[Use of summaries of product characteristics (SmPC) among family doctors and pharmacists in the context of the aut-idem regulation: Results of an exploratory cross-sectional survey]. / Nutzung von Fachinformationen bei Hausärzten und Apothekern im Zusammenhang der Aut-idem-Regelung: Ergebnisse einer explorativen Querschnittsbefragung.

INTRODUCTION: Summaries of product characteristics (SmPC) of same-substance medications may feature content-related differences. This may cause difficulties regarding informed consent in the case of prescriptions of drugs in the context of the aut-idem regulation. A survey among family doctors (FD) and pharmacists (PH) was conducted in order to evaluate the usage behaviour of SmPCs, sources used to obtain information about drugs and the awareness of the existence of differences between SmPCs of same-substance medications. METHODS: An exploratory/non-representative, questionnaire- and telephone-based, semi-structured cross-sectional survey was performed (June to August 2018). RESULTS: Participation rate of FD and PH was 29.8 % (34/114) and 73.0 % (73/100), respectively. In the previous month, all PH and 82.4 % of FD said that they had used a SmPC at least once (p=0.001). FD used SmPCs 6.4±4.9 and PH 65.0±52.5 times a month (p<0.001). In both occupational groups SmPCs were used most frequently to obtain information about dosing and/or type of application (FD: 97.1 %; PH: 98.6 %) and contraindications (97.1 % and 86.3 %, resp.). In both samples, the internet was the most frequently used drug information source (FD: 97.1 %; PH: 98.6 %), followed by the Rote/Gelbe Liste (97.1 % and 71.2 %, resp.) and the SmPCs of the original product (52.9 % and 65.8 %, resp.) or generic drug (52.9 % and 61.6 %, resp.). Only 32.4 % of the FD vs. 79.5 % of PH believed that differences might exist between SmPCs of same-substance medications (p<0.001). FD stated that they never (11.8 %) or rarely (85.3 %) use SmPCs for informed consent. It was indicated that the aut-idem substitution is excluded in 10.3 %±5.0 (FD) and 9.6 %±6,1 (PH) of issued or received prescriptions. DISCUSSION: The results of the present survey indicate a low utilization rate of SmPCs by FD and little awareness of the existing differences of SmPCs of same-substance medications in this occupational group. Both aspects may impede proper information of patients, particularly in cases of aut-idem prescriptions of substances for which many same-substance medications with different SmPCs are available. CONCLUSION: Physicians should use SmPCs regularly and keep themselves informed about differences between SmPCs of same-substance medications.

Abnormal cerebellar volume in somatic vs. non-somatic delusional disorders.

BACKGROUND: There is abundant evidence for cerebellar involvement in schizophrenia, where the cerebellum has been suggested to contribute to cognitive, affective and motor dysfunction. More recently, specific cerebellar regions have also been associated with psychotic symptoms, particularly with auditory verbal hallucinations. In contrast, little is known about cerebellar contributions to delusions, and even less is known about whether cerebellar involvement differs by delusional content. METHODS: Using structural magnetic resonance imaging at 1.0 T together with cerebellum-optimized segmentation techniques, we investigated gray matter volume (GMV) in 14 patients with somatic-type delusional disorder (S-DD), 18 patients with non-somatic delusional disorder (NS-DD) and 18 patients with schizophrenia (SZ) with persistent non-somatic delusions. A total of 32 healthy controls (HC) were included. Between-group comparisons were adjusted for age, gender, chlorpromazine equivalents and illness duration. RESULTS: Compared to HC, S-DD patients showed decreased GMV in left lobule VIIIa. In addition, S-DD patients showed decreased GMV in lobule V and increased GMV in bilateral lobule VIIa/crus II compared to NS-DD. Patients with SZ showed increased GMV in right lobule VI and VIIa/crus I compared to HC. Significant differences between HC and NS-DD were not found. CONCLUSIONS: The data support the notion of cerebellar dysfunction in psychotic disorders. Distinct cerebellar deficits, predominantly linked to sensorimotor processing, may be detected in delusional disorders presenting with predominantly somatic content.

[Different number of contraindications between summaries of product characteristics (SmPC) of drugs with the same active ingredients - an analysis of data from SmPCs of neuropsychiatric drugs]. / Unterschiedliche Anzahl von Kontraindikationen zwischen Fachinformationen wirkstoffgleicher Arzneimittel ­ eine Analyse von Daten aus Fachinformationen von neuropsychiatrischen Arzneimitteln.

OBJECTIVE: In the case of prescriptions of pharmaceuticals in the context of the aut-idem-regulation the physician frequently does not know, which same-substance medication is dispensed in the pharmacy; the contemplable same-substance medications may differ in numerous features which raises questions regarding the obligation to give information and medical liability for medical malpractice. Currently, systematic evaluations regarding differences between summaries of product characteristics (SmPCs) of same-substance medications are missing. To determine size and type of those differences SmPCs of most (neuro)psychiatric drugs that are approved in Germany were evaluated regarding the number of listed contraindications (CI). METHODS: Basis for the selection of substances was the Anatomical Therapeutic Chemical (ATC) Classification System (group ATC N Nervous System). Substances that are approved in Germany for the treatment of mental disorders according to ICD-10 F were included. Brand-name medications and SmPCs were searched by means of further in- and exclusion criteria via the online services of PharmNet.Bund, Gelbe Liste, Rote Liste®/Fachinfo-Service® and communication with the manufacturer. RESULTS: N = 941 SmPCs (=116 substances) were evaluated. Considering only the group of SmPCs with > 1 brand-name medication (n = 78; 67.2 %) differences in the number of CIs were found in more than the half of substances (N = 43; 55.1 %). Considering indication groups most groups of SmPCs of same-substance medications with differences in the numbers of CIs were found in - considering only substances with > 1 brand-name medication - hypnotics and sedatives (77.8 %), anxiolytics (75.0 %), drugs for treatment of substance use disorders (66.7 %), antidepressants (61,9 %), anticonvulsant drugs and mood stabilizers (53.8 %), followed by antipsychotics (41.2 %), antidementia-drugs (20.0 %), and psychostimulants (0 %). Largest ranges regarding the number of CIs were found in the SmPCs of morphine (14), amitriptyline (8), chlorprothixene (6), lorazepam (6) and citalopram (4). CONCLUSION(S): In numerous (neuro-)psychopharmacologic substances differences exists between the SmPCs of the associated same-substance medications regarding the number of CIs. Due to the outstanding evaluation of content aspects of these differences and legal evaluation the relevance of this result for clinical practice is not yet clear.

Retinal single-layer analysis with optical coherence tomography (OCT) in schizophrenia spectrum disorder.

BACKGROUND: Volume reductions in brain structures of patients with schizophrenia spectrum disorder (SSD) have repeatedly been found in voxel-based morphometry MRI studies. Hence, an underlying neurodegenerative etiological component of SSD is currently being discussed. In recent years, the imaging method of optical coherence tomography (OCT) has shown its potential in evaluating structural changes in the retina in patients with confirmed neurodegenerative disorders, providing a window into the brain. METHODS: Twenty-six patients with schizophrenia or schizoaffective disorder and 23 age- and sex-matched healthy controls were examined with the Heidelberg Spectralis OCT system to derive a single-layer analysis of both retinas. The segmentation of retinal layers was manually corrected to minimize artifacts and software imprecisions. RESULTS: Compared to the control group, SSD patients showed reduced thickness and volume measurements for nearly all retinal layers, and these differences reached significance for macular volume, macular thickness, retinal nerve fiber layer (RNFL) and inner nucleiform layer (INL). Furthermore, a significant correlation between the duration of illness and the total volume of the RNFL was found. CONCLUSION: Our OCT measurements demonstrate reduced single retinal layer thickness in patients with SSD. In the context of the MRI volume changes, our results provide further evidence that structural changes seen in the brain of patients are also observable in the retina, potentially allowing further insights into the different components of the nervous system that are altered in this highly etiologically complex disorder.

Psychiatrists' and dentists' knowledge and attitudes regarding adverse drug reactions of psychotropic drugs.

Psychotropic drugs may induce impairments in the mouth, jaw and face area. Currently, appropriate pharmacoepidemiologic data are missing. Therefore, a questionnaire-based telephone survey of two non-representative samples of psychiatrists and dentists was conducted. Most of the psychiatrists (79.7%) and dentists (76.5%) indicated that psychotropic drugs may induce dental adverse drug reactions (ADR); in both samples there was an approximately equally sized, relevant proportion of participants who did not believe in the risk of dental ADR of psychotropic drugs (psychiatrists 20.3%; dentists 23.5%). About one third of the participants of both samples (psychiatrists 34.9%; dentists 35.9%) felt that dental ADRs of psychotropic drugs are a serious health problem. The majority of both groups (psychiatrists 97.8%; dentists 97.0%) had never reported a dental ADR. Most psychiatrists and dentists appeared to be aware of the risk of dental ADRs by psychotropic drugs. A relevant proportion of participants of both groups considered psychotropic drugs to be irrelevant regarding dental ADRs; therefore, there may be information needs in both groups. The willingness to report dental ADRs of psychotropic drugs was low in both groups; the evaluation of the actual relevance of this drug-related risk is impeded by the absence of reports of suspected ADRs.

Longer Duration of Untreated Psychosis is Associated with Poorer Outcomes for Patients with Delusional Infestation.

We examined the association between the duration of untreated psychosis and outcome for patients with delusional infestation. This multi-centre international study included 211 consecutive patients. Illness severity was evaluated at first presentation and outcome was measured with the Clinical Global Impression scale (CGI) at baseline and follow-up. A regression analysis showed a clear clinical and statistically significant association between shorter duration of untreated psychosis and better outcome at follow-up. Patients with a duration of untreated psychosis of less than one year showed a CGI-S change from 5.37 to 2.07; those with a duration of untreated psychosis of 1-5 years a change from 5.48 to 2.59, and those with a duration of untreated psychosis of >5 years a change from 5.59 to 3.37. This difference of 1.1 CGI points between the groups resembles a clinically relevant difference in patient outcome. Our results suggest that longer duration of untreated psychosis in patients with delusional infestation is associated with significantly less favour-able clinical outcomes.

Regional gray matter volume and structural network strength in somatic vs. non-somatic delusional disorders.

BACKGROUND: Monothematic delusional disorders are characterized by a single tenacious belief. They provide a great opportunity to study underlying brain structures in the absence of confounding symptoms that accompany delusions in schizophrenia. Delusional beliefs include persecution, jealousy or somatic delusions including infestation. It is unclear whether specific delusional content is associated with distinct neural substrates. METHODS: We used magnetic resonance imaging in patients presenting with somatic vs. non-somatic delusional disorders. Patients with delusional infestation (DI, n=18), and individuals with non-somatic delusional disorders (n=19) were included, together with healthy volunteers (n=20). Uni- and multivariate techniques for structural data analysis were applied to provide a comprehensive characterization of abnormal brain volume at both the regional and neural network level. RESULTS: Patients with DI showed lower gray matter volume in thalamic, striatal (putamen), insular and medial prefrontal brain regions in contrast to non-somatic delusional disorders and healthy controls. Importantly, these differences were consistently detected at regional and network level. Compared to healthy controls, patients with delusional disorders other than DI showed lower gray matter volume in temporal cortical regions. CONCLUSION: The data support the notion that dysfunctional somatosensory and peripersonal networks could mediate somatic delusions in patients with DI in contrast to delusional disorders without somatic content. The data also suggest putative content-specific neural signatures in delusional disorders and in delusion formation per se.

Retinal changes in patients with major depressive disorder - A controlled optical coherence tomography study.

BACKGROUND: Recent studies on the pathophysiology of major depression (MD) indicate that degenerative and inflammatory processes may play a role. This finding is supported by magnetic resonance imaging (MRI)-based meta-analysis that show volume reductions in circumscribed areas of the brain in patients with MD. Using optical coherence tomography (OCT), retinal changes have been demonstrated in neurodegenerative disorders. In light of this inflammatory/degenerative hypothesis, we tested whether patients with MD exhibit retinal alterations that might correlate with the severity and duration of the disease. METHODS: Patients with MD and age- and gender-matched healthy controls were recruited for the measurement of the total volume and thickness of their retina as well as the thicknesses and volumes of five different retinal layers using single-layer-analysis provided by the spectral-domain-OCT. RESULTS: OCT data from 28 patients with MD and 20 healthy controls were available for evaluation. The exploratory intra-individual group comparison of the two eyes showed a small but significant difference in the retinal total volume (right = 8.69mm3; left = 8.72mm3; p = 0.03) only in patients with MD. There were no other significant differences between the patients with MD and the healthy controls with respect to the OCT measurements. LIMITATIONS: The small group size as well as the absence of correction for multiple testing due to the exploratory design should be considered as limitations of our study. CONCLUSION: While retinal total volume differs between the eyes of patients with MD, the comparison of retinal parameters between these patients and age- and gender-matched healthy volunteers did not show any differences.

[Psychiatric Emergencies in the Preclinical Emergency Medicine Service in Ulm, Germany in 2000 and 2010, and Practical Consequences]. / Psychiatrische Notfälle im Notarzt- und Rettungsdienst in Ulm in den Jahren 2000 und 2010 und Konsequenzen für die Praxis.

Background Psychiatric emergencies (PE) in preclinical emergency medical services are about 5 - 10 % of all emergencies and represent often a source of difficulties in handling for the non-psychiatric professional helpers that deal with them. Studies informing about quantitative and qualitative changes of PEs in preclinical emergency medicine in Germany are scarce. Methods Therefore, we conducted a retrospective cross-sectional study of PE in a preclinical emergency medical service based on the protocols of the emergency ambulance of the Section for Emergency Medicine at the University Hospital Ulm comparing the years 2000 and 2010. Results We observed a significant increase of PEs from 8.8 % in the year 2000 (n = 285, from a total of n = 3227) to 10.3 % in 2010 (n = 454, from a total of n = 4425). In both years intoxications were the most common PE [2000: n = 116 (44.4 %); 2010: n = 171 (37.7 %)], followed by suicide-related behavior [2000: n = 59 (22.6 %); 2010: n = 78 (17.2 %)] and acute anxiety disorders [2000: n = 37 (13 %); 2010: n = 105 (23.1 %)]. The mentioned three conditions accounted for about 80 % of all PE. Most frequently PE occurred at the weekend and with the highest density in the evening and at night (18 - 24 h) in both years. Patients with PE were predominantly men, but the rate of women causing PE increased between 2000 and 2010. Discussion/Conclusion This study provides preliminary data on current trends in PEs in preclinical emergency medicine in Germany and has implications for improving the medical care provided.

[Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)]. / Arterielle Hyper- und Hypotonie assoziiert mit Psychopharmaka: eine Risikobewertung basierend auf den Fachinformationen.

Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.

Cortical features of distinct developmental trajectories in patients with delusional infestation.

BACKGROUND: Although there is strong neuroimaging evidence that cortical alterations are a core feature of schizophrenia spectrum disorders, it still remains unclear to what extent such abnormalities occur in monothematic delusional disorders. In individuals with delusional infestation (DI), the delusional belief to be infested with pathogens, previous structural MRI studies have shown prefrontal, temporal, parietal, insular, thalamic and striatal gray matter volume changes. Differential contributions of cortical features of evolutionary and genetic origin (such as cortical thickness, area and folding) which may distinctly contribute to DI pathophysiology are unclear at present. METHODS: In this study, 18 patients with DI and 20 healthy controls (HC) underwent MRI scanning at 1.0T. Using surface-based analyses we calculated cortical thickness, surface area and local gyrification index (LGI). Whole-brain differences between patients and controls were investigated. RESULTS: Surface analyses revealed frontoparietal patterns exhibiting altered cortical thickness, surface area and LGI in DI patients compared to controls. Higher cortical thickness was found in the right medial orbitofrontal cortex (p<0.05, cluster-wise probability [CWP] corrected). Smaller surface area in patients was found in the left inferior temporal gyrus, the precuneus, the pars orbitalis of the right frontal gyrus, and the lingual gyrus (p<0.05, CWP corr.). Lower LGI was found in the left postcentral, bilateral precentral, right middle temporal, inferior parietal, and superior parietal gyri (p<0.01, CWP corr.). CONCLUSION: This study lends further support to the hypothesis that cortical features of distinct evolutionary and genetic origin differently contribute to the pathogenesis of delusional disorders. Regions in which atrophy was observed are part of neural circuits associated with perception, visuospatial control and self-awareness. The data are in line with the notion of a content-specific neural signature of DI.

Drug safety and adverse drug reaction reporting behavior related to outpatient opioid replacement therapy: Results from a survey among physicians.

To study drug safety and the reporting behavior of adverse drug reactions (ADR) related to agents used for opioid replacement therapy (ORT) we conducted a cross-sectional questionnaire-based telephone survey among physicians who provide outpatient ORT in Germany (n=176; response rate=55.7%). Most respondents (n=97/55.1%) reported that they observe ADR related to buprenorphine, (dihydro)codeine, and (levo)methdone rarely (n=38/21.6%), very rarely (n=39/22.2%) or never (n=20/11.4%). Methadone was reported to be most frequently associated with the occurrence of ADR (n=82/46.6%), followed by levomethadone (n=33/18.8%), buprenorphine (n=6/3.4%), and dihydrocodeine (n=3/1.7%). Frequently observed ADR related to these agents were gastrointestinal, nervous system/psychiatric disorders, and hyperhidrosis. Methadone and levomethadone (not buprenorphine) were frequently associated with fatigue, weight gain, and sexual dysfunction. Hundred twenty nine participants (73.3%) stated that they never report ADR related to ORT; n=19 (10.8%) did so when referring to ADR related to their complete medical practice (X2=141.070; df=1; p<0.001). Similar patterns of ADR related to outpatient ORT as those reported in the product information or in pain therapy were found. Motivation to report ADR related to ORT may be reduced compared to ADR related to the general medical practice.

[Psychiatric Emergencies in the Emergency Room of the Ulm University Hospital in 2000 and 2010]. / Psychiatrische Notfälle auf der medizinischen Notaufnahme des Universitätsklinikums Ulm in den Jahren 2000 und 2010.

Objective: Despite of the importance of psychiatric emergencies (PE) requiring treatment at an emergency room (ER) little is known about their frequency and current trends in terms of quantity and quality. Methods: A retrospective analysis of all PE treated at the ER of the University Hospital Ulm (Germany) in 2000 and 2010. Results: 6 % (2000) or 5 % (2010) of the ER cases were PE. Despite an increase from 369 to 430 cases (+ 16,5 %) their share decreased because of an even stronger increase of other emergencies (+ 33 %). The most frequent PE in 2000 was alcohol intoxication (37,7 %), while it was intoxication with prescribed and/or illicit drugs in 2010 (47,9 %). Patients with alcohol intoxications were significantly younger in 2010 as compared with 2000. Suicide attempts were seen in every fourth PE. They were significantly more frequent in 2010. PEs were generally more frequent in the evening and over the night. Conclusion: This study provides first insight into current trends in PE treated at the ER in Germany. Our data provide an empirical starting point for optimizing clinical care, although the study is limited by its retrospective and mono-centric design.

Mild Hypothermia in a Child with Low-Dose Risperidone.

Risperidone is a widely used, second-generation antipsychotic approved for treating schizophrenia as well as for treating aggression in children and adolescents with mental retardation. The substance has a well-established risk profile including alterations of body temperature. Apart from hyperthermia with and without full-blown malignant neuroleptic syndrome, low body temperatures (hypothermia) have also been reported anecdotally, usually appearing in the context of comedication. Here, we report a case of hypothermia associated with a low-dose risperidone monotherapy in a child.

From Imaging the Brain to Imaging the Retina: Optical Coherence Tomography (OCT) in Schizophrenia.

Optical Coherence Tomography (OCT) is a noninvasive imaging method, which provides an in vivo image of the retina. It allows for quantitative measurements of retinal and macular thickness, including single-layer analysis. Because the retinal nerve fibre layer comprises the first axons of the visual pathway and is unmyelinated, it can be considered a unique anatomical model, which may provide insight into the pathophysiological processes of diseases with a neurodegenerative character. In fact, past OCT studies have emphasized the role of the visual pathway as an ideal structure for exploring neurodegeneration and have demonstrated the potential of the method as an instrument for longitudinally monitoring structural changes in neurological disorders such as multiple sclerosis. Progress in signal processing and advancements to the OCT technique enables the illustration of structural changes in the retinal layers in a quick, reproducible, and objective manner with a spatial resolution comparable to those of histological slices.Findings from computer-based magnetic resonance imaging analyses and neuropathological studies support the hypothesis of a degenerative component of certain psychiatric disorders such as schizophrenia. Studies in schizophrenia incorporating OCT are currently rare and have yielded further heterogeneous results. This article elucidates the method of OCT and the retina's role as a "window to the brain". Furthermore, in delineating the degenerative components of schizophrenia, we discuss the possible applications of OCT in the schizophrenia population.

Association between haemorrhages and treatment with selective and non-selective serotonergic antidepressants: Possible implications of quantitative signal detection.

Inhibition of serotonin uptake in platelets seems to be the crucial mechanism underlying SSRI-associated haemorrhages. This effect is also present in antidepressants featuring non-selective serotonin reuptake inhibition (non-SSRI). Impact of selectivity of serotonin reuptake and/or affinity to the serotonin reuptake transporter on the bleeding risk have not yet been studied sufficiently. We retrieved country- and SSRI-/non-SSRI-specific data from the Uppsala Monitoring Centre and used a case/non-case approach to calculate substance-specific reporting odds ratios (ROR) to evaluate the statistical association of treatment with SSRI/non-SSRI and haemorrhages. Country-specific analysis revealed no clear trends towards an increased risk of bleeding related to particular agents of group SSRI/non-SSRI (sporadically ROR>1 for citalopram, duloxetine, escitalopram, fluvoxamine, paroxetine, sertraline, St. John's wort). There was a clear trend in the total dataset towards a "reduced protective effect" (suggested by ROR<1) on the development of haemorrhages with agents featuring comparatively high affinity to the 5-HTT and/or selective serotonin reuptake inhibition (as with escitalopram, citalopram, duloxetine or venlafaxine) in comparison to agents with lower affinity or non-selective serotonin reuptake inhibition (as with mirtazapine or doxepin). Comparison of group-specific aggregated data (SSRI vs. non-SSRI) revealed significant differences regarding the "protective effect" on the development of haemorrhages between groups SSRI vs. non-SSRI in favour of non-SSRI in nearly all countries as well as in the total dataset. Our findings provide preliminary evidence that agents with increased affinity to the 5-HTT and/or selective serotonin reuptake inhibition may be associated with an increased risk of bleeding.