Somnolence among the eldery is a common adverse drug event (ADR) in clinical practice. Preventing the aged from this ADR a tool will be developed to calculate the sedative burden of a medication. Methods: Medical files of somnolent patients (n = 22) and non-somnolent patients (n = 107) are compared. The files are provided from an observational trial conducted at the BKH Regensburg (inclusion criteria ≥ 65 years). The number of antipsychotics, interactions, affinity to H1-receptor, dosages of antipsychotics are supposed to be risk factors. Proofing the correlation between risk factors and somnolence Χ²-Test and t-tests (SPSS®) are performed. Results: The probability to suffer from a sedation is higher, if the patient takes at least 2 antipsychotics (somnolent patients 40.9% vs. 18.7% non-somnolent patients) (Χ²-Test p < 0,083). Sedation risk is also higher with an increasing number of drugs with affinity to the H1-receptor. (Χ²-test p < 0,277). To obtain the final sedative burden a classification of the h1-receptor affinity and a larger number of patients are necessary. Risk factors will be ranked by performing a multivariate analysis. Results will be presented at the AGNP.

Diagnosis of late-life depression is given when depressive symptoms emerge in persons older than 65 years. Great care is needed when elderly patients receive psychopharmacotherapy due to altered pharmacokinetic status. As a consequence, age is considered to have a significant effect on serum concentrations of antidepressant drugs. The magnitudes of age-dependent changes, however, are uncertain. By utilizing a large therapeutic drug monitoring (TDM) database, this cross-sectional study aimed to retrospectively assess pharmacotherapy in elderly patients in comparison with their younger counterparts, when treated with venlafaxine, which is widely used to treat late-life depression. In addition, the influence of sex and body mass index (BMI) was evaluated. Serum concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine requested during routine TDM in two University Medical Centers in Germany were analyzed. Patients with concomitant CYP2D6 inhibiting drugs as co-medication were excluded. In total, 1,417 samples were available for the analysis. Elderly patients had by average 42 % higher dose-adjusted serum concentrations (ng/mL/mg) of the active moiety (venlafaxine plus O-desmethylvenlafaxine) than younger patients. In addition, our study demonstrated that the difference between age groups is independent of sex and BMI. However, age groups only explain 4.5 % of the total dose-adjusted serum concentration variation of the venlafaxine active moiety. Dose adjustments for venlafaxine are recommended in patients aged 65 years or older, particularly in elderly female patients who are exceptionally vulnerable to high serum concentrations of venlafaxine. TDM is recommended during venlafaxine pharmacotherapy.

Introduction: Polypharmacy of geriatric patients very often leads to pharmacodynamic and pharmacokinetic interactions and a high risk for adverse drug reactions. Several drugs have been characterized as potentially inappropriate medication (PIM). The aim of this study was to analyse the prescription behaviour in the psychiatric hospitals which are associated in the pharmacovigilance system AGATE (Arbeitsgemeinschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen e.V.) during the last 25 years.

INTRODUCTION:The main objective of this study was to investigate the influence of the use of multiple medications and other risk factors on citalopram plasma concentrations.METHODS:A retrospective cohort study with a naturalistic population of 957 patients for whom routine therapeutic drug monitoring (TDM) of citalopram had been requested between 2006 and 2013 was conducted.RESULTS:Concomitant drugs inhibiting at least 2 different CYP subtypes involved in the metabolism of citalopram decreased statistically significantly the total clearance (Clt). Compared to younger patients over 64-year-old patients had on average a 4.5 times higher risk rate of supra-therapeutic plasma concentrations. However, binary logistic regression showed that age, sex and co-medication accounted only for 26% of the inter-individual variability of citalopram plasma concentrations.DISCUSSION:Due to pharmacokinetic interactions, citalopram plasma concentrations are often higher than expected with a given dose. Especially in geriatric and often multimorbid patients who are usually prescribed high numbers of concomitant drugs and are at higher risk for adverse drug reactions (ADR), restriction of the maximal dose of citalopram is not sufficient to prevent supra-therapeutic plasma concentrations.

Falls belong to the most frequent adverse drug events (ADEs) among geriatric patients. At the Bezirksklinikum Regensburg an observational study is conducted that aims to examine the frequency of ADEs in this subgroup. Falls were seen in 20.34 percent of the patients. Thus, a risk assessment based on medication and pre-existing conditions is needed.

Introduction: Due to a dose-dependent risk for QTc prolongations, torsade de pointes tachyarrhythmia and sudden death age-dependet maximal daily doses of citalopram are recommended. Concomitant drugs which prolong QTc or inhibit the metabolism of citalopram may increase the risk for adverse events. The aim of this study was to further analyse the influence of the concomitant medication on the total clearance (Clt)of citalopram. Method: Plasma concentrations of citalopram – a total of 959 – were collected during routine therapeutic drug monitoring (TDM). The means of Clt values of different subgroups of patients were compared by one-way analysis of covariance (ANCOVA) after controlling for potential confounders. Results: 1. Age over 65 years and female sex significantly reduced the Clt of citalopram by 25% and 16%, respectively. 2. About 40% of the patients younger than 65 years who were prescribed more than 40 mg of citalopram daily and 35% of the older patients with doses of more than 20 mg per day had plasma concentrations exceeding the therapeutic reference range of citalopram. 3. Only concomitant medications with inhibitors of at least two different CYP enzymes (CYP2C19, CYP2D6 or CYP3A4) reduced significantly the Clt of citalopram. Conclusion: For patients with risk factors as female sex, age over 65 years or concomitant medications including inhibitors of more than two CYP enzymes TDM is recommended to minimize the risk for adverse reactions of citalopram.

Introduction: Psychotropic drugs have varying degrees of affinity to peripheral and central muscarinic cholinergic receptors. The aim of this study was to further determine the importance of risk factors as age, sex and concomitant medication for the occurrence of psychotropic drug-induced anticholinergic adverse reactions (ADR). Methods: The numbers of psychotropic drug-induced ADRs (n = 214) reported to our spontaneous ADR reporting system AGATE (Arbeitsgemeinschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen e.V.) were corrected with the prescription numbers estimated at two reference days per year which were also used for the control group. The anticholinergic load of the patients' medications was calculated with an anticholinergic risk scale. Results: – Compared to younger patients over 50 year-old men and women had an about three to five times or twofold higher risk for anticholinergic ADRs, respectively. – Although the numbers of prescribed drugs increased with age they did not differ significantly between patients suffering from anticholinergic ADRs and the control group. – Patients suffering from anticholinergic ADRs had an about threefold higher anticholinergic burden than the control group. Conclusion: The risk for psychotropic drug-associated anticholinergic ADRs increases already with age above 50 years. Our data suggest that this might be due to a gradual loss of cholinergic function caused by normal aging and increasing comorbidity.

Introduction: QT-time prolongation is an indicator for adverse events, especially in elderly patients due to polypharmacy and multimorbidity. We rated the influence of prescribed medication on QT-time and compared the theoretical risk with observed effects on repolarization time. Methods: Based on two publications that considered the effect of drugs on QT-time, a risk-scale was established. Elderly patients were selected from ECG records and their medication was obtained from medical files. Risk-points of the drugs were summarized to a total score. Using Spearman's correlation analysis, a suggested correlation between risk-score points and severity of QT-prolongation was determined. Results: 174 patients aged from 64 to 76 years (mean ± SD 68.7 ± 4.7; 50.9% women) were included for analysis. They had 295 ECGs (mean 1.7 per patient). Theoretical risk-points correlated significantly with observed QT-time. The Spearman correlation-coefficient was 0.247 (P < 0.01, CI 95%). A lower threshold associated with an increased risk to exceed the critical QT-time of 460 ms was computed by receiver operating characteristics (ROC) analysis, resulting in 5 risk points (AUC = 0.623). Conclusions: Since the theoretical risk for QT-prolongation correlated well with the observed QT time, we recommend the implementation of the risk-scale in clinical practice to improve the safety of pharmacotherapy in gerontopsychiatry. For practical reasons it can be amalgamated with therapeutic drug monitoring.

Introduction: Due to affinity to peripheral and central muscarinic cholinergic receptors of varying degree, tricyclic antidepressants (TCA) can cause anticholinergic adverse reactions (ADRs) such as dry mouth, blurred vision, constipation, urinary retention, increase of intraocular pressure, and tachycardia. Central side effects include impaired cognitive functions, confusion and delirium. Because of high sensitivity to anticholinergic effects and polypharmacy, elderly patients are more susceptible to these events. The aim of this study was to further determine the importance of risk factors such as age, sex and concomitant medication for the occurrence of TCA-induced anticholinergic ADRs. Methods: Databases of the spontaneous ADR reporting system AGATE (Arbeitsgemeinschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen) which systematically surveys and assesses psychotropic drug-induced adverse events. The risks for anticholinergic ADRs were corrected for the prescription numbers of drugs estimated on two reference days per year. Results: In comparison to younger patients, patients 51 to 65 and over 65 years-old had an about 3 or 5 times higher risk for all TCA-associated anticholinergic ADR. Compared to younger patients, 51 to 65 and over 65 year-old patients were about 6 or 10 times more likely to develop a TCA-associated delirium. The risk for anticholinergic ADRs was not sex-dependent. In average, patients suffering from anticholinergic ADRs got 3.0 (18–50 year-old), 4.0 (51–65 year-old), and 4.5 (>65 year-old) drugs, respectively. Conclusions: The risk for anticholinergic ADRs increases already in middle age. It is therefore advisable to pay attention to the risks of anticholinergic drugs and drug interactions within this age group.

Introduction: Antipsychotics which are inhibitors of dopamine D2-receptors but also antidepressant dugs with serotoninergic activity can cause hyperprolactinemia. The most frequent symptoms of chronic hyperprolactinemia include reproductive dysfunction (anovulation, menstrual irregularity, sub-fertility, decreased estrogen and testosterone production), sexual impairment, galactorrhea, breast enlargement, disorders associated with chronic hypogonadism (decreased bone mineral density and osteoporosis, increased cardiovascular risk) and possibly an increased malignity of breast cancer. The aim of this study was to further elaborate age-, sex- and drug-dependency of psychotropic drug-induced hyperprolactinemia. Methods: Data from 210 patients whose prolactin values were estimated in the last four years and of cases collected by the spontaneous ADR reporting system AGATE (Arbeitsgemeinschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen) were analysed retrospectively. Results: 66% percent of all cases with hyperprolactinemia and associated symptoms reported to AGATE occurred in women who were younger than 45 years. In the group of 18–45 year-old patients with hyperprolactinemia, 70% of the women but only 40% of the men reported hyperprolactinemia-associated symptoms. Compared to postmenopausal women and men, premenopausal women had significantly higher values of prolactin. Hyperprolactinemia and associated symptoms (n=65) were most frequently reported for patients under therapy with risperidone/paliperidone (n=27) and amisulpride (n=16). The remaining cases were associated with olanzapine (n=6), classical antipsychotics (n=6), SSRI/SSNRI (n=2) or combinations of these drugs. Conclusions: Premenopausal women have the highest risk of symptomatic hyperprolactinemia. It is therefore recommendable to monitor prolactin values and hyperprolactinemia associated symptoms especially in this group of patients.

Introduction: Blood dyscrasias are rare psychotropic drug-related adverse reactions (ADR) and are usually only identified by spontaneous and unsystematic ADR reporting systems. The aim of this study was to further determine the importance of the patients' sex and age for the risk of psychotropic drug-related agranulocytosis, neutropenia, leukopenia, and thrombocytopenia. Methods: Currently, 45 psychiatric institutions are participating in the drug safety program AGATE (Arbeitsgemeinschaft Arzneimittelsicherheit bei psychiatrischen Erkrankungen), which systematically surveys and assesses psychotropic drug-related adverse events. For each drug, sex- and age-dependent risk factors were calculated using the drug prescription numbers which were recorded for every patient on all participating wards on two reference days per year as denominators. Results: The relative risk for women compared to men to suffer from psychotropic drug-induced blood dyscrasias was almost twice as high (120 women, 61 men). Compared to younger patients women over 60 years had a slightly higher risk (+21%). In addition, women were three times more likely to suffer from severe clinical symptoms such as pneumonia, sepsis or high fever as men. Furthermore, women had a ten times higher risk for carbamazepine-related blood dyscrasias. Conclusions: Female sex and age over 60 years additively increase the risk for occurence and clinical severity of psychotropic drug-induced haematological disorders.

Introduction: Clozapine is particularly used in the treatment of schizophrenic patients who are refractory to other antipsychotics. Highly variable plasma concentrations are found in patients receiving the same dose of clozapine. Therefore, routine therapeutic drug monitoring (TDM) is recommended to increase the response rate and to minimize dose-dependent toxic adverse events. Clozapine is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Cigarette smoke is a potent inducer of CYP1A2. The majority of schizophrenic patients are smokers. It was, therefore, the primary objective of this study to investigate the dose-dependent effect of smoking on the pharmacokinetics of clozapine. Materials and Methods: A retrospective study was conducted of data already collected from psychiatric patients in several Bavarian hospitals during routine TDM from 2000 to 2010. A total of 2493 clozapine serum concentrations assayed in our laboratory was anonymously stored in our TDM data bank in addition with information on date and time of blood withdrawal, clozapine dose, dosing schedule, duration of treatment, comedication, patient's sex, age, body weight and height, diagnosis, smoking behaviour, caffeine consumption, occurrence of adverse effects and clinical status. Clozapine concentrations were not only analyzed in relation to therapeutic reference range but also to a dose-related reference range which was calculated with a fixed total clearance value of 29.6 ± 14.1 l/h reported in the literature. Serum concentrations of patients with comedications which are known to interact with the metabolism of clozapine were excluded for most evaluations. Results: The total clearance of clozapine for non-smoking women was 23% lower than for men (17.9 ± 8.8 versus 23.3 ± 11.3 l/h). Smoking increased the total clearance of women by 63% (29.2 ± 19.1 l/h) and of men by 46% (34.0 ± 17.3 l/h). There were no significant differences in oral clearance of clozapine between patients smoking 1–10, 11–20 or more cigarettes daily. Serum concentrations of non-smoking women and men exceeded the upper limit of the therapeutic window twice to five-fold as often as smoker. In addition, in the non-smoking subgroup 48% of women and 36% of men displayed clozapine concentrations above the upper limit of the dose-related reference range (smokers: ♀ 7%, ♂ 23%). Conclusion: Serum concentrations of clozapine are mainly influenced by smoking status. Even a daily consumption of 1–10 cigarettes is sufficient for maximum induction of clozapine metabolism. To avoid adverse effects non-smokers should receive an about 50% lower starting dose of clozapine. In addition, similar clozapine dose reduction should be considered during smoking cessation.

In former years it was generally accepted to use therapeutic drug monitoring (TDM) to prevent toxic side effects of drugs with a narrow therapeutic window. Very often it was just used to confirm that a side effect that had already occurred was due to an elevated drug plasma concentration. For this purpose the quantified drug concentration was related to the therapeutic reference range of the drug. We relate the drug concentration to both the therapeutic reference range and the dose-related reference range. Dose-related reference ranges are calculated according to the mathematical equation De = Clt * c, where De is the maintenance dose and Clt the total clearance taken as x ± SD from phase II trials of the drug. A drug concentration outside this range is taken as a signal that the patient does not belong to the study population because of a comedication or a pharmacologically active food or drug component (drug-drug-interaction), an age below 18 years (children), an age above 65 years (old people), a genetically determined alteration in drug metabolism (fast/slow metabolizers), diseases in the elimination organs, or non-compliance. KONBEST, an internet platform that is programmed to allow clinical pharmacological commenting of drug concentrations in TDM, contains the relevant pharmacological data to calculate among others the dose-related reference ranges. By this approach we are able to prevent adverse drug reactions before the drug concentration is high enough to cause them.

Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants and are generally well tolerated. Specifically, less cardiovascular toxicity has been reported in comparison with tricyclic antidepressants. However, an increasing number of case reports and reviews of pharmacovigilance and toxicology databases describes an association of life-threatening cardiac arrhythmias known as torsade de pointes (TdP) with the use of citalopram and fluoxetine in therapeutic and toxic doses. In therapeutic doses, SSRI-associated Tdp concerned patients with additional risk factors such as concomitant cardiovascular disease, age over 65 years, female sex, hypokalemia and hypomagnesemia. Prolongation of the QTc interval predisposing to the occurrence of TdP has been observed with all SSRIs in supratherapeutic concentrations.