurement of antidepressants by liquid chromatography: a review of current methodology

Antidepressant measurement by liquid chromatography (LC) has enhanced the therapy of patients who are being treated with some of the first generation tricyclic antidepressants; the merits of routinely monitoring the other antidepressants await further study. Currently, the role of LC is changing from dominant to complementary as a result of the recent availability of monoclonal antibody immunoassays with increased specificity. For successful application of LC, considerations would include designing the sampling protocol and matching assay that together are uniquely suitable for a particular laboratory. The assay should be simple, the sample preparation manual (liquid-liquid, solid-phase extraction columns), semi-automated, or automated. Normal- or reversed-phase columns with functionalities such as C-18, CN, C-8, and phenyl are used. Other useful LC variables include particle size, capping, ion-pairing, and recycling. This survey of LC methods includes the first and second generations, and new antidepressants such as alprazolam, amoxapine, bupropion, maprotiline, trazodone, and selected metabolites. Potential chromatographic interference by (e.g.) benzodiazepines and neuroleptics is addressed, followed by proposed guidelines for their resolution. Future developments are discussed.     

Monitoring tricyclic antidepressant plasma levels

Patients receiving tricyclic antidepressants exhibit extreme variability in steady-state plasma concentrations because of differences in metabolism. At routine dosages, rapid metabolizers may have suboptimal concentrations while slow metabolizers can suffer from adverse effects due to inappropriately high concentrations. Neither may benefit from the drug therapy. Through analysis of plasma levels of tricyclic antidepressants, an optimal therapeutic response can be achieved, and the risk of serious side effects can be reduced.     

Urine drug screening: practical guide for clinicians

Drug testing, commonly used in health care, workplace, and criminal settings, has become widespread during the past decade. Urine drug screens have been the most common method for analysis because of ease of sampling. The simplicity of use and access to rapid results have increased demand for and use of immunoassays; however, these assays are not perfect. False-positive results of immunoassays can lead to serious medical or social consequences if results are not confirmed by secondary analysis, such as gas chromatography-mass spectrometry. The Department of Health and Human Services' guidelines for the workplace require testing for the following 5 substances: amphetamines, cannabinoids, cocaine, opiates, and phencyclidine. This article discusses potential false-positive results and false-negative results that occur with immunoassays of these substances and with alcohol, benzodiazepines, and tricyclic antidepressants. Other pitfalls, such as adulteration, substitution, and dilution of urine samples, are discussed. Pragmatic concepts summarized in this article should minimize the potential risks of misinterpreting urine drug screens.     

Tricyclic antidepressant poisoning

Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies.     

A critical review of selected pharmacoeconomic analyses of antidepressant therapy

OBJECTIVE: To evaluate the pharmacoeconomic benefits of treating depression and compare the available therapies by reviewing the current literature on economic analyses of depression. DATA SOURCES: A MEDLINE search (January 1966-June 1998) of English-language literature relating to economic analyses of depression was conducted. Key search terms included depression, antidepressant, economics, pharmacoeconomics, outcomes, and costs. Additional literature was collected from reference lists of articles found through the MEDLINE search. STUDY SELECTION AND DATA EXTRACTION: A MEDLINE search was performed using the above key words. Search and evaluation were limited to pharmacoeconomic evaluations of major depressive disorder. All available studies were considered for inclusion in the review. DATA SYNTHESIS: The advent of newer, brand-name antidepressants as well as increased concern regarding healthcare costs has raised interest in the costs associated with treating depression. Although the selective serotonin-reuptake inhibitors (SSRIs) and other newer antidepressants have higher acquisition costs, both modeling and naturalistic studies have shown that the total cost of treating depression is no higher with SSRIs than with the tricyclic antidepressants. These differences are primarily due to increased patient adherence with the newer agents and lower costs secondary to physician visits, laboratory monitoring, and hospitalization. CONCLUSIONS: The economic aspects of treating depression are becoming more frequently evaluated as newer antidepressant medications become available and as healthcare entities attempt to address increasing costs. In general, most pharmacoeconomic research on depression has been conducted on one of the SSRIs in comparison with various tricyclic antidepressants. These studies frequently use simulation techniques and rely heavily on data from clinical trials. Few studies have compared the newer antidepressants, and no clear evidence exists that any one of these agents is more cost-effective than others. Even fewer studies have addressed the pharmacoeconomics of medication management of depression in various healthcare environments (e.g., public mental health care vs. private psychiatry vs. primary care).     

Tricyclic antidepressant overdose at Westmead and Mount Druitt Hospitals

Tricyclic antidepressants are frequently taken in overdose and may be lethal. In this study, over nearly four years, there was only one death from tricyclic antidepressant overdose at the Westmead Hospital, that patient being transferred comatose and probably brain-dead after a cardiac arrest at another hospital. The pharmacology of tricyclic antidepressants is reviewed and recommendations are made for the treatment of overdose.     

Therapeutic drug monitoring of non-tricyclic antidepressant drugs.

Therapeutic drug monitoring (TDM) of many of the tricyclic antidepressants (TCAs) has been demonstrated to be of clear clinical value. This article reviews studies of TDM for the selective serotonin reuptake inhibitors (SSRIs) and other non-tricyclic antidepressants such as venlafaxine, nefazodone, trazodone, mianserin and bupropion. No definitive therapeutic concentrations have been demonstrated for these agents, nor have levels indicative of toxicity been reported. The major benefit of TDM for these agents would appear to be in the assessment of the apparently treatment-refractory depressed patient, to determine whether such lack of response is related to inadequate levels that would suggest either poor compliance, ultra-rapid metabolism, or drug interactions leading to induction of metabolising enzymes. Potential future applications of TDM, in conjunction with genotyping of cytochrome P450 enzymes and pharmacogenomic evaluations, are discussed.     

Myoclonus caused by a tricyclic antidepressant

I have reported a case of myoclonus induced by nortriptyline. Serum nortriptyline levels were measured in an attempt to find whether there was any correlation between serum level and onset of myoclonus. There is clearly a need for scientific research in the neuropharmacologic features of myoclonus caused by tricyclic antidepressants, as well as possible methods of treatment.     

Invited review: the evolution of antidepressant mechanisms

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.     

Tricyclic antidepressant overdose: a review

Overdoses of tricyclic antidepressants are among the commonest causes of drug poisoning seen in accident and emergency departments. This review discusses the pharmacokinetics, clinical presentation and treatment of tricyclic overdose.     

Quetiapine cross-reactivity with plasma tricyclic antidepressant immunoassays

BACKGROUND: Toxicology screens obtained on patients who have overdosed on drugs frequently include tricyclic antidepressants (TCAs) as part of the evaluation. Quetiapine is an antipsychotic agent with structural similarity to the TCAs. OBJECTIVE: To determine whether quetiapine may cross-react with plasma TCA immunoassays in vitro using commonly available autoanalyzers. METHODS: Quetiapine stock solution was added to 9 separate samples of pooled drug-free human plasma to produce concentrations ranging from 1 to 640 ng/mL that were verified by gas chromatography. No quetiapine metabolites were present. Each spiked plasma sample was tested in a blinded fashion using the Abbott Tricyclic Antidepressant TDx Assay on the TDxFLx autoanalyzer in 2 separate laboratories, the Syva Emit tox Serum Tricyclic Antidepressant Assay on the AU400 autoanalyzer and the S TAD Serum Tricyclic Antidepressant Screen on the ACA-Star 300 autoanalyzer. The TDx assay is quantitative, while Emit and S TAD are qualitative screening assays with a threshold of 300 ng/mL for TCA positivity. The outcome of interest was a positive TCA result. RESULTS: The quantitative assay showed concentration-related TCA cross-reactivity beginning at quetiapine concentrations of 5 ng/mL. The 640-ng/mL spiked sample produced TCA results of 379 and 385 ng/mL in labs 1 and 2, respectively. The qualitative assays were screened as TCA positive at quetiapine concentrations of 160 and 320 ng/mL for the S TAD and Emit assays, respectively. CONCLUSIONS: Quetiapine cross-reacts with quantitative and qualitative plasma TCA immunoassays in a concentration-dependent fashion. Therapeutic use or overdose of quetiapine may result in a false-positive TCA immunoassay result.     

Tricyclic antidepressants and histamine H1 receptors.

Tricyclic antidepressants and some structurally related compounds were tested for their ability to antagonize histamine H1 and muscarinic acetylcholine receptors of cultured mouse neuroblastoma cells. As a group, tertiary amine tricyclic antidepressants tended to be more potent than secondary amine drugs at both receptors. The most potent antihistamine, doxepin hydrocholoride, was about 4 times more potent than amitriptyline hydrochloride, about 800 times more potent than diphenhydramine hydrochloride, and about 8,000 times more potent than desipramine hydrochloride, the least potent tricyclic antidepressant at both the histamine H1 and the muscarinic acetylcholine receptors. All tricyclic drugs except desipramine hydrochloride were more potent as antihistamines than as anticholinergics. Doxepin hydrochloride and amitriptyline hydrochloride may be the most potent antihistamines known, and the antihistaminic potencies of these and the other tricyclic antidepressant drugs may relate directly to their ability to cause sedation and drowsiness in patients.     

Tricyclic antidepressant and cardiovascular drug interactions.

Tricyclic antidepressants have anticholinergic, adrenolytic and quinidine-like activity. These actions result in a variety of cardiac and blood pressure effects. Tricyclic antidepressants can reverse the antihypertensive effect of guanethidine and clonidine. Orthostatic hypotension may be increased with diuretics and hydralazine. Myocardial depression may occur with lidocaine, phenytoin or propranolol. Dangerous additive effects may result from concomitant use of a tricyclic antidepressant and either quinidine or procainamide.     

Criteria for admitting patients with tricyclic antidepressant overdose

Several investigators have recently developed guidelines for determining which patients with tricyclic antidepressant overdose should be hospitalized. The width of the QRS complex on the ECG and several clinical parameters have been proposed to identify patients at risk for major complications. To validate these, we developed an algorithm and then applied it to 45 patients who had overdosed on tricyclic antidepressants. This algorithm correctly predicted which patients required admission, whether due to present or impending complications, and which patients could have been discharged without morbidity or mortality. We conclude that use of the modified algorithm can identify patients with tricyclic antidepressant overdose who can be safely discharged from the emergency department.     

Studies on the effects of antidepressant drugs on the antinociceptive action of morphine and on plasma morphine in rat and man

In the rat we studied the effect of 3 tricyclic antidepressants: chlorimipramine, amitriptyline and nortriptyline, and the atypical antidepressant trazodone on pain thresholds when administered alone or together with morphine. Moreover, we evaluated the effect of the antidepressants on free morphine plasma concentrations both in the rat and in man. We observed that chlorimipramine and amitriptyline, two tricyclic antidepressants active on the serotoninergic system, induce analgesia and potentiate morphine analgesia in a dose-related fashion. The noradrenergic tricyclic nortriptyline and trazodone did not elicit analgesia and inconsistently affected morphine analgesia. In the rat, all drugs tested increased plasma concentrations of morphine with the exception of amitriptyline. In man, only chlorimipramine and amitriptyline increased the plasma concentration of the free opiate.     

Sodium Channel Blockade May Contribute to the Analgesic Efficacy of Antidepressants

Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel–blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na_V1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 μmol/L for amitriptyline to 11.6 μmol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na_V1.7. Moreover, IC₅₀s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC₅₀s for Na_V1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants.PerspectiveTricyclic antidepressants are often considered first-line treatment for neuropathic pain. Some tricyclic antidepressants block sodium channels, which may contribute to their antihyperalgesic efficacy. In the current study, we compared the potency of peripheral sodium channel blockade for several tricyclic antidepressants and selective serotonin reuptake inhibitors with their therapeutic efficacy.