Original Article Taiwanese Journal of Psychiatry (Taipei) Vol. 32 No. 4 2018 • 323 •

Quetiapine Shows Cross-reactivity in Urine Drug Screening for Ketamine

Yen-Feng Lee, M.D.1, Chih-Sung Liang, M.D.1,2, Yu-Ting Tseng, M.D.1, Chia-Ho Peng, M.D.1*

Background: Ketamine use disorder has become a major public-health prob- lem. Urine drug screening for ketamine is essential in prevention programs at both individual and community levels. But no data exist for compounds in urine that may interfere with drug tests and cause false-positive results. We suspect that que- tiapine may show cross-reactivity in urine drug screening for ketamine. Methods: We recruited 573 patients and divided them into a quetiapine-treated group (QTG) and a quetiapine-untreated group (QUG). Then, we determined the association between the dosage of quetiapine and that of false-positive results. Results: We collected 51 patients in the QTG, and 522 patients in the QUG. In the QTG, 44.2% of patients showed false positive. In the QUG, the ratio of false-positive results was 0.8%. The dose of quetiapine was found to be signifi cantly associated with false-positive results (p < 0.05, odds ratio = 1.415, 95% confi dence interval = 1.013-1.977). But the factors of patients’ sex, age, body weight, height of did not show any signifi cant difference between two groups. Conclusion: Quetiapine is a widely used second-generation (atypical) antipsychotic drug. To avoid mis-inter- pretating the data and misleading clinical decisions, physicians should be aware of its potential of cross-reaction of ketamine and quetiapine in urine drug screening tests. Double-check for the ketamine use is required to confi rm the ketamine use in quetiapine-medicated patients with ketamine use disorder.

Key words: cross-reactivity, urine drug screening, ketamine, quetiapine (Taiwanese Journal of Psychiatry [Taipei] 2018; 32: 323-30)

Substance use can have a severe impact not only Introduction on individuals but also on their families and com- munities. Hence, efforts should be stressed on de- Substance use disorder is a major public veloping prevention programs at both individual health issue. The effects of repeated drug expo- and community levels. sure are cumulative and devastating, leading to In the past few decades, urine drug screens costly physical, mental, and social problems [1]. have been well-developed and are commonly

1 Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, 2 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan Received: September 15, 2018; revised: October 17, 2018; acceptance: October 25, 2018 *Corresponding author. No. 60, Xinmin Road, Taipei 112, Taiwan E-mail: Chia-Ho Peng • 324 • Quetiapine Causes False-positive for Ketamine

used in detecting potential drug use [2]. An advan- health. The harmful physical consequences in- tage of urine drug tests is that it does not need clude ulcerative cystitis, renal dysfunction, ab- complex laboratory facilities or expensive equip- dominal pain, and biliary duct dilatation, while ment. It can be done without extensive training, the psychological sequela consist of neurocogni- and the results obtained from these tests are easy tive impairment, depression, and psychosis [6]. to be analyzed. When compared to other bodily Many agents, such as venlafaxine and trama- fl uids, urine can be obtained in adequate quanti- dol, have been shown to cross-react with phency- ties without causing discomfort to the patient, and clidine on immunoassay-based urine drug tests can be tested repeatedly if needed. In fact, urine [12]. But no data exist for cross-reactivity of such drug tests are widely used in criminal justice sys- agents with ketamine. In clinical practice, several tems and mental health services for detecting il- patients treated with quetiapine showed false-pos- licit drug use and monitoring treatment effi cacy, itive results on ketamine urine tests [13]. Those respectively. fi ndings have motivated us to examine whether To be used in clinical practice in a screening quetiapine may cross-react with urine immunoas- test needs to have good sensitivity and specifi city. say kit for ketamine being possibly due to the con- False-positive results in urine drug screening can jugation of quetiapine to the colloidal gold conju- happen when other structurally related or unrelat- gated (CGC) anti-ketamine antibody. ed compounds cross-react with the test kits as those involve immunoassay techniques [3]. Urine Methods drug tests help drug users to confi rm their real drug-use behavior, and give clinicians with an ob- Study subjects and procedures jective measurement in addiction treatment. A bet- The current study is a retrospective design ter understanding of the potential interferents in using data from Beitou Branch, Tri-Service urine drug tests can prevent patients from being General Hospital, which is a psychiatric teaching incorrectly judged about their eligibility for reha- hospital in Taiwan. In our hospital, all patients bilitation programs, the risk of a prison sentence, presenting at our emergency department receive unjustifi ed termination of an employment, and urine drug tests before they are interviewed by also the possibility of receiving inappropriate clinicians. medical treatment [4]. Between March 2015 and July 2015, 573 pa- Ketamine, a derivative of phencyclidine, is tients were brought to our emergency department. used in general anesthesia for obstetric, pediatric, For confi rmation, the urine samples of patients and geriatric patients [5]. It also benefi ts patients who tested positive during the urine drug tests with neuropathic, infl ammatory, ischemic limb, were sent to the laboratory of National Defense and cancer pain [6]. Ketamine also has antidepres- Medical Center for further test with gas chroma- sant effects in patients with refractory depression tography mass spectrometry (GC-MS). [7]. But recreational use of ketamine has become In this study, GC-MS cutoff concentration of a major public health problem not only in Taiwan ketamine was 100 ng/mL. In addition to the re- [8], but also in the United Kingdom [9], Hong sults of urine drug tests, we also collected infor- Kong [10], and China [11]. Repeated exposures to mation about other clinical and demographic ketamine impairs both physical and psychological characteristics (sex, age, psychiatric diagnosis, Lee YF, Liang CS, Tseng YT, et al. • 325 •

body weight, height, current medication, smoking sion. All tests were two-sided. The differences habits, alcohol consumption, and history of drug between the groups were considered signifi cant if use). The results of the urine drug tests were ex- p-value were smaller than 0.05. cluded if the patients refused to provide urine samples, left the testing area without permission, Results or failed to sign all relevant drug-testing forms. We excluded the subjects who were duplicated Figure 1 depicts the recruitment of partici- during the study. This study protocol was ap- pants and the process of urine sampling. A total of proved by the institutional review board at the Tri- 573 patients were included in this study. There Service General Hospital at the National Defense were 51 patients (male, 59%) in the QTG, and 522 Medical Center in Taipei, Taiwan. patients (male, 85%) in the QUG. The mean ± standard deviation age of the patients was 44.0 ± Laboratory confi rmations of data 12.3 years in the QTG, and 31.1 ± 13.2 in the As we suspected that quetiapine cross-reacts QUG. The dosage of quetiapine varied between with the urine immunoassay kit for ketamine, all 50 mg/d to 800 mg/d (average 350 ± 234 mg/d). the patients were divided into a quetiapine-treated Urine drug tests for ketamine (Formosa One Sure group (QTG) and a quetiapine-untreated group KET Rapid test kit, Taipei, Taiwan) were done in (QUG). The patients, quetiapine treatment group 529 patients. The ketamine test kit showed that the were based on their self-reports and medical re- results for 28 patients were positive for ketamine. cords. The accuracy of the data source was also But gas chromatography mass spectrometry re- confi rmed by the PharmaCloud System of National vealed that only fi ve of those results were true Health Insurance which contains a complete list of positive while the other 23 were false-positive re- prescribed and dispensed medications from differ- sults. Therefore, the false-positive rate was 4.4%. ent hospitals, clinics and pharmacies for all insured The positive predictive value was 17.9%, and the patients [14]. The ketamine assay is defi ned as negative predictive value was 100%. The sensitiv- false positive if a positive result is obtained on the ity and the specifi city of the test were 100% and urine drug test and a negative result is obtained on 95.6%, respectively. gas chromatography mass spectrometry. Table 1 shows the data of demographics and the results of urine drug tests in the QTG and the Statistical analysis QUG. In the QTG, 44 patients provided the urine Data entry and analysis were conducted us- samples. Although the ketamine kit showed that ing Statistical Package for Social Science soft- the results for 20 of these patients were positive ware version 22.0 for Windows (SPSS, IBM for ketamine, gas chromatography mass spec- Corp., Armonk, New York, USA.). We analyzed trometry results confi rmed that 19 of these 44 re- group differences of continuous variables with in- sults were false positive (43.2%). In the QUG, dependent sample t-tests. We also used Pearson’s four samples had false-positive results, and the chi-squared tests to compare the distributions of ratio of false-positive results was 0.8%. categorical variables. To determine whether the In the QTG, the urine drug test results for 24 dosage of quetiapine was associated with false- patients were true negative, while those of 19 pa- positive results, we did a binary logistic regres- tients were false positive. Table 2 illustrates the • 326 • Quetiapine Causes False-positive for Ketamine

Figure 1. The recruitment of participants and the process of sample collection clinical and demographic characteristics of these 43 patients. No signifi cant between-group differ- Discussion ences existed in the sex, age, body weight, and height. In the QTG, a logistic regression was done Urine drug screening is a useful ancillary test to determine whether the dose of quetiapine was for monitoring patients with a record of drug use. associated with false-positive results obtained Inaccurate results from urine drug tests may nega- from the urine immunoassay kit for ketamine be- tively affect therapeutic alliance, leading to misin- tween patients with true-negative and false-posi- terpretation of data and subsequent misleading tive results. The entered covariates were sex, age, clinical decisions and unfair burden to the patient. body weight, height, and the dose of quetiapine Therefore, knowledge about the compounds in (per 100 mg). The dose of quetiapine reached sig- urine that may interfere with drug tests and result nifi cance (p < 0.05, odds ratio = 1.415, 95% con- in false-positive results is highly relevant for cli- fi dence interval = 1.013 - 1.977), while the other nicians. Although few studies exist to address variables did not. false-positive urine drug tests for ketamine, this Lee YF, Liang CS, Tseng YT, et al. • 327 •

Table 1. Demographics and results of urine drug tests in patients with and without quetiapine treatment (N = 573)

Quetiapine group Non-quetiapine group n = 51 n = 522 n (%) n (%) Exposure to ketamine 3 (5.9) 48 (9.2) Recent use 1 (2.0) 4 (0.8)

Urine collected 44 485 Positive ketamine urine test 20 (45.5) 8 (1.6) True positive 1 4 False positive 19 (43.2) 4 (0.8) Non-cooperative patient 7 23 Patient left without permission 0 14 Quetiapine dosage/day, m ± SD, mg/dL 350 ± 234 Not applicable m, mean; SD, standard deviation

Table 2. Demographic characteristics in patients with true-negative and false-positive results on ketamine urine tests (N = 43)

True negative False positive n = 24 n = 19 (mean ± SD) (mean ± SD) Male/Female 15/9 10/9 Age, years 45.42 ± 11.45 46.42 ± 12.48 Height, cm 164.93 ± 9.39 163.54 ± 7.97 Weight, kg 69.26 ± 14.01 68.89 ± 13.08 Dose, mg/dL 260 ± 201 408 ± 226 Nonsignifi cant differences in all items SD, standard deviation study is the fi rst report showing that quetiapine ketamine in the urine sample is below 100 ng/mL, may cross-react with the urine immunoassay kit the colloidal gold conjugated (CGC) monoclonal for ketamine. anti-ketamine antibody will bind to ketamine on Ketamine is predominantly metabolized to the T zone, forming a band on it. If the concentra- norketamine in the liver and it is excreted mainly tion of ketamine is above 100 ng/ml, most of the through the urine, and only less than 5% of ket- CGC anti-ketamine antibody will conjugate to the amine is eliminated unchanged [6]. The Formosa ketamine in the urine. As a result, there is no free One Sure KET Rapid test kit, which is based on form antibody that binds to the capture line and the principle of competitive immunochromatogra- hence no band will be formed in the T zone. phy, is a fast and inexpensive method to screen Quetiapine, a second-generation (atypical) ketamine in the urine. When the concentration of antipsychotic drug is commonly used to treat • 328 • Quetiapine Causes False-positive for Ketamine

schizophrenia [15], schizophrenia-spectrum dis- Limitations of the study orders [16], bipolar disorders [17], agitation in The findings from our study should be inter- dementia [18], and psychosis in Parkinson disease preted with caution. [19]. Quetiapine undergoes extensive metabolism • In addition to the Formosa One Sure KET to quetiapine sulfoxide by the cytochrome P450 Rapid test kit, we are unsure whether quetiap- system [20]. When taken orally, quetiapine is pre- ine will cross-react with other urine immunoas- dominantly excreted out in the urine in the form of say kits for ketamine. metabolites and only 1% of a dose excretes out • We are unable to ascertain at this time if this is unchanged [21]. Even that quetiapine causes due to parent quetiapine, its metabolites, a com- false-positive results in ketamine urine drug bination of parent and metabolites, or a combi- screen has been reported [13], the mechanism is nation of all medications or food the patient still not well-known. Drugs that have been shown was taking. But quetiapine can still be impli- to cross-react with ketamine feature a ring struc- cated in cross-reactivity with ketamine kits, as ture with a nitrogen atom next to the ring, which is the ratio of false-positive results obtained in common for both quetiapine sulfoxide and ket- this study was 44.2% in patients treated with amine. Therefore, it is possible that this structural quetiapine. similarity between quetiapine sulfoxide and ket- • The kit could not detect the sample when the amine produces cross-reactivity in the ketamine concentration of urinary ketamine was below drug screen. 100 ng/ml. There are no negative sample The results of ketamine drug screens were screened with GC-MS to ascertain a false-neg- not false positive in every quetiapine-treated pa- ative rate. tient. In the QTG, patients whose test results were false-positive did not differ from those whose re- Summary sults were true negative with respect to sex, age, Globally, ketamine use has been on the rise, body weight, and height, implying that the false- accompanied by a rapid increase in drug users. positive results were not associated with the pa- Urine drug tests can detect ketamine use and mon- tient’s demographic characteristics (Table 2). But, itor treatment adherence. Interpreting urine drug the dose of quetiapine was associated with the tests requires an understanding of the common false-positive results. We found that every 100 mg reasons for false-positive and false-negative test increment in the dose of quetiapine would in- results. Quetiapine is a common second-genera- crease the false-positive results by 41.5%, and tion (atypical), and widely used antipsychotic. To that the dose of quetiapine was found to be signifi - avoid misinterpretating data and misleading clini- cantly associated with false-positive results (p < cal decisions, physicians should be aware of its 0.05, odds ratio = 1.415, 95% confi dence interval potential to cross-react with ketamine in urine = 1.013 - 1.977). This fi nding is concordant with drug screening tests, thus leading to false-positive the mechanism of urine immunoassay kit for ket- results. Moreover, double-check mechanism is re- amine, in which a high dose of quetiapine (and its quired to confi rm the drug abuse case. Further metabolite quetiapine sulfoxide) conjugates to the studies are required to confi rm if quetiapine cross- CGC anti-ketamine antibody and then there is no reacts with ketamine in other urine drug screening free form antibody binding to the capture line. tests as well, as such information is of value for Lee YF, Liang CS, Tseng YT, et al. • 329 •

clinical practice. Besides, there may be other psy- Kong: a review of 233 cases. Hong Kong Med J chotropic and over the counter medication which 2010; 16: 6-11. could potentially interfere with this kit results and 11. Lian Z, Liu Z, Liu R, et al.: Epidemiological survey would also need further study. of ketamine in China. Chin J Drug Depend 2005; 14: 280-3. Acknowledgement 12. Saitman A, Park HD, and Fitzgerald RL: False- positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol 2014; 38: All authors declare that they do not have any 387-96. potential confl icts of interest in writing this 13. Liu CH, Wang HY, Shen SH, et al.: False positive paper. ketamine urine immunoassay screen result induced by quetiapine: a case report. J Formos Med Assoc References 2017; 116: 720-2. 14. Huang SK, Wang PJ, Tseng WF, et al.: Nhi- 1. Leonard KE: Perspective: beyond the neural circuits. pharmacloud in taiwan‒a preliminary evaluation us- Nature 2015; 522: S56. ing the re-aim framework and lessons learned. Int J 2. Johnson-Davis KL, Sadler AJ, Genzen JR: A retro- of Medical Informatics (Taipei) 2015; 84: 817-25. spective analysis of urine drugs of abuse immunoas- 15. Harvey RC, James AC, Shields GE: A systematic re- say true positive rates at a national reference labora- view and network meta-analysis to assess the relative tory. J Anal Toxicol 2016; 40: 97-107. effi cacy of antipsychotics for the treatment of posi- 3. Herring C, Muzyk AJ, Johnston C: Interferences with tive and negative symptoms in early-onset schizo- urine drug screens. J Pharm Pract 2011; 24: 102-8. phrenia. CNS Drugs 2016; 30: 27-39. 4. Moeller KE, Lee KC, Kissack JC: Urine drug screen- 16. Pagsberg AK, Tarp S, Glintborg D, et al.: Acute anti- ing: Practical guide for clinicians. Mayo Clin Proc psychotic treatment of children and adolescents with 2008; 83: 66-76. schizophrenia-spectrum disorders: a systematic re- 5. White PF, Way WL, Trevor AJ: Ketamine‒its phar- view and network meta-analysis. J Am Acad Child macology and therapeutic uses. Anesthesiology Adolesc Psychiatry 2017; 56: 191-202. 1982; 56: 119-36. 17. Lindstrom L, Lindstrom E, Nilsson M, et al.: 6. Quibell R, Fallon M, Mihalyo M, et al.: Ketamine. J Maintenance therapy with second generation anti- Pain Symptom Manage 2015; 50: 268-78. psychotics for bipolar disorder - a systematic review 7. Kavalali ET and Monteggia LM: How does ketamine and meta-analysis. J Affect Disord 2017; 213: elicit a rapid antidepressant response? Curr Opin 138-50. Pharmacol 2015; 20: 35-9. 18. Farlow MR, Shamliyan TA: Benefi ts and harms of 8. Chen WY, Huang MC, Lin SK: Gender differences in atypical antipsychotics for agitation in adults with subjective discontinuation symptoms associated with dementia. Eur Neuropsychopharmacol 2017; 27: ketamine use. Subst Abuse Treat Prev Policy 2014; 9: 217-31. 39. 19. Samudra N, Patel N, Womack KB, et al.: Psychosis 9. Schifano F, Corkery J, Oyefeso A, et al.: Trapped in in parkinson disease: a review of etiology, phenome- the “K-hole”: Overview of deaths associated with nology, and management. Drugs Aging 2016; 33: ketamine misuse in the UK (1993-2006). J Clin 855-63. Psychopharmacol 2008; 28: 114-6. 20. Fisher DS, Handley SA, Taylor D, et al.: Measurement 10. Ng SH, Tse ML, Ng HW, et al.: Emergency depart- of quetiapine and four quetiapine metabolites in hu- ment presentation of ketamine abusers in Hong man plasma by lc-ms/ms. Biomed Chromatogr 2012; • 330 • Quetiapine Causes False-positive for Ketamine

26: 1125-32. ics of quetiapine: an atypical antipsychotic. Clin 21. DeVane CL, Nemeroff CB: Clinical pharmacokinet- Pharmacokinet 2001; 40: 509-22.