How to determine whether conceptual endophenotypes can improve clinical outcomes in patients suffering from major depression: An exploratory approach.

Depression is a complex mental health disorder, resulting in a high degree of disability. Since symptom constellation, course, and outcome are heterogeneous in these patients, current research initiatives are striving to establish stratified diagnostic and treatment approaches. In the past two decades, Dirk Hellhammer and his team introduced Neuropattern, a new diagnostic concept, which is based on conceptual endophenotypes of the stress response network. We explore how to use this concept in clinical practice in order to ultimately determine whether it brings any value over standard care. In view of the novelty of the concept and the difficulties dealing with such a concept at a practical level, it was necessary to initiate an exploratory study to determine key factors for planning future clinical trials. We report results and knowledge gained from an exploratory single-site study investigating the use and potential benefits of Neuropattern in standard care. Inpatients (ICD-10 diagnosis F32, F33; Nö=ö178) were allocated to either treatment as usual (standard group, SG) or a novel Neuropattern oriented exploratory treatment (intervention group, IG). Symptom severity was assessed with psychometric tests at admission to hospital, during the first six weeks, and upon discharge from the hospital. In addition, direct and indirect costs were assessed for the 3-month-intervals prior to and after the hospital stay. Compared to the SG, depression scores of patients in the IG showed a faster decline once psychotherapeutic and pharmacological treatment were based on an individualized explanatory model. The patients in the IG with an F33 diagnosis showed a more pronounced reduction of depression severity during the stay in the hospital and a stronger and quicker reduction of general symptom severity. Comparing the average depression scores at the start of the study and after six weeks, symptom severity was reduced in all Neuropattern groups. Some limitations of the study have to be mentioned: The study was not blinded, was single-site, included highly depressed inpatients only, and was conducted for no longer than 8 months. The results highlight some important issues regarding taking the Neuropattern approach to the bedside and researching its efficacy and effectiveness to support personalized treatments in clinical care.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

QLiS-SF: Development of a short form of the quality of life in schizophrenia questionnaire.

BACKGROUND: There is a need for useful standardized Quality of Life (QoL) measures for people diagnosed with schizophrenia. Therefore, a short form of the self-administered Quality of Life in Schizophrenia (QLiS) scale was developed and validated. METHODS: Four steps were taken to develop the abridged version using samples from the Clinical Analysis of the Treatment of Schizophrenia (CATS) study. Firstly, a model with second order scales was developed using exploratory factor analysis (EFA). Secondly, it was tested in an independent sample using confirmatory factor analysis (CFA). Thirdly, this model served as the basis for selecting items for the short form. Distributional properties, content reviews, and factor loadings were taken into account in this step. Fourthly, the resulting short form was validated through confirmatory factor analysis (CFA). Composite reliability scores were calculated for the new subscales. RESULTS: Three second order scales were constructed: illness-related quality of life (QoL), social life and finances, and global subjective well-being. CFA of the new theoretical model resulted in a CFI of 0.67 and absolute fit indices of CMIN/df = 2.55, RMSEA = 0.08, SRMR = 0.09. The selected 13 items showed good statistical properties and good fit of content to subscale. Fit of the underlying theoretical model with the reduced number of items was tested in an independent sample. Absolute and fit indices of the short form model were satisfactory (CFI = 0.95, CMIN/df = 2.23, RMSEA = 0.06, SRMR = 0.04). Composite reliability scores for three subscales were above 0.70. CONCLUSIONS: The short form of the QLIS (QLiS-SF) showed good model fit and reliability. It should only be considered for use if the application of the long version is not suitable.

[Affective disorders during pregnancy : Therapy with antidepressants and mood stabilizers]. / Affektive Störungen in der Schwangerschaft : Therapie mit Antidepressiva und Mood Stabilizern.

BACKGROUND: It is not rare that the first manifestation or relapse of an affective disorder occurs during pregnancy. Should a pharmacological treatment be indicated, the selection of a suitable substance should be made on a basis which is as safe as possible. Even when treating women of childbearing age it should be assured that the psychotropic drug selected is safe to use during pregnancy as a high percentage of pregnancies are unplanned. OBJECTIVE: When assessing the risks and benefits of psychopharmacotherapy in women who are or wish to get pregnant, not only the exposure of the child to potentially teratogenic drug effects but also potential complications during or after pregnancy and long-term neuropsychological issues need to be addressed. METHODS: This article provides an overview of the currently available literature on the use of antidepressants and mood stabilizers during pregnancy. RESULTS: A growing body of increasingly reliable data for many antidepressants and mood stabilizers are available, which allow a good prediction of their suitability for use during pregnancy and lactation. CONCLUSION: When treating affective disorders during pregnancy an individual assessment of the benefits and risks for mother and child is required. The benefit of an appropriate treatment for the mother by including medication which may be potentially harmful to the child versus the risk of an insufficient treatment for the mother by excluding medication which may be potentially harmful to both the mother and the child need to be weighed up. When a suitable psychopharmacotherapy during pregnancy has been selected, the risk for mother and child can be minimized by incorporation of therapeutic drug monitoring.

[Psychopharmacotherapy during pregnancy : Which antipsychotics, tranquilizers and hypnotics are suitable?]. / Psychopharmakotherapie in der Schwangerschaft : Welche Antipsychotika, Tranquilizer und Hypnotika sind geeignet?

BACKGROUND: When administering psychotropic drugs during pregnancy not only the potential teratogenic effects on the child must be addressed but also the fetotoxic implications for pregnancy and/or the peripartum phase as well as possible neurocognitive developmental disorders must be considered. OBJECTIVE: Evaluation of the risks and benefits of administering psychotropic drugs during pregnancy or for women who wish to become pregnant. METHODS: The literature has been reviewed with the purpose of providing information on psychotropic drugs which can safely be administered during pregnancy. The review considers antipsychotics as well as tranquilizers and hypnotics. RESULTS: Data are available for a multitude of psychotropic drugs that allow a safe estimation on their suitability for use during pregnancy. CONCLUSION: When treating mental illnesses during pregnancy the option of administering drugs must not principally be ruled out. What is required is an individual assessment of benefits and risks. The risk of an untreated mental illness versus the benefit of a suitable treatment, which may include the use of medication and the potential harm to the infant must be evaluated. If certain rules are observed and a suitable drug is selected the risk to the newborn child and/or mother during pregnancy can be minimized. During pregnancy, therapeutic drug monitoring is indicated and increases the safety for use of drugs and preventing harm to both mother and infant.

Ca(BH4)2-Mg2NiH4: on the pathway to a Ca(BH4)2 system with a reversible hydrogen cycle.

The Ca(BH4)2-Mg2NiH4 system presented here is, to the best of our knowledge, the first described Ca(BH4)2-based hydride composite that reversibly transfers boron from the Ca-based compound(s) to the reaction partner. The ternary boride MgNi2.5B2 is formed upon dehydrogenation and the formation of Ca(BH4)2 upon rehydrogenation is confirmed.

A new potassium-based intermediate and its role in the desorption properties of the K-Mg-N-H system.

New insights into the reaction pathways of different potassium/magnesium amide-hydride based systems are discussed. In situ SR-PXD experiments were for the first time performed in order to reveal the evolution of the phases connected with the hydrogen releasing processes. Evidence of a new K-N-H intermediate is shown and discussed with particular focus on structural modification. Based on these results, a new reaction mechanism of amide-hydride anionic exchange is proposed.

Assessment of cardiovascular disease risk in patients with schizophrenia spectrum disorders in German psychiatric hospitals: results of the pharmacoepidemiologic CATS study.

PURPOSE: Patients with severe mental illness are at high risk for metabolic and cardiac disorders. Thus, monitoring of cardiovascular risks is imperative and schedules for screening for lipids, glucose, body mass index (BMI), waist-hip ratio and blood pressure have been developed. We intended to analyze screening for metabolic disorders in German patients with schizophrenia spectrum disorders in routine psychiatric care. METHODS: We included 674 patients with any F2 diagnosis in out- and inpatient settings and analyzed metabolic screening procedures as practiced under conditions of usual care. RESULTS: Except BMI (54 %), all other values were documented only in a minority of patients: waist circumference (23 %), cholesterol (28 %), fasting glucose (19 %), triglycerides (25 %) and blood pressure (37 %). We found evidence for less than perfect quality of blood pressure measures. The group of patients who met the individual metabolic syndrome ATP III criteria was comparable to the US CATIE trial. CONCLUSIONS: We conclude that frequency and quality of metabolic monitoring in German in- and outpatients settings are not in accordance with the respective recommendations. Similar to previous reports we found evidence for a high prevalence of metabolic disturbances in German patients with schizophrenia spectrum disorders.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

High bone turnover but normal bone mineral density in women suffering from schizophrenia.

BACKGROUND: A potential association between schizophrenia and osteoporosis or osteopenia has recently been reported. Various factors affect bone mineral density (BMD) such as polydipsia, nicotine, alcohol abuse, lack of physical activity, an unbalanced diet, a lack of ultraviolet exposure and/or vitamin D. In addition, decreased BMD in women with schizophrenia has been attributed to drug-induced hyperprolactinaemia and/or secondary hypogonadism. This study was undertaken because empirical evidence from larger patient cohorts is limited and the data are still controversial. METHOD: Seventy-two premenopausal, regularly menstruating women suffering from schizophrenia and 71 age- and sex-matched healthy controls were included in the study. Biochemical markers of bone turnover (serum osteocalcin, urinary pyridinium crosslinks), parathyroid hormone and 25-hydroxyvitamin D were measured. BMD at the femoral neck and lumbar spine was determined by dual-energy X-ray absorptiometry in a subgroup of 59 patients. In addition, 17beta-oestradiol, prolactin, testosterone, gonadotrophins and dehydroepiandrosterone sulfate were measured. RESULTS: Compared with healthy controls, both markers of formation and resorption were increased in women with schizophrenia. However, in the subgroup of 59 patients, BMD was within the normal range. In women suffering from schizophrenia, testosterone levels were higher than in controls, and serum oestradiol levels were lower compared with the normal range. CONCLUSION: Despite significantly increased bone turnover, we conclude that premenopausal and regularly menstruating women suffering from schizophrenia have normal spine and hip BMD. This may be due to the opposite effects of the various parameters influencing bone metabolism, especially of the gonadal hormones, and due to an intact coupling mechanism.

[Exacerbation of a schizoaffective psychosis after in vitro fertilization with leuproreline acetate]. / Exazerbation einer schizoaffektiven Psychose nach In-vitro-Fertilisation mit Leuprorelinacetat.

Leuproreline acetate is a gonadotropin-releasing hormone (GnRH) analog which is used for in vitro fertilization (IVF) treatment. This compound suppresses gonadal estrogen secretion prior to hormonal stimulation. We report a 37-year-old woman who suffered from a schizoaffective psychosis for several years. She received IVF treatment with leuproreline acetate (Uno-Enantone) because of primary infertility. Under this treatment she developed acute schizoaffective symptoms. Suppression of gonadal secretion can result in exacerbation of schizophrenic psychosis, which is in line with the hypothesis of protective effects of estrogen in schizophrenia. We recommend that IVF treatment with leuproreline acetate in patients with psychiatric disorders be initiated only with special attention to their mental condition. In addition, patients should be informed about the possible mental effects of the treatment.

Plasma amisulpride levels in schizophrenia or schizoaffective disorder.

The atypical antipsychotic drug amisulpride is a benzamide with specific antagonistic properties, which target dopamine D(2) and D(3) receptors, preferentially in the limbic system. Amisulpride is readily absorbed from the gastrointestinal tract, distributed to all body systems with little binding to plasma proteins. Elimination occurs mainly through the kidneys as unchanged drug. In contrast, hepatic metabolism is of minor significance and primarily yields two inactive metabolites. Very little is known about the plasma concentrations of amisulpride in patients at varying oral doses or about clinically relevant interactions with co-medication. The aim of the present investigation was to elucidate the factors, which affect amisulpride levels in schizophrenic patients. The plasma amisulpride levels of 85 patients with schizophrenia or schizoaffective disorder (mean age: 34.0+/-11.4 years; 40 women, 45 men) were assessed by high-performance liquid chromatography (HPLC) with fluorometric detection. The average daily dose of amisulpride was 772.3 mg (S.D. 346.7 mg) and the mean amisulpride plasma concentration was 424.4 ng/ml (S.D. 292.8 ng/ml). The interindividual variance of the amisulpride plasma concentration was high; furthermore, the plasma concentration increased linearly with the daily oral dose (r=0.50, p<0.001). Age and gender showed a significant effect on the dose-corrected amisulpride plasma concentrations-older patients and women had higher dose-corrected amisulpride plasma concentrations than younger patients and men. However, cigarette consumption had no effect on the amisulpride plasma concentrations. Regarding co-medication with lithium and/or clozapine, significantly higher amisulpride plasma concentrations were found as compared to monotherapy, whereas other co-medications such as benzodiazepines and various conventional antipsychotics had no effect on the amisulpride plasma concentrations. The results, the possible pathomechanisms and the clinical relevance are discussed. The findings need to be confirmed in larger patient samples and with a wider range of co-medications.

Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients.

BACKGROUND: Olanzapine, a thienobenzodiazepine, is one of the relatively new atypical antipsychotic drugs. The lowest threshold of effective olanzapine plasma levels in inpatient treatment is assumed to be 9 ng/ml. Very little is known about the plasma concentration in patients at various oral doses of olanzapine or about the clinically relevant interactions with co-medications. METHODS: In 71 schizophrenic patients (age 32.6 +/- 12.1, range 18-63 years; 31 women, 40 men), plasma olanzapine levels were assessed in 377 tests by high-performance liquid chromatography (HPLC) with electrochemical detection. Fifty-six of these plasma levels were assessed while patients were receiving olanzapine as monotherapy; otherwise, the plasma levels were assessed with the patients receiving various co-medications. RESULTS: The mean daily oral dose of olanzapine was 17.5 mg (SD = 7.0, range 5-40 mg), and the mean olanzapine plasma concentration was 54.2 ng/ml (SD 37.8 ng/ml, range 1.2-208 ng/ml). The plasma concentration of olanzapine increased linearly with the daily oral dose (r = 0.64, p < 0.001). A multiple variance analysis considering age and sex as covariables showed a significant difference in the dose-corrected plasma levels of olanzapine among 40 smokers and 31 non-smokers; age and sex did not affect the dose-corrected plasma levels. However, women received a significantly lower daily dose of olanzapine under routine clinical study conditions. No differences could be detected among the dose-corrected plasma concentration of those patients who were taken off olanzapine because they did not respond (n = 14) or because of side effects (n = 5) and those who were discharged while still on olanzapine. Under the co-medication with fluvoxamine, significantly higher dose-corrected olanzapine plasma concentrations were found than with olanzapine monotherapy, whereas significantly lower dose-corrected olanzapine plasma concentrations were detected under lithium and trimipramine co-medication. Under co-medication with amitriptyline, benperidol, carbamazepine, flupentixol, and lorazepam, the dose-corrected olanzapine plasma concentrations were no different than the plasma levels under olanzapine monotherapy. CONCLUSIONS: The relevance of therapeutic drug monitoring is emphasized with respect to the data presented and to the literature. Future studies should examine, in particular, the effects of a wider range of co-medications in a larger patient sample.

Omeprazole reduces clozapine plasma concentrations. A case report.

A number of interactions of the atypical antipsychotic clozapine with other drugs are well known, some of which can be attributed in part to the pharmacokinetic interactions associated with cytochrome P450 enzymes during drug metabolism. Clozapine is mainly metabolized by the cytochrome P450 isoenzyme 1A2. The proton pump inhibitor omeprazole can induce CYP1A2. We report on two patients with schizoaffective disorder who received omeprazole in addition to clozapine because of gastrointestinal complaints. Before the co-medication with omeprazole was started, the patients had been receiving clozapine for 78 and 41 days and for 40 and 8 days at a stable daily dose of 325 mg (patients 1 and 2, respectively). The co-medication with omeprazole was associated with a reduction in the plasma levels of clozapine of 41.9 % and 44.7 %, respectively, in these patients. The decrease in the plasma concentrations of clozapine in the presence of omeprazole might be due to the induction of the cytochrome P450 isoenzyme CYP1A2. If patients are receiving omeprazole as co-medication, close monitoring of plasma clozapine levels is recommended. If clozapine levels drop, the drug should be adjusted accordingly. If necessary, an alternative to omeprazole should be chosen.

H(2)-histamine antagonist (famotidine) induced adverse CNS reactions with long-standing secondary mania and epileptic seizures.

We report on the case of a 65-year-old female who was treated for one week with famotidine, a reversible H(2)-histamine antagonist, due to gastric pain. Shortly after treatment began, she presented manic symptoms and developed two generalized seizures, after which famotidine was discontinued. Manic symptoms were present for three months; intermittent treatment with both carbamazepine and antipsychotic medication was necessary before her mental status was completely restored. While cimetidine and ranitidine are known to cause secondary mania, this symptom has not been described for famotidine. CNS side effects are usually short-lived and respond to discontinuation of the drug, which was not the case in our patient. During a follow-up period that has so far lasted four years, the patient has been stable without any psychiatric medication. Adjusting the maintenance dosage of H(2)-histamine antagonists has been recommended in elderly patients since age-related reduction in renal plasma flow, glomerular filtration rate and renal tubular function may be present, which can in turn elevate histamine levels in plasma and cerebrospinal fluid. Our patient, however, had normal renal function and was free of organic or psychiatric diseases, so what pathogenetic mechanism led to the remarkably long standing manic syndrome after a relatively short course of famotidine remained unknown; famotidine seems to cause the same spectrum of adverse central nervous system (CNS) reactions as other H(2)-histamine antagonists.

Acute psychiatric admission and menstrual cycle phase in women with schizophrenia.

The clinical observation of a possible relation between the phases of the menstrual cycle and psychotic illness dates well back to the beginning of the nineteenth century. This relation is considered to provide further evidence for the protective effect of oestrogens in schizophrenic women and is summarised by the so-called oestrogen hypothesis. In addition, the hypoestrogenism hypothesis postulates a hypofunction of the gonads in women with schizophrenia with subsequent oestrogen deficiency syndrome. The aim of the present clinical study was to answer the question whether there is a perimenstrual increase in hospital admissions of women suffering from an exacerbation of schizophrenia. Two samples of premenopausal women with schizophrenia were investigated (sample 1: n = 115; sample 2: n = 170). In both samples there was a significant increase in admissions in the perimenstrual phase - three days before and three days after the first day of the menses (sample 1: P = 0.002, sample 2: P = 0.028, binomial test). 37.4% of the patients were admitted during the perimenstrual phase of the cycle in sample 1, 31.8% in sample 2. Regarding age, age at onset, and duration of illness, no difference was found between the group admitted to hospital during the perimenstrual phase versus the group admitted during the rest of the menstrual cycle in either of the samples. The results are discussed in relation to the possibly underlying physiological mechanisms.

Asymptomatic pancreatitis associated with clozapine.

Besides the well-known adverse effects of clozapine, such as granulocytopenia, tiredness and hypersalivation, acute pancreatitis is known to be a very rare complication of the drug. In the literature a total of five case reports have been published so far. We report a case of asymptomatic pancreatitis subsequent to clozapine treatment at therapeutic doses in a 38-year-old male patient with chronic paranoid-hallucinatory schizophrenia. The patient was rehospitalized after an acute exacerbation of the psychosis subsequent to an attempt to change medication on an outpatient basis. Treatment with clozapine was initiated again. During phases of progressively increasing the clozapine dose, serum levels of amylase and lipase were increased; after maintaining daily doses of clozapine of 300 mg and/or 600 mg the pancreatic enzymes normalized quickly within a few days. The patient did not report any pancreas-related complaints, nor did specific diagnostic studies produce any indicative result, only a minor thickening of the head and body of the pancreas in the ultrasound. It is assumed that the phenomenon of subclinical, asymptomatic pancreatitis during increasing dosage of clozapine occurs more often than previously supposed. The monitoring of serum amylase levels during slow increase in clozapine is recommended; if leukocytosis or eosinophilia is present, the possibility of even a subclinical and asymptomatic pancreatitis should be considered.

Concentration-effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

1. The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (+/- 9.1 s.d.) ng ml-1 h per mg and 23.2 (+/- 4.6 s.d.) ng ml-1 h per mg after the CR-formulation. Cmax was 1714 (+/- 1027 s.d.) ng ml-1 after the IR-formulation and 1494 (+/- 383 s.d.) ng ml-1 after the CR-formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/- 144 s.d.) ng ml-1 (IR) and 1024 (+/- 502 s.d.) ng ml-1 (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/- 0.5 s.d.) h (IR) and 2.8 (+/- 0.7 s.d.) h (CR), respectively (95%-CI: 1.12-2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)