The incidence of psychoactive substances and alcohol among impaired drivers in Denmark in 2015-2019.

This study examines the presence of psychoactive drugs and alcohol in blood from apprehended drivers driving under the influence of drugs (DUID) and alcohol in Denmark in a five-year period from 2015 to 2019. Data were analysed with respect to gender, age, substances with concentrations above the Danish legal limit, arresting time of day and repeat arrest. By request of the police, the blood samples were subjected to analysis for alcohol and/or tetrahydrocannabinol (THC) alone, for "other drugs" (covering all drugs including new psychoactive substances (NPS), except THC, listed in the Danish list of narcotic drugs) or for both THC and other drugs. About the same number of alcohol traffic cases (37,960) and drug traffic cases (37,818) were submitted for analysis for the five-year period. The number of drug traffic cases per year increased from 5660 cases in 2015 to 9505 cases in 2019, while the number of alcohol traffic cases per year (average, 7600) was unchanged. Ethanol (89.2%) was the overall most frequent single substance, followed by THC (68.2%). CNS stimulants (46.8%) were the second most prevalent group of non-alcoholic drugs. Cocaine (23.8%) and amphetamine (22.9%) were the most frequent CNS stimulants. The proportion of CNS-stimulant positive drivers more than doubled in ten years. Benzodiazepines/z-hypnotics (12.7%) were the third most prevalent drug group detected, with clonazepam (8%) as the most frequent drug. Opioids were above the legal limit in 9.8% of the cases. NPS was above the legal limit in 128 cases (0.6%). Poly-drug use occurred in 40% of the DUID cases in the requested groups: other drug or other drug/THC. Young males dominated the DUID cases (median age 26). Drink-drivers (median age 39) were also mainly men, but the age distribution was equally spread over the age groups. Re-arrest occurred more often in DUID drivers (18-29%) than in drinking drivers (6-12%). DUID was evenly spread over the week, while drink-driving was most frequent on weekends. This study is an important supplement to the knowledge of drug use in Denmark. It was the well-known psychoactive substances that were detected. Only a few NPS occurred. However, the abuse pattern has changed, and CNS stimulants now account for a much higher proportion than earlier. Our results indicate a drug use problem among DUID drivers. This gives rise to concern because of a risk of traffic accidents. Treating the underlying abuse problem is therefore recommended, rather than focusing solely on prosecuting.

A review on the forensic toxicology of global drug-facilitated sexual assaults.

OBJECTIVE: Drug-facilitated sexual assault (DFSA) is an act of sexual violence towards a victim who is incapacitated due to the voluntary or involuntary consumption of intoxicating substances. Sexual assaults are generally considered underreported and the toxicological analysis of DFSA cases is particularly challenging when there is a time delay from assault to medical examination. The aim of this review was to investigate typical toxicological findings in global DFSA cases and describe a typical DFSA case. MATERIALS AND METHODS: A database search was conducted in PubMed using relevant search terms in order to identify studies reporting toxicological results in DFSA cases. RESULTS: In total, 22 studies were included, covering toxicological findings in DFSA cases in North America, Europe, Asia, South Africa and Australasia from 1996 to 2018. Biological matrices used for analysis included blood, urine and hair. Toxicological findings were comparable among countries, with ethanol, cocaine, cannabis, benzodiazepines, amphetamines and analgesics being among the most frequently detected substances. Ethanol was frequently detected in combination with one or more drugs. A variety of benzodiazepines were observed, with the most common being diazepam, clonazepam, alprazolam, and oxazepam. The majority of cases involved women (87%-100%). CONCLUSIONS: The findings suggest that a diverse range of substances are associated with DFSA and that victims are rendered vulnerable through recreational substance consumption at social events. As such, typical DFSA cases appear to be opportunistic in nature and primarily involves women in their mid-twenties and an acquaintance as the perpetrator.

Postmortem analysis of three methoxyacetylfentanyl-related deaths in Denmark and in vitro metabolite profiling in pooled human hepatocytes.

Methoxyacetylfentanyl belongs to the group of fentanyl analogues and has been associated with several deaths in recent years. We present three case reports of deceased individuals that tested positive for methoxyacetylfentanyl consumption, as well as in vitro and in vivo metabolite profiles. Methoxyacetylfentanyl was quantified by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in femoral blood, as well as in urine and brain tissue when these were available. Metabolite profiling was performed by incubating methoxyacetylfentanyl with pooled human hepatocytes (pHH) in Leibovitz's L-15 medium supplemented with fetal bovine serum. Metabolites were identified in vivo and in vitro using UHPLC-high resolution (HR)-MS/MS. The measured methoxyacetylfentanyl concentration was 0.022-0.056mg/kg (N=3) in femoral blood, 0.12mg/kg (N=1) in urine, and 0.074mg/kg (N=1) in brain tissue homogenate. A total of 10 metabolites were identified. The observed metabolic pathways were: hydroxylation(s), N-dealkylation, O-demethylation, deamination, glucuronidation, and combinations thereof. Major analytical targets in vitro and across measured biological samples in vivo were methoxyacetylfentanyl, the O-demethyl- metabolite, and the deamide-metabolite. Intoxication with methoxyacetylfentanyl was judged as the cause of death or a major contributing factor in all three presented cases.

The significance of sampling time in therapeutic drug monitoring of clozapine.

OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis. CONCLUSION: The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.

Do patients initiate therapy? Primary non-adherence to statins and antidepressants in Iceland.

BACKGROUND: Primary non-adherence occurs when a drug has been prescribed but the patient fails to have it dispensed at the pharmacy. AIMS: To assess primary non-adherence to statins and antidepressants in Iceland, the association of demographic factors with primary non-adherence, and the time from when a prescription is issued until it is dispensed. METHODS: Data on patients receiving a new prescription for a statin or an antidepressant from the Primary Health Care database were linked with dispensing histories from The Icelandic Prescription Database. The proportion of patients who did not have their prescription dispensed within a year from issuing (primary non-adherent) was assessed, as well as the time from issue until dispensing. Associations between demographic factors and primary non-adherence were estimated using logistic regression. RESULTS: The overall primary non-adherence was 6.3% and 8.0% for statins and antidepressants, respectively. The majority of patients had their prescription dispensed within 7 days (85% for statins, 87% for antidepressants). Being disabled and receiving a prescription for an expensive drug was associated with higher rates of primary non-adherence. CONCLUSION: The rate of primary non-adherence to statins and antidepressants in Iceland is low. Vulnerable groups such as the disabled should be given special attention when new drugs are prescribed.

Psychoactive substances in seriously injured drivers in Denmark.

This study assesses the presence of a number of psychoactive substances, including alcohol, based on blood samples from 840 seriously injured drivers admitted to five selected hospitals located in five different regions of Denmark. The study was a part of the EU 6th framework program DRUID (Driving Under the Influence of Drugs, Alcohol and Medicines). Blood samples were screened for 30 illegal and legal psychoactive substances and metabolites as well as ethanol. Danish legal limits were used to evaluate the frequency of drivers violating the Danish legislation while limit of quantification (LOQ) was used for monitoring positive drivers. Tramadol is not included in the Danish legislation therefore the general cut off, as decided in the DRUID project was used. Overall, ethanol (18%) was the most frequently identified compound (alone or in combination with other drugs) exceeding the legal limit, which is 0.53g/l in Denmark. The percentage of seriously injured drivers testing positive for medicinal drugs at levels above the Danish legal limit was 6.8%. Benzodiazepines and Z-drugs (6.4%) comprised the majority of this group. One or more illegal drugs (primarily amphetamines and cannabis) were found to be above the Danish legal limit in 4.9% of injured drivers. Young men (median age 31 years) were over-represented among injured drivers who violated Danish law for alcohol and drugs. Diazepam (4.4%), tramadol (3.2%), and clonazepam (3.0%) were the medicinal drugs most frequently detected at levels above LOQ, whereas amphetamines (5.4%) (amphetamine [5.2%] and methamphetamine [1.5%]), tetrahydrocannabinol (3.7%), and cocaine (3.3%), including the metabolite benzoylecgonine, were the most frequently detected illegal drugs. A driver could be positive for more than one substance; therefore, percentages are not mutually exclusive. Poly-drug use was observed in 112 (13%) seriously injured drivers. Tramadol was detected above DRUID cutoffs in 2.1% of seriously injured drivers. This is 3.5 times that observed in a Danish survey of randomly selected drivers. Moreover, illegal and medicinal drug levels above the Danish legal limit were present more than 10 times as frequently as in injured drivers, whereas ethanol was present more than 30 times as frequently than in randomly selected drivers. The results indicate that there is an increased risk in traffic when driving under the influence of psychoactive drugs, especially alcohol in young male drivers.

Presence of psychoactive substances in oral fluid from randomly selected drivers in Denmark.

This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Oral fluid samples (n=3002) were collected randomly from drivers using a sampling scheme stratified by time, season, and road type. The oral fluid samples were screened for 29 illegal and legal psychoactive substances and metabolites as well as ethanol. Fourteen (0.5%) drivers were positive for ethanol (alone or in combination with drugs) at concentrations above 0.53g/l, which is the Danish legal limit. The percentage of drivers positive for medicinal drugs above the Danish legal concentration limit was 0.4%; while, 0.3% of the drivers tested positive for one or more illicit drug at concentrations exceeding the Danish legal limit. Tetrahydrocannabinol, cocaine, and amphetamine were the most frequent illicit drugs detected above the limit of quantitation (LOQ); while, codeine, tramadol, zopiclone, and benzodiazepines were the most frequent legal drugs. Middle aged men (median age 47.5 years) dominated the drunk driving group, while the drivers positive for illegal drugs consisted mainly of young men (median age 26 years). Middle aged women (median age 44.5 years) often tested positive for benzodiazepines at concentrations exceeding the legal limits. Interestingly, 0.6% of drivers tested positive for tramadol, at concentrations above the DRUID cut off; although, tramadol is not included in the Danish list of narcotic drugs. It can be concluded that driving under the influence of drugs is as serious a road safety problem as drunk driving.

Lack of interaction between sertraline and lamotrigine in psychiatric patients: a retrospective study.

INTRODUCTION: This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. METHODS: We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. RESULTS: The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 µmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 µmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). DISCUSSION: The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Breath alcohol analysis incorporating standardization to water vapour is as precise as blood alcohol analysis.

A novel breath-alcohol analyzer based on the standardization of the breath alcohol concentration (BrAC) to the alveolar-air water vapour concentration has been developed and evaluated. The present study compares results with this particular breath analyzer with arterial blood alcohol concentrations (ABAC), the most relevant quantitative measure of brain alcohol exposure. The precision of analysis of alcohol in arterial blood and breath were determined as well as the agreement between ABAC and BrAC over time post-dosing. Twelve healthy volunteers were administered 0.6g alcohol/kg bodyweight via an orogastric tube. Duplicate breath and arterial blood samples were obtained simultaneously during the absorption, distribution and elimination phases of the alcohol metabolism with particular emphasis on the absorption phase. The precision of the breath analyzer was similar to the determination of blood alcohol concentration by headspace gas chromatography (CV 2.40 vs. 2.38%, p=0.43). The ABAC/BrAC ratio stabilized 30min post-dosing (2089±99; mean±SD). Before this the BrAC tended to underestimate the coexisting ABAC. In conclusion, breath alcohol analysis utilizing standardization of alcohol to water vapour was as precise as blood alcohol analysis, the present "gold standard" method. The BrAC reliably predicted the coexisting ABAC from 30min onwards after the intake of alcohol.

Is prenatal alcohol exposure related to inattention and hyperactivity symptoms in children? Disentangling the effects of social adversity.

BACKGROUND: Studies concerning whether exposure to low levels of maternal alcohol consumption during fetal development is related to child inattention and hyperactivity symptoms have shown conflicting results. We examine the contribution of covariates related to social adversity to resolve some inconsistencies in the extant research by conducting parallel analyses of three cohorts with varying alcohol consumption and attitudes towards alcohol use. METHODS: We compare three population-based pregnancy-offspring cohorts within the Nordic Network on ADHD from Denmark and Finland. Prenatal data were gathered via self-report during pregnancy and birth outcomes were abstracted from medical charts. A total of 21,678 reports concerning inattention and hyperactivity symptoms in children were available from the Strengths and Difficulties Questionnaire or the Rutter Scale completed by parents and/or teachers. RESULTS: Drinking patterns differed cross-nationally. Women who had at least some social adversity (young, low education, or being single) were more likely to drink than those better off in the Finnish cohort, but the opposite was true for the Danish cohorts. Prenatal alcohol exposure was not related to risk for a high inattention-hyperactivity symptom score in children across cohorts after adjustment for covariates. In contrast, maternal smoking and social adversity during pregnancy were independently and consistently associated with an increase in risk of child symptoms. CONCLUSIONS: Low doses of alcohol consumption during pregnancy were not related to child inattention/hyperactivity symptoms once social adversity and smoking were taken into account.

Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts.

OBJECTIVES: We examine whether pregnancy weight (pre-pregnancy body mass index (BMI) and/or weight gain) is related to core symptoms of attention deficit hyperactivity disorder (ADHD) in school-age offspring. DESIGN: Follow-up of prospective pregnancy cohorts from Sweden, Denmark and Finland within the Nordic Network on ADHD. METHODS: Maternal pregnancy and delivery data were collected prospectively. Teachers rated inattention and hyperactivity symptoms in offspring. High scores were defined as at least one core symptom rated as 'severe' and two as 'present' (approximately 10% of children scored in this range). Logistic regression and latent class analyses were used to examine maternal pregnancy weight in relation to children's ADHD core symptoms. RESULTS: Teacher rated 12 556 school-aged children. Gestational weight gain outside of the Institute of Medicine guidelines was not related to ADHD symptoms (below recommendations: odds ratio (OR): 0.96; 95% confidence interval (CI): 0.81, 1.14; above recommendations: OR: 0.98; 95% CI: 0.82, 1.16). To examine various patterns of pre-pregnancy BMI and weight gain, we used latent class analysis and found significant associations between classes that included pre-pregnancy overweight or obesity and a high ADHD symptom score in offspring, ORs ranged between 1.37 (95% CI: 1.07, 1.75) and 1.89 (95% CI: 1.13, 3.15) adjusted for gestational age, birth weight, weight gain, pregnancy smoking, maternal age, maternal education, child gender, family structure and cohort country of origin. Children of women who were both overweight and gained a large amount of weight during gestation had a 2-fold risk of ADHD symptoms (OR: 2.10, 95% CI: 1.19, 3.72) compared to normal-weight women. CONCLUSIONS: We show for the first time that pre-pregnancy BMI is associated with ADHD symptoms in children. Our results are of public health significance if the associations are causal and will then add ADHD symptoms in offspring to the list of deleterious outcomes related to overweight and obesity in the prenatal period.

Performance of four mixed-mode solid-phase extraction columns applied to basic drugs in urine.

Four different mixed-mode cation exchange solid-phase extraction columns were compared for extraction of basic drugs from urine using HPLC-DAD analysis: Isolute HCX-3, ABN, Bond Elut Certify and Oasis MCX. With one exception, all the studied drugs attained recoveries exceeding 50 % for all columns. We considered the following drugs: amphetamine, amlodipine, chlorprothixene, fentanyl, haloperidol, ketobemidone, methadone, mirtazapine, olanzapine, quetiapine, sertraline and zopiclone. The average recoveries for the four column types ranged from 68.5 % to 92.1 % in the experiments. In conclusion, the basic compounds performed reasonably well in all columns, and other factors, such as availability and price, may be decisive in regard to choice of column.

Gestational age, birth weight, and the risk of hyperkinetic disorder.

AIMS: To study the association between gestational age and birth weight and the risk of clinically verified hyperkinetic disorder. METHODS: Nested case-control study of 834 cases and 20 100 controls with incidence density sampling. RESULTS: Compared with children born at term, children born with gestational ages of 34-36 completed weeks had a 70% increased risk of hyperkinetic disorder (rate ratio (RR) 1.7, 95% confidence interval (CI) 1.2 to 2.5). Children with gestational ages below 34 completed weeks had an almost threefold increased risk (RR 2.7, 95% CI 1.8 to 4.1). Children born at term with birth weights of 1500-2499 g had a 90% increased risk of hyperkinetic disorder (RR 1.9, 95% CI 1.2 to 2.9), and children with birth weights of 2500-2999 g had a 50% increased risk (RR 1.5, 95% CI 1.2 to 1.8) compared with children born at term with birth weights above 2999 g. The results were adjusted for socioeconomic status of the parents, family history of psychiatric disorders, conduct disorders, comorbidity, and maternal smoking during pregnancy. Results related to birth weight were unchanged after adjusting for differences in gestational age. CONCLUSIONS: Children born preterm, also close to term, and children born at term with low birth weights (1500-2499 g) have an increased risk of clinically verified hyperkinetic disorder. These findings have important public health perspectives because the majority of preterm babies are born close to term.

Fully automated on-line quantification of quetiapine in human serum by solid phase extraction and liquid chromatography.

A quantitative method for determination of quetiapine (QTP) in human serum is presented. The method is fully automated and based on high performance liquid chromatography (HPLC) with on-line solid phase extraction (SPE). The extraction procedure is based on a C2 cartridge, which is eluted with methanol. The eluate is injected onto a silica column with a mobile phase consisting of methanol:20 mM NH(4)CH(3)COO, pH 5.0 (99:1). Quetiapine is quantified by ultra-violet (UV) absorbance at 257 nM with trifluoperazine as the internal standard (I.S.). The extraction recoveries for quetiapine and trifluoperazine were 69 and 57%, respectively. The total inter day coefficient of variation was 11.1, 3.8 and 3.1% at 20, 500 and 1000 nM, respectively. The detection limit was 10.3 nM quetiapine. The method has been used in our therapeutic drug monitoring (TDM) laboratory where co-administered drugs often are observed. In an investigation of analytical interference from co-administered drugs, demethyl-mianserine was the only drug which interfered with the internal standard. There was no interference with quetiapine itself. The method showed good agreement with mass spectrometric quantification of quetiapine.

Estimation of in vivo capillary or venous blood glucose concentration from analysis on stored venous blood or its plasma and use in quality control of near-patient glucose tests.

Glucose concentrations were determined in capillary and venous blood and in venous plasma from 100 consecutive patients referred to an oral glucose tolerance test. The capillary blood was immediately transferred to a haemolysing and glucose stabilizing solution and frozen within 4h. Venous blood was drawn in heparin-sodium fluoride tubes and stored for 0, 4 or 24h at 4 or 20 degrees C. Aliquots of the venous blood were then treated in the same way as the capillary blood. The primary tubes were centrifuged, and aliquots of the plasma were stabilized, as described. All specimens from the same sampling event were analysed in the same analytical series on EBIO compact. Deming linear regression equations y = a + bx were calculated to estimate the glucose concentration in one specimen from that in a differently treated specimen e.g.: B(cB:fPt)---Glucose (0h) = 0.61 + 0.897*P(vB;fPt)-Glucose (24h. 20 C). n = 100, SD(y/x) = 0.25 mmol/L and B(vB) Glucose (0h) = 0.53 + 0.897*P(vB)--Glucose (24h. 20 degrees C), n = 196, SD(y/x) = 0.26 mmol,/L. The non-analytical part of the standard deviation of the ratio between the near-patient test result and its predicted value was 0.038 for both of the above predictions. In conclusion, the analytical (including sampling) variation of near-patient tests of glucose can be assessed by laboratory analysis on mailed, heparin-fluoride stabilized venous blood or on plasma samples made from the mailed blood.

Contributions of five human cytochrome P450 isoforms to the N-demethylation of clozapine in vitro at low and high concentrations.

The authors assessed the in vitro contribution of cytochrome P450 (CYP) isoforms 1A2, 3A4, 2C9, 2C19, and 2D6 to the N-demethylation of clozapine mediated by human liver microsomal preparations (HLM). In contrast to previous studies, the authors focused on a relatively low hepatic concentration level, 5 microM, to assess the conditions at a therapeutically relevant hepatic concentration level of clozapine. The optimal concentrations of specific inhibitors were initially established using cDNA-expressed CYP isoforms. The mean contributions of CYPs 1A2, 2C19, 3A4, 2C9, and 2D6 amounted to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the total HLM-mediated N-demethylation. Thus, the present in vitro study on clozapine N-demethylation suggests that CYP1A2 is the most important form at low concentrations, which is in agreement with clinical findings. CYP2C19 is also of considerable importance, while the roles of CYP2C9 and 2D6 are more modest. CYP3A4 attained a dominating role with an average contribution of 37% at a high clozapine concentration (50 microM). The rate of other metabolic routes mediated by CYP2D6 only corresponded to about one fifth of the CYP2D6 catalyzed N-demethylation rate.

Models for combining random and systematic errors. assumptions and consequences for different models.

A series of models for handling and combining systematic and random variations/errors are investigated in order to characterize the different models according to their purpose, their application, and discuss their flaws with regard to their assumptions. The following models are considered 1. linear model, where the random and systematic elements are combined according to a linear concept (TE = absolute value(bias) + z x sigma), where TE is total error, bias is the systematic error component, sigma is the random error component (standard deviation or coefficient of variation) and z is the probability factor; 2. squared model with two sub-models of which one is the classical statistical variance model and the other is the GUM (Guide to Uncertainty in Measurements) model for estimating uncertainty of a measurement; 3. combined model developed for the estimation of analytical quality specifications according to the clinical consequences (clinical outcome) of errors. The consequences of these models are investigated by calculation of the functions of transformation of bias into imprecision according to the assumptions and model calculations. As expected, the functions turn out to be rather different with considerable consequences for these types of transformations. It is concluded that there are at least three models for combining systematic and random variation/errors, each created for its own specific purpose, with its own assumptions and resulting in considerably different results. These models should be used according to their purposes.

Fully automated on-line determination of olanzapine in serum for routine therapeutic drug monitoring.

A method is presented for unattended fully automated extraction and on-line determination of the atypical antipsychotic drug olanzapine in serum. An ASPEC automatic sample-preparing apparatus with Isolute cyanopropyl-bonded silicagel cartridges was used for solid-phase extraction of the drugs from serum. The adsorbed drugs were eluted with methanol and an aliquot injected into a high-performance liquid chromatograph (HPLC) apparatus. Trifluoperazine was used as internal standard, and the analytes were separated on an unmodified silicagel column using methanol-ammonium acetate buffer pH 9.9 (85:15) as mobile phase. Ultraviolet detection at 257 nm was used for quantitation. Within the therapeutic range for the serum concentration of olanzapine, the interday variations for the quantitative determinations were <8%. Comparisons between concentrations measured using liquid-liquid extraction and the present on-line extraction method showed good agreement. Other drugs often used in combination with olanzapine did not interfere with the quantitative determinations. The method has been in routine use for more than 1 year for therapeutic drug monitoring.