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Tianeptine (7-[([3-chloro-6,11]-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl) amino] heptanoic acid S, S dioxide) is a tricyclic compound prescribed as an antidepressant in European countries, but is not currently approved for use in the United States. There are few published case reports of tianeptine intoxication. Presented is the first case of acute toxicity associated with the intravenous use of tianeptine. A 36-year-old male intentionally injected tianeptine powder intravenously to "help him see into the future". He became unresponsive and a bystander called emergency medical services. Upon arrival to the Emergency Department, excessive constriction of the pupils, sedation, and a respiratory rate of 6 respirations per minute (rpm) were noted. Blood and urine were collected ~2 h post admission. The patient's serum ethanol concentration was 133 mg/dL. His toxicity was successfully reversed with two doses of naloxone 0.4 mg IV. He was started on a naloxone infusion at 0.2 mg/h and discharged 13 h after admittance awake, alert and oriented. The patient's urine sample screened negative for common drugs of abuse and total tricyclic antidepressants. A high performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify tianeptine in urine. The calibration range was 1-100 ng/mL with linear regression correlation (r2) of 0.9996 or greater. The limit of quantitation was administratively set at 1 ng/mL. The bias of the assay was determined to be within ±20% of the target value for each quality control specimen. The intra-day and inter-day precision did not exceed 15% coefficient of variation for each quality control specimen. Matrix effects, absolute recovery, carryover and specificity were also evaluated. The patient's tianeptine urine concentration was determined to be 2 ng/mL., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Variability in imipramine and desipramine metabolism was evaluated using urinary excretion data from patients with pain. Liquid chromatography-tandem mass spectrometry was used to quantitate concentrations in urine specimens. Interpatient population contained 600 unique imipramine specimens, whereas intrapatient population had 137 patients with two or more specimens. Normal concentration ranges of imipramine, desipramine and the desipramine/imipramine metabolic ratio (MR) were established, and various factors were tested for MR impact. Geometric mean of imipramine urine concentration was 0.46 mg/g of creatinine, and desipramine was 0.67 mg/g of creatinine. Gender, concomitant known CYP2C19 inhibitor use and urine pH did not affect MR. However, proton-pump inhibitor (PPI) users had a significantly lower mean MR than those without a listed PPI. Early age group (18-36 years) had a significantly higher mean MR than middle (37-66 years) and late (67-90 years) age groups. Approximately one-third were positive for one or more of hydrocodone, oxycodone, hydromorphone or oxymorphone. Patients with no opioids reported in the medication list had a significantly lower geometric mean MR than those with prescribed opioids (1.03 vs. 1.54, P = 0.004). Patients with only one prescribed opioid had a lower MR than those with two or more prescribed opioids. Patients with younger age, prescribed opioids and no listed PPI were more likely to have a higher geometric mean urinary desipramine/imipramine MR., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A method for the simultaneous determination of six commonly prescribed cyclic antidepressants and their major metabolites in urine is presented. This method can be used for quantitation of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, desmethyldoxepin, and maprotiline in human urine, in addition to the qualitative determination of their hydroxylated metabolites. This method is suitable for confirmation of drug abuse in health care professionals and overdose cases where the identity of the abused cyclic antidepressant may not be known. Samples are spiked with internal standard and hydrolyzed with beta-glucuronidase from Escherichia coli. Hydrolysis is found to be essential to the extraction procedure as the tertiary cyclic antidepressants are found to be extensively conjugated in urine. The secondary cyclic antidepressants, on the contrary, are found to be minimally conjugated. Drugs are extracted from alkalinized urine into solvent and derivatized with MSTFA/ammonium iodide/ethanethiol reagent. This reagent produces more stable derivatives compared to reagents previously employed. Gas chromatographic (GC)-mass spectrometric analysis is performed in electron ionization mode by selective ion monitoring, using hydrogen as a carrier gas, a short narrow bore GC capillary column, and fast temperature program, allowing for a rapid analytical cycle. While maintaining specificity for these drugs, concentrations in human urine ranging from 50 to 20,000 ng/mL can be measured with intraday and interday precisions, expressed as variation coefficient, of less than 2.8% for all analytes.

Patients taking tricyclic antidepressants (TCA) can experience toxicity or severe side effects. As a rapid and less technically demanding alternative to quantitative serum analysis, most laboratories offer qualitative immunoassays to assist in the evaluation of a suspected TCA overdose. However, the relationship between quantitative serum and qualitative urine levels of TCA-related compounds and their metabolites has not been comprehensively studied. Serum high-performance liquid chromatography results were compared to the qualitative urine results using the Syva Rapid Test and the Biosite Triage. Serum concentrations of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline ranging from subtherapeutic to toxic triggered a positive response on both urine immunoassay devices. On the other hand, neither immunoassay uniformly detected clomipramine, even at serum levels greater than the therapeutic range. False positives due to cyclobenzaprine were more common with the Biosite assay. For virtually all positive urine TCA findings, it was not possible to determine whether the positive results corresponded to subtherapeutic, therapeutic, supratherapeutic, or toxic serum concentrations. Because urine immunoassays are the only option for many laboratories analyzing specimens for TCAs (especially in an emergency setting), clinicians must understand the limitations and interpret results in conjunction with clinical findings and/or quantitation of serum levels.

Improvements have been made in recent years in on-site or point-of-care (POC) immunoassay testing devices. We evaluated the DrugCheck 9 cup, a new qualitative visually read, competitive binding, immunoassay cup that measures nine analytes. The study was performed according to the recent National Laboratory Certification Program (NLCP) guidelines for validating a laboratory-based immunoassay. The study included a linearity challenge with 5 replicates at concentrations 0, 25%, 50%, 75%, 100%, 125%, and 150% of the cutoff and also determination of the limit of detection. Interference (specificity) studies were included to evaluate the cross-reactivity of common structural analogues or others purported to interfere with the assay. The ability to differentiate positive and negative samples was evaluated by positive and negative quality control specimens and also parallel comparisons of laboratory verified positive and negative donor specimens previously analyzed by immunoassay and gas chromatography-mass spectrometry. The results indicated a high degree of correlation (97.6%) with the laboratory immunoassay and a high degree of specificity and sensitivity with extended linearity below the cutoff.

In six cases of suspected opipramol overdose, commercially available immunoassays for tricyclic antidepressants (TCA) EMIT tox serum Assay and ADxR serum TCA Assay indicated arbitrarily high or toxic TCA concentrations. However, opipramol concentrations determined by high-performance liquid chromatography (HPLC) analysis were in the high-normal or low-toxic range. This finding prompted us to study opipramol metabolism by mass spectral techniques and to determine the cross-reactivity of opipramol and its metabolites in immunoassays. Three previously unknown metabolites (I, II, V) included an oxidation product of the hydroxyethyl moiety to an acetic acid group at the piperazine side chain (1), a decarboxylation product of the latter metabolite (II), and opipramol-N-oxide (V). In addition, two previously reported metabolites were identified, which included a deshydroxyethyl metabolite (III) and dibenzazepine (IV). One of the major metabolites of opipramol is the acetic acid metabolite (I), which may exceed the opipramol plasma concentration immensely and contribute to an arbitrarily high concentration in commercially available immunoassays. The cross-reactivities of the metabolite (I) were determined to be 64 and 66% with EMIT and ADx, respectively.

Human urine was tested for tricyclic antidepressants with fluorescence polarization immunoassay (FPIA) reagents on Abbott's ADx system and with EIA reagents on Syva's ETS system. A 75-ng/mL imipramine calibrator cutoff was used with the ADx system and a 300-ng/mL nortriptyline calibrator cutoff with the ETS system. The ETS system was adapted to analyze tricyclic antidepressant (TCA) samples using the Syva Emittox serum TCA assay. Negative urine was spiked with various tricyclic and tetracyclic antidepressants, phenothiazines, and other medications with potential to interfere with the assays. Verification of samples was performed by thin-layer chromatography and gas chromatography/mass spectrometry. The different compounds were added to urine at concentrations of 200, 400 and 1,000 ng/mL. At 1,000 ng/mL all TCA compounds tested gave positive results with the ADx and ETS systems. However, some non-TCA medications spiked at 1,000 ng/mL gave false positive results with both systems. The tetracyclic antidepressants did not cross-react and gave negative results. Clomipramine-spiked urine at 400 ng/mL yielded a false negative result on the ETS system.

The EMITtox serum tricyclic antidepressant (TCA) assay is intended for use with serum or plasma. Currently, there are no commercially available immunoassay kits available for the detection of TCAs in urine. The proposed method utilizes the EMITtox serum TCA assay for the direct analysis of urine samples. The minimum detectable concentration of nortriptyline in urine is 25 ng/mL. The within-run CV was determined to be 0.6% and the between-run CV was 2.6%. The TCA assay cross-reacts with phenothiazines and antihistamines. The proposed methodology should be applicable to other EMIT serum assays to allow their use with urine.

Blood, urine, heart, liver, and psoas muscle concentrations of tricyclic antidepressant (TCA) drugs and their N-desmethyl metabolites were determined in forty medical examiner cases. The cases were evaluated for the role played by the TCA drugs in the cause of death and compared to a literature survey of previously reported cases. The incidence of the various individual TCA drugs as a factor and the significance of the disposition of the drugs and their metabolites is included. Comparing TCA drug concentrations in the heart and skeletal muscle and considering the differences in perfusion to these organs, TCA drugs and metabolites showed an affinity for the cardiac over the skeletal muscle. The case results were correlated with experimental studies to suggest the relationships of blood concentrations with toxicity.