[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

Implementation of a cost-effective HPLC/UV approach for routine medical quantification of memantine in human serum.

BACKGROUND: In the near future, there will be no innovative drug principle for the treatment of dementia. Therefore, optimizing the efficacy of a drug is at present the most promising way to exploit its full pharmacological potential. METHOD: A high performance liquid chromatography with ultraviolet assay for memantine in serum from demented patients has been developed and validated. The analytical procedure involves offline solid phase extraction cartridges. Because memantine molecules lack chromophoric π-electrons, a derivatization with dansyl chloride was required for detection by ultraviolet (UV) photometry. Analyses were performed on a Dionex high-performance liquid chromatography system with a Phenomenex Luna Phenyl-Hexyl analytical column and 0.02 mol/L potassium dihydrogen phosphate buffer/acetonitrile (40/60 V/V) as mobile phase at a flow rate of 0.4 mL/min. Dansylated memantine was detected at 218 nm; 2 more ultraviolet wavelengths at 254 nm and 336 nm were used as an overlay-control check. RESULTS: The retention time for dansylated memantine was 17.1 ± 0.2 minutes. The calibration curve was linear over a concentration range from 5 to 160 ng/mL (n = 8/r² > 0.999). The method had an accuracy of >90%. Intra-assay and inter-assay coefficients of variation were <5% and <13%, respectively, at 3 different concentrations. The limit of quantification and the limit of detection were 2.9 ng/mL and 0.8 ng/mL, respectively. Among 100 substances prescribed as comedications in the treatment of dementia only fluvoxamine and zuclopenthixole showed retention times close to dansylated memantine (17.8 minutes and 18.1 minutes, respectively). However, these 2 drugs were removed from patients' specimens during solid-phase extraction sample preparation. CONCLUSIONS: The method is applicable under conditions of daily routine as has been demonstrated by application of the method to patient serum samples. The quantification of 29 samples showed that memantine concentrations suggested as "therapeutic" in the literature may only be reached by high doses of memantine.

Disentangling dyskinesia from parkinsonism in motor structures of patients with schizophrenia.

Patients with schizophrenia frequently suffer from motor abnormalities, but underlying alterations in neuroarchitecture remain unclear. Here, we aimed to disentangle dyskinesia from parkinsonism in motor structures of patients with schizophrenia and to assess associated molecular architecture. We measured grey matter of motor regions and correlated volumetric estimates with dyskinesia and parkinsonism severity. Associations with molecular architecture were identified by cross-modal spatial correlations between ensuing maps of abnormality-related volume alterations and neurotransmitter maps from healthy populations. Both phenomena were linked to (specific) striatal and basal forebrain reductions as well as to D1 receptor density. Dyskinesia also manifested in cerebellar decrease, while parkinsonism was associated with less motor cortex volume. The parkinsonism-related brain pattern was additionally associated with 5-HT1A/2A and µ-opioid receptors distribution. Findings suggest the need to develop psychopharmacological compounds that display not only selectivity for receptor subtypes but also anatomical selectivity for alleviating dyskinesia without worsening parkinsonism and vice versa.

[Delirium induced by drug treatment]. / Verwirrtheitszustände als wichtige Arzneimittelwirkung.

Delirium may be induced by a variety of reasons, among them drugs and in particular the combination of drugs. In elderly people a delirium is often misinterpreted as dementia. Anticholinergic activity is the mode of action by which drugs cause delirium. Antipsychotic drugs, antidepressants, antihistamines, and of course anticholinergic drugs themselves are the major anticholinergic classes of drugs. In addition some opioids have anticholinergic effects. Other drugs may induce delirium by dehydration (loop diuretics like furosemide) or sedation (benzodiazapines like lorazepam). Elderly people are at especially high risk to develop delirium, because of the multitude of drugs often prescribed to them, because they tend to drink to little, and because their brain is more sensitive to psychoactive drugs.

Individual clearance and therapeutic drug monitoring of quetiapine in clinical practice.

OBJECTIVE: Quetiapine is one of the most frequent prescribed antipsychotics. Based on the consensus guidelines of therapeutic drug monitoring (TDM) in clinical practice, TDM of Quetiapine is "useful". In this pilot study, using a natural sample, we investigated the influence of co-medication, age and gender on the serum concentrations and clearance of Quetiapine. Also we compared the individual clearance in our sample with the expected clearance for healthy subjects, obtained in controlled studies. METHODS: 150 blood samples were collected anonymously under clinical conditions, Quetiapine trough serum levels were determined using HPLC. Additional information about gender, age, co-medication and dosage was obtained. RESULTS: There was a significant, positive, but weak correlation between daily dose and serum levels of Quetiapine (r=0.44; p=0.01). When Carbamazepine was co-administered, the clearance was significantly higher (p=0.01). 83% of the serum levels were outside the therapeutic range, only 28% were within the expected clearance. CONCLUSIONS: In addition to the therapeutic range the individual clearance related to the expected clearance may help to optimize individual pharmacotherapy, especially for combination therapy or in case of incompliance or abnormal metabolism.

SARS-CoV-2 Risk Management in Clinical Psychiatry: A Few Considerations on How to Deal With an Unrivaled Threat.

The pandemic spread of the corona virus SARS-CoV-2 has even-handedly shattered national and international health systems and economies almost in an instant. As numbers of infections and COVID-19-related deaths rise from day to day, fears and uncertainties on how to deal with this unknown threat are extremely present both for individuals and societies as a whole. In this manuscript, we aim to exemplarily describe the bullet points concerning (a) the internal risk management, (b) the organizational and structural changes, and (c) the communicational strategies applied in a Psychiatric University Hospital in the Southern part of Germany. The authors are well aware about the fact that almost none of these considerations may be considered as evidence-based at the moment. However, the authors trust that these reflections and experiences may be useful as an orientation for similar risk constellations in other afflicted countries due to the temporal delay of the pandemic course.

Acute psychiatric inpatient care: a cross-cultural comparison between two hospitals in Germany and Japan.

BACKGROUND: Intercultural differences influence acute inpatient psychiatric care systems. AIMS: To evaluate characteristics of acute inpatient care in a German and a Japanese hospital. METHOD: Based on a sample of 465 admissions to the Psychiatric State Hospital Regensburg (BKR) and 91 admissions to the Hirakawa Hospital (HH) over a six-month period in 2008, data from the psychiatric basic documentation system (BADO) were analysed with regard to socio-demographic characteristics, treatment processes and outcome indicators. RESULTS: Schizophrenia and related psychosis was the most common diagnosis in both hospitals. Cases at the BKR were admitted more quickly after onset of the present episode. Global Assessment of Psychosocial Functioning (GAF) ratings at admission were lower at the HH. Most admissions to both hospitals received psychopharmacological treatment, but more at the HH received psychotherapy. Length of stay was significantly longer at the HH (75 days) than at the BKR (28 days). Admissions to the HH were more improved with regard to GAF and clinical global impression (CGI). CONCLUSIONS: Acute admissions in Germany provide intensive care with short hospitalization as crisis intervention. For acute admissions in Japan, comprehensive care for severe mental illness precedes emergency admissions and achieves greater improvement with longer hospitalization.

Recognizing and treating peripartum depression.

BACKGROUND: In this article, we review current data on the prevalence of, risk factors for, and treatment of peripartum depression. METHOD: Pertinent publications were retrieved by searches in Medline and the Cochrane Library using the key words "peri/pre/post", "partum/partal/natal", "maternal/motherhood/pregnancy", and "depression/affective disorder". RESULTS: Depression is the most common peripartal disease: The prevalence of depressive disorders is 18.4% during pregnancy and 19.2% in the puerperium. Prepartum depression is associated with preterm birth, low birth weight, and an abnormal fetal heart rate. In the long run, children of depressed mothers have been found to have impaired cognitive and emotional abilities. Risk factors for peripartal depression include prior depression, poor social support, poor quality of intimate relationship, and negative live events. Peripartum depression can be treated effectively with psychotherapy or drug therapy. Current data support the use of antidepressants during pregnancy and breastfeeding. In many places, pregnancy counseling centers offer low-threshold psychosocial assistance. Nonetheless, no more than 20% of the affected women are identified, even though rapid screening would be possible with instruments such as the Edinburgh Postnatal Depression Scale (EPDS) and the two Whooley questions. CONCLUSION: Peripartum depression is both common and treatable. Screening for depression should become a routine part of both prepartum care by gynecologists and postpartum care by midwives. This will only be possible, however, with expanded availability of ambulatory and inpatient psychotherapy and psychiatric care for the affected women and their children.

Hypothermia associated with antipsychotic drug use: a clinical case series and review of current literature.

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5-HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.

Implementation of a cost-effective HPLC/UV-approach for medical routine quantification of donepezil in human serum.

A novel, simple, specific and sensitive high performance liquid chromatography (HPLC) assay for the detection and quantification of donepezil in serum of demented patients has been developed and validated. The analytical procedure involves an offline serum preextraction using solid phase extraction (SPE) cartridges (Oasis® HLB, Waters Co). The chromatographic analyses were performed on a Dionex HPLC system with a Phenomenex Luna Phenyl-Hexyl analytical column, and a mobile phase with the two components 0.02 mol/l phosphate buffer and acetonitrile. The flow rate was 0.4 ml/min. For the detection of donepezil three different UV wavelengths were used as an interference-control check. Interference tests between donepezil and 100 of the most commonly used concomitant medications allow quantification of donepezil under the polypharmaceutical conditions of the daily clinical routine. The retention time for donepezil was 12.1 min. The method was validated according to the guidelines of the Society of Toxicology and Forensic Chemistry (GTFCh): The calibration curve was linear over a concentration range from 5 to 160 ng/ml (n=8/r²>0.999). No endogenous compounds were found to interfere with the analyte, which was shown by retention times for the comedication most often prescribed to demented patients. The method had an accuracy of >85%. Intra- and inter-assay coefficients of variation were <6% and <8%, respectively, at three different concentrations. The limit of quantification (LOQ) and the limit of detection (LOD) were found to be 6.1 and 1.7 ng/ml for donepezil. Application of the method to patient serum samples discovered that concentrations suggested as "therapeutic" in the literature may only be reached either by high, off-label dosages or by utilization of inhibitory metabolic effects of the comedication.

QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes.

INTRODUCTION: Many psychotropic drugs can delay cardiac repolarization and thereby prolong the rate-corrected QT interval (QTc). A prolonged QTc often arouses concern in clinical practice, as it can be followed, in rare cases, by the life-threatening polymorphic ventricular tachyarrhythmia called torsade de pointes (TdP). METHOD: We searched PubMed for pertinent literature on the risk of QTc prolongation and/or TdP associated with commonly used psychotropic drugs. RESULTS: Thioridazine and ziprasidone confer the highest risk of QTc prolongation and/or TdP. There is also a clinically significant risk associated with haloperidol given intravenously in high doses. TdP has been reported in a few cases in association with the use of newer antipsychotic drugs (mainly quetiapine and amisulpride), most of the tri- and tetracyclic antidepressants, and the selective monoamine reuptake inhibitors citalopram, fluoxetine, paroxetine, and venlafaxine. As a rule, however, QTc prolongation and/or TdP occur only in the presence of multiple additional risk factors, such as age over 65 years, pre-existing cardiovascular disease, bradycardia, female sex, hypokalemia, hypomagnesemia, a supratherapeutic or toxic serum concentration, or the simultaneous administration of other drugs that delay repolarization or interfere with drug metabolism. CONCLUSION: Before prescribing a psychotropic drug, the physician should carefully assess its risks and benefits to avoid this type of adverse reaction, particularly when additional risk factors are present. The ECG and electrolytes should be regularly monitored in patients taking psychotropic drugs.

[Small numbers, big results: Weiden--a suicide stronghold?]. / Kleine Zahlen, große Ergebnisse: "Suizidhochburg" Weiden?

OBJECTIVE: According to a recent survey based on the years 2005-2007, the highest suicide rate in Germany was found for the town Weiden (Bavaria, Upper Palatinate). We aimed at having a closer look at this finding by using a longer investigation period (2000-2008). METHODS: Suicide rates of Weiden were contrasted with suicide rates of Bavaria and Germany. Data were obtained from the Bavarian State Office for Statistics and Data Processing and the German Federal Statistical Office. RESULTS: The finding named above was based on the influence of a data outlier (2006) in the number of annual suicides which is clearly evened out by examining the longer investigation period from 2000-2008. The suicide rate of Weiden is indeed higher than suicide rate of Germany and slightly higher than suicide rate of Bavaria, but not to such a drastic degree as had been stated. CONCLUSIONS: Investigation period and number of inhabitants have to be considered at interpreting suicide rate studies to prevent jumping to a conclusion.

[Antipsychotic treatment of dementia after publication of new risks]. / Folgen neu erkannter Arzneimittelrisiken auf die Antipsychotikaverordnung bei Demenzerkrankten.

OBJECTIVE: We investigated the change of antipsychotic treatment of elderly persons with dementia after several publications indicated an association between use of antipsychotics and cerebrovascular events in this population. METHODS: Twice a year, the complete medication, age, diagnosis and gender of all inpatients in 30 German psychiatric sites is collected anonymously in a data base for statistical analysis. RESULTS: The treatment changed for the benefit of Quetiapine and Haloperidol. The use of both Risperidone and Olanzapine decreased markedly. CONCLUSION: The antipsychotic treatment changed due to critical publication. But, the evidence for the risk profile is still a matter of debate.

[Psychopharmacoepidemiology: differences in prescribing strategies in the inpatient and outpatient settings]. / Psychopharmakoepidemiologie: Qualitative Unterschiede zwischen stationären und ambulanten Verordnungsstrategien.

OBJECTIVE: Doctors' prescribing behaviour in 34 psychiatric hospitals in southern Germany was investigated and compared with outpatient prescribing behaviour of doctors licensed to practise within the German health insurance system. METHODS: On the basis of the AGATE cut-off dates for 2000-2006, we analysed developments in the drug groups antidepressants, neuroleptics, benzodiazepines, and antidementia drugs over time. RESULTS: The proportion of inpatient prescriptions of antidepressants and antidementia drugs is increasing, whereas neuroleptics and benzodiazepines are undergoing the reverse trend. The proportion of generics in inpatient prescriptions is notably lower than in outpatient prescriptions. CONCLUSIONS: The differences between inpatient and outpatient prescribing behaviour results in a lack of continuity of care. Health economic incentive systems therefore require standardisation.

[Genetic tau-variants in patients with frontotemporal dementia]. / Tau-assoziierte genetische Polymorphismen bei frontotemporaler Demenz.

OBJECTIVE: [corrected] To evaluate tau-associated genetic polymorphisms in patients with sporadic frontotemporal dementia (FTD) and healthy control subjects. METHOD: Tau-gene sequence of 30 patients with FTD and 30 healthy controls was analysed by polymerase-chain-reaction (PCR). Subsequent sequencing was performed to identify exonic and intronic differences between both groups. RESULTS: The following polypmorphisms, which are localized closely to each exon-intron-border, have been identified: In 37 % (n = 11) of the control subjects three different intronic polymorphisms occur simultaneously (Intron 2, 263, C --> Y; Intron 3, 590, A --> R; Intron 11, 150, G --> A). In the FTD group, this coexistance has been observed only in 17 % (n = 5). CONCLUSIONS: In how far there exists a significant correlation between the newly identified triple polymorphism in the Tau gene and an alternated risk for FTD must be evaluated in a lager population. The proximity of these polymorphisms to the exon-intron border would facilitate functional influences on gene expression patterns. These preliminary results described, above potentially point to further pathogenetic factors in the genesis of FTD.