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Human mental disorders can be currently classified as one of the most relevant health topics. Including in this are depression and anxiety, which can affect us at any stage of life, causing economic and social problems. The treatments involve cognitive psychotherapy, and mainly the oral intake of pharmaceutical antidepressants. Therefore, the development of analytical methods for monitoring the levels of these drugs in biological fluids is critical. Considering the current demand for sensitive and automated analytical methods, the coupling between liquid chromatography and mass spectrometry, combined with suitable sample preparation, becomes a useful way to improve the analytical results even more. Herein we present an automated multidimensional method based on high-performance liquid chromatography-tandem mass spectrometry using a lab-made, graphene-based capillary extraction column connected to a C8 analytical column to determined five pharmaceutical drugs in urine. A method enhancement was performed by considering the chromatographic separation and the variables of the loading phase, loading time, loading flow, and injection volume. Under optimized conditions, the study reports good linearity with R 2 > 0.98, and limits of detection in the range of 0.5-20 µg L -1 . Afterward, the method was applied to the direct analysis of ten untreated urine samples, reporting traces of citalopram in one of them. The results suggest that the proposed approach could be a promising alternative that provides direct and fully automated analysis of pharmaceutical drugs in complex biological matrices.

This article describes a method for the modification of paper with single-wall carbon nanohorns (SWCNHs) to form stable suprastructures. The SWCNHs form stable dahlia-like aggregates in solution that are then self-assembled into superior structures if the solvent is evaporated. Dipping paper sections into a dispersion of SWCNHs leads to the formation of a thin film that can be used for microextraction purposes. The coated paper can be easily handled with a simple pipette tip, paving the way for disposable extraction units. As a proof of concept, the extraction of antidepressants from urine and their determination by direct infusion mass spectrometry is studied. Limits of detection (LODs) were 10 ng/L for desipramine, amitriptyline, and mianserin, while the precision, expressed as a relative standard deviation, was 7.2%, 7.3%, and 9.8%, respectively.

Tranylcypromine is an effective antidepressant from the class of monoamine oxidase inhibitors and is structurally related to amphetamine. However, reports differ regarding the potential metabolism of tranylcypromine to amphetamine and methamphetamine within the human body. We report a 25-year-old woman with severe depression who died due to a fatal tranylcypromine overdose in 2016. She had been prescribed tranylcypromine one day previously and had no history of previous suicide attempts or substance abuse. The body was transferred to a forensic medicine department in Tehran, Iran for the autopsy. A urine sample was positive for tranylcypromine, amphetamine and methamphetamine using gas chromatography/mass spectrometry after derivatisation with heptafluorobutyric acid. As amphetamines were present in the urine sample, it was assumed that the tranylcypromine had been converted to amphetamines metabolically. As such, it is possible that the legitimate use of certain prescription drugs may complicate the interpretation of test results for illegal drugs.

High-resolution mass spectrometry (HRMS) has gained recognition as a valuable tool for comprehensive drug screening in a variety of biological matrices. HRMS instruments collect untargeted, accurate mass data, which permit identification of known and unknown compounds in a single analytical run. One of the most challenging aspects of implementing an HRMS drug screen is establishing appropriate data analysis parameters for identifying compounds. Unlike other types of mass spectrometry data, guidelines for HRMS data analysis and acceptability criteria have not been established. Although many laboratories have published on the utility of HRMS for drug screening, few have included details on how they determined allowable errors and set positivity criteria. Previously, we developed and validated a comprehensive 169-compound drug screen on a high-resolution quadrupole time of flight mass spectrometer. Here we report the detailed procedure that we used to determine appropriate positivity criteria for our screening procedure. Our approach was empirical; we collected data and analyzed it with commonly available software. We found that a combined scoring approach using a threshold of 70, with 70% weight given to library match and 10% weight given to each of mass error, retention time error and isotope pattern difference provided optimum drug identification efficiency of 99.2%. Our results demonstrate the importance of library matching in accurately identifying compounds, and underscore the utility of robust product ion spectra that contain information on the lineage, mass and relative abundance of fragments. The method we describe is easily adaptable to include alternative parameters that may be available in software associated with a variety of HRMS platforms. With careful selection of error limits and positivity criteria, HRMS instruments are capable of producing high-quality, high-confidence results that may reduce the need for confirmatory testing., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This paper reports, for the first time, the development of a modified Quick, Easy, Cheap Effective, Rugged and Safe (QuEChERS) combined with a dispersive SPE (d-SPE) based clean-up procedure as a new and powerful strategy for the simultaneous and efficient isolation of two different antidepressants, fluoxetine and clomipramine, and their active metabolites in human urine samples. A univariate experimental design with four independent variables such as sample volume, extraction solvent, buffered salts and clean-up step, was performed and used to investigate the effect of process variables on the extraction efficiency. Good linearity was achieved at the studied concentration range (0.1-5.0 µg mL -1 ), with correlation coefficients (R 2 ) higher than 0.9961. Low detection limits, ranging between 0.060 and 0.092 μg mL -1 were obtained for all analytes, whereas the lowest quantification limit was 0.1 μg mL -1 , corresponding to the lowest concentration of the standard curve. The method also showed good results for accuracy, with values ranging from 91% to 105%. Intra- and inter-day precision, expressed as the relative standard deviation (RSD), were also satisfactory (<10%). Consistent recoveries of antidepressants ranging from 86% to 109% were observed when urine samples were fortified at three concentrations, namely 0.1, 2.5 and 5.0 μg mL -1 In order to evaluate the proposed method for clinical use, the QuEChERS/UHPLC-PDA method was applied to analysis of 12 urine samples from depressed patients., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Patients on opioid replacement therapy (ORT) to treat opioid use disorder are frequently monitored for these medications, but it is not known if they are also adhering to their psychotropic medications. This is an analysis of measure of potential adherence to psychotropic medications by patients on ORT., Methods: This is a retrospective cohort study of patients (n=1470) on antidepressants and/or antipsychotics and tested by the Millennium Health laboratory. Potential adherence to psychotropic medications was measured by urine drug test (UDT) results. The consistency of UDT for expected psychotropic medication in patients on ORT was compared to patients not on ORT (control group) during 3-months period. The study used propensity score methods to match individuals from both groups on their demographics and their psychotropic medication., Results: There were 457 participants (31.09%) on ORT and 1013 participants (68.91%) in the control group. Only 55.33% of UDTs (n=1388) were consistent for expected psychotropic medications in the ORT group compared to 73.69% of UDTs (n=4953) consistent for expected psychotropic medications in the control group (χ 2 =172.99, p<0.001). After matching, patients in the ORT group were less likely than the control group to have consistent UDTs for expected psychotropic medications (OR: 0.81, 95% CI: 0.76-0.85, P<0.001)., Conclusion: There is a high rate of inconsistent UDT for prescribed psychotropic medication among patients on ORT. This could reflect potential poor adherence. Monitoring adherence to psychotropic medications should be part of every clinical visit for patients on ORT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A hollow fiber solid-phase microextraction method for pre-concentration of venlafaxine and o-desmethylvenlafaxine in biological matrices is described for the first time. The functionalized MWCNTs with an amino acid, glycine, were synthesized and held in the pore of a hollow fiber by sol-gel technique. In order to extract venlafaxine and o-desmethylvenlafaxine from real samples, the hollow fiber was immersed into the sample solution under a magnetic stirring for 20 min. The extracted venlafaxine and o-desmethylvenlafaxine from the fibers were then desorbed with methanol by sonication and analyzed using high-performance liquid chromatography. Important microextraction parameters including pH of donor phase, donor phase volume, stirring rate, extraction time, and desorption conditions such as the type and volume of solvents and desorption time were thoroughly investigated and optimized. The optimized technique provides good repeatability (RSD of the intraday precision 3.7 and 3.4, interday precision of 5.8 and 5.4 %), linearity of (0.1-300 and 0.2-360 ng mL(-1)), low LODs of (0.03 and 0.07 ng mL(-1)), and high enrichment factor of (164 and 176) for venlafaxine and o-desmethylvenlafaxine, respectively. The analytical performance of Gly-MWCNTs as a new SPME sorbent was compared with MWCNTs and carboxylic MWCNTs. The results indicate that Gly-MWCNTs are quite effective for extraction of venlafaxine and o-desmethylvenlafaxine. Feasibility of the method was evaluated by analyzing human urine and real water samples. The results obtained in this work show a promising, simple, selective, and sensitive sample preparation and determination method for biological and water samples.

Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [(14)C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all species. Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.3%, 7.5%, and 5.6%, respectively. Similar results were seen in monkeys. N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats. Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively. N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.9% of administered dose, respectively). Human and monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively) and N-desethyl levomilnacipran glucuronide (3.2% and 2.3% of administered dose, respectively); these metabolites were not detected in rat urine. The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤ 1.2% of administered dose), and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose). None of the metabolites were pharmacologically active. Levomilnacipran was widely distributed with low plasma protein binding (22%).

Urine drug testing is an important tool that is commonly used to assess patient compliance with prescription regimens. Point-of-collection immunoassay devices allow for timely availability of laboratory test results to guide therapy during the same office visit. Two waived immunoassay-based urine drug screen cups were evaluated in this study. The NexScreen cup and the DrugCheck Waive RT cup claim to detect 10-12 drug classes of commonly used and/or abused drugs. This study included a sensitivity and precision challenge with 4-6 replicates at concentrations 0-150% of the manufacture's claimed cutoff, using drug-free urine spiked with purified reference standards. The stability of test results was evaluated by reading the results at intervals between five and 1,440 min. Specificity was evaluated by parallel comparison of pooled patients' specimens, representing 56 patients and 41 known drug compounds. When comparing results to validated liquid chromatography-mass spectrometry results, false positives were observed in the NexScreen cups for benzodiazepine, methamphetamine, methadone, opiates and tricyclic antidepressant tests, but there were no false negatives. The DrugCheck Waive RT cups showed false negative results for barbiturates and opiates, but no false positives. Overall, the NexScreen cup demonstrated better sensitivity than claimed, whereas the sensitivity of the DrugCheck Waive RT cup did not meet claims.

In contrast to GC-MS libraries, currently available LC-MS libraries for toxicological detection contain besides parent drugs only some main metabolites limiting their applicability for urine screening. Therefore, a metabolite-based LC-MS(n) screening procedure was developed and exemplified for antidepressants. The library was built up with MS(2) and MS(3) wideband spectra using an LXQ linear ion trap with electrospray ionization in the positive mode and full-scan information-dependent acquisition. Pure substance spectra were recorded in methanolic solution and metabolite spectra in urine from rats after administration of the corresponding drugs. After identification, the metabolite spectra were added to the library. Various drugs and metabolites could be sufficiently separated. Recovery, process efficiency, matrix effects, and limits of detection for selected drugs were determined using protein precipitation. Automatic data evaluation was performed using ToxID and SmileMS software. The library consists of over 700 parent compounds including 45 antidepressants, over 1,600 metabolites, and artifacts. Protein precipitation led to sufficient results for sample preparation. ToxID and SmileMS were both suitable for target screening with some pros and cons. In our study, only SmileMS was suitable for untargeted screening being not limited to precursor selection. The LC-MS(n) method was suitable for urine screening as exemplified for antidepressants. It also allowed detecting unknown compounds based on known fragment structures. As ion suppression can never be excluded, it is advantageous to have several targets per drug. Furthermore, the detection of metabolites confirms the body passage. The presented LC-MS(n) method complements established GC-MS or LC-MS procedures in the authors' lab.

A novel method based on three-phase hollow fiber microextraction technique (HF-LPME) coupled with electrospray ionization-ion mobility spectrometry (ESI-IMS) was developed for the simultaneous determination of two antidepressant drugs (trimipramine and desipramine) in urine and plasma samples. The effects of various parameters such as type of organic solvent, composition of donor and acceptor phase, stirring rate, salt addition, extraction time, and temperature were investigated. Under the optimized conditions, the relative standard deviation was in the range of 5-6%, and the method quantitation limit (MQL) of utilizing HF-LPME/ESI-IMS was 5 μg/L for both drugs. The relative recoveries obtained by the proposed method from urine and plasma samples were in the range 94% to 97% for trimipramine and 92% to 96% for desipramine. Finally, the feasibility of the proposed method was successfully confirmed by extraction and determination of trace amounts of trimipramine and desipramine in biological samples without any significant matrix effect.

A series of patients whose urine screened positive for 3,4-methylenedioxymethamphetamine (MDMA) using a commercial enzyme immunoassay test (Ecstasy EMIT II assay), failed to confirm by substance-specific liquid chromatography-tandem mass spectrometry tests for MDMA. Further evaluation of these urine specimens indicates that they were positive for trazodone and its metabolite meta-chlorophenylpiperazine (m-CPP). Independent tests of standards showed significant crossreactivity on the Ecstasy EMIT II assay with trazodone, m-CPP, and the related recreational drug trifluoromethylphenylpiperazine (TFMPP). This is of further forensic significance because m-CPP is emerging as an illicit recreational drug in its own right or as an adulterant in illicit cocaine and MDMA. The hallucinogen benzylpiperazine was also assessed but found not to cross-react significantly with this assay. Patients taking trazodone may get false-positive results on the urine EMIT test for MDMA.

Antidepressants are widely used for the treatment of psychiatric disorders and therefore their monitoring in biological fluids is quite important taking into account that they can produce dangerous biochemical imbalances in toxic doses. A method for the determination of antidepressants in urine samples is presented using solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Home-made cartridges containing 30 mg multiwall carbon nanotubes are employed for isolation of the analytes from the sample, allowing also the preconcentration of the analytes prior to the HPLC analysis. Chromatographic separation was achieved in a reversed-phase C(8) column using the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate as silanol activity suppressor, which enhances peak symmetry and chromatographic resolution. Limits of detection were 12.3 ng mL(-1) for trazodone and 90.1 ng mL(-1) for fluoxetine. The repeatability of the proposed method expressed as RSD (n = 11) varied between 3.4% (fluoxetine) and 5.0% (desipramine and mianserine). Thus, the method is suitable for the therapeutic monitoring of antidepressants in urine samples.

Aims: The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA-receptor antagonist memantine., Methods: In a randomized, open, four-period cross-over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow)., Results: The renal clearance of memantine (CL(R)) in regimen A and B was 7-10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CL(R) between the two regimens with acidic urine pH (A: median: 210.2 ml min(-1) vs B: median: 218.7 ml min(-1)) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min(-1) vs D: median: 30.5 ml min(-1)). The amount of memantine excreted into the urine within one regimen (Ae0-24h) was 5.7-7.4 fold higher in regimens A and B than C and D (P< 0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D., Conclusions: The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.

Medifoxamine is a new monoamine re-uptake inhibiting antidepressant drug. Twelve volunteers received 100 mg by i.v. infusion over 15 min and 500 mg by mouth fasting. The treatments were given 1 week apart in a randomised cross-over design. Venous blood samples (10 ml) were taken at intervals for 24 h for h.p.l.c. measurement of serum medifoxamine. A biexponential decline of serum medifoxamine concentration was observed after intravenous administration in all subjects and similar terminal elimination half-lives were observed following both routes, indicating that oral absorption is not rate-limiting. The absolute bioavailability of oral medifoxamine was 21%.

Phenelzine cannot be extracted as such from biological fluids. Formation of the acetonide derivative prior to extraction allows phenelzine to be extracted and assayed by gas chromatography at levels down to 0.5 microg/ml. At this sensitivity the drug can be detected in urine but not in plasma, after therapeutic doses. Persons typed as slow acetylators of sulphadimidine excreted approximately twice as much unmetabolized phenelzine in urine compared to fast acetylators.