Antidepressant prescribing in Irish children: secular trends and international comparison in the context of a safety warning.

BACKGROUND: In 2003, the Irish Medicines Board (IMB) warned against the treatment of childhood depression with selective serotonin reuptake inhibitors (SSRIs) due to increased risk of suicide. This study examined the effect of this warning on the prevalence of anti-depressants in Irish children and compared age and gender trends and international comparisons of prescription rates. METHODS: A retrospective cohort study of the Irish Health Service Executive (HSE) pharmacy claims database for the General Medical Services (GMS) scheme for dispensed medication. Data were obtained for 2002-2011 for those aged ≤ 15 years. Prevalence of anti-depressants per 1000 eligible population, along with 95% confidence intervals, were calculated. A negative binomial regression analysis was used to investigate trends and compare rates across years, sex and age groups (0-4, 5-11, 12-15 years). International prescribing data were retrieved from the literature. RESULTS: The prevalence of anti-depressants decreased from 4.74/1000 population (95% CI: 4.47-5.01) in 2002 to 2.61/1000 population (95% CI: 2.43-2.80) in 2008. SSRI rates decreased from 2002 to 2008. Prescription rates for contra-indicated SSRIs paroxetine, sertraline and citralopram decreased significantly from 2002 to 2005, and, apart from paroxetine, only small fluctuations were seen from 2005 onwards. Fluoxetine was the most frequently prescribed anti-depressant and rates increased between 2002 and 2011. Anti-depressant rates were higher for younger boys and older girls. The Irish prevalence was lower than the US, similar to the U.K. and higher than Germany and Denmark. CONCLUSIONS: The direction and timing of these trends suggest that medical practitioners followed the IMB advice.

Benzodiazepine prescribing in children under 15 years of age receiving free medical care on the General Medical Services scheme in Ireland.

OBJECTIVE: To examine the prevalence and secular trends in benzodiazepine (BZD) prescribing in the Irish paediatric population. In addition, we examine coprescribing of antiepileptic, antipsychotic, antidepressant and psychostimulants in children receiving BZD drugs and compare BZD prescribing in Ireland to that in other European countries. SETTING: Data were obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive (HSE)--Primary Care Reimbursement Services (PCRS). PARTICIPANTS: Children aged 0-15 years, on the HSE-PCRS database between January 2002 and December 2011, were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Prescribing rates were reported over time (2002-2011) and duration (≤ or >90 days). Age (0-4, 5-11, 12-15) and gender trends were established. Rates of concomitant prescriptions for antiepileptic, antipsychotics, antidepressants and psychostimulants were reported. European prescribing data were retrieved from the literature. RESULTS: Rates decreased from 2002 (8.56/1000 GMS population: 95% CI 8.20 to 8.92) to 2011 (5.33/1000 GMS population: 95% CI 5.10 to 5.55). Of those children currently receiving a BZD prescription, 6% were prescribed BZD for >90 days. Rates were higher for boys in the 0-4 and 5-11 age ranges, whereas for girls they were higher in the 12-15 age groups. A substantial proportion of children receiving BZD drugs are also prescribed antiepileptic (27%), antidepressant (11%), antipsychotic (5%) and psychostimulant (2%) medicines. Prescribing rates follow a similar pattern to that in other European countries. CONCLUSIONS: While BZD prescribing trends have decreased in recent years, this study shows that a significant proportion of the GMS children population are being prescribed BZD in the long term. This study highlights the need for guidelines for BZD prescribing in children in terms of clinical indication and responsibility, coprescribing, dosage and duration of treatment.

Antibiotic prescribing trends in a paediatric sub-population in Ireland.

PURPOSE: Little is known about antibiotic prescribing in Irish children. This study aims to examine antibiotic prescribing patterns in Irish children and associated costs and to compare this with European findings. METHODS: A retrospective analysis of the Irish Health Services Executive (HSE) pharmacy claims database 2004-2009 for the General Medical Services (GMS) scheme for dispensed medications. This represents 28% of Irish children but over-represents lower socio-economic groups. Overall prescribing rates were reported over time (2004-2009), age (0-4, 5-11, 12-15 years) and gender. Statistical comparison is made using negative binomial regression. Overall prescribing rates for the most commonly prescribed drugs were calculated. Associated cost of prescribing also was calculated. European prescribing data were retrieved from the literature. RESULTS: Rates remained stable from 2004 (631/1000 GMS population; 95%CI 628-634) to 2009 (621/1000; 95%CI 618-624). An interaction effect emerged between gender and age. Rates were generally higher for girls, except for the boys aged 0-4 years. The preferred choice of agents changed across years, with co-amoxiclav becoming the most prescribed drug in 2009 (308/1000; 95%CI 306-310). The total cost of antibiotics increased from €4.4 million in 2004 to €6.0 million in 2009. Higher overall rates of antibiotic prescribing emerged compared with available European data. Differences were observed between prescribing of some first-line and second-line drugs. CONCLUSIONS: Age and gender trends are consistent with international literature. However, Ireland has higher overall prescribing rates relative to some European countries. This suggests that a quality improvement in prescribing intervention is warranted.

Noninvasive magnetic resonance imaging of vessels affected by transplant arteriosclerosis in an experimental mouse aortic allograft model.

BACKGROUND: Transplant arteriosclerosis is still the leading cause of late mortality after heart transplantation despite advances in immunosuppression regimes. Experimental mouse models have substantially contributed to a better understanding of the multifactorial pathogenesis, but the major limitation of these studies is the difficulty in monitoring progression of transplant arteriosclerosis over time. Therefore, the aim of this study was to investigate whether MR measurements are sensitive enough to detect characteristic vascular lesions in a small animal transplantation model. METHODS: For this purpose we investigated 22 iso- and allogeneic aortic graft transplanted mice in vivo with a 4.7 T MR scanner using a 2D-RARE technique, 3D time-of-flight angiography and 3D phase contrast angiography as well as a special snake-based reconstruction algorithm. The MR lumen values of patency from native images and from 3D vessel reconstructions of the respective methods were correlated with conventional histological analysis. RESULTS: A comparison of the different techniques showed that angiographic MR modalities correlated well with histological measurements. 2D-RARE sequences were inferior to the sequences obtained by other ones. Superior correlations and the most accurate results were found for vessel reconstruction based on 3D angiographic time-of-flight data. CONCLUSION: These data demonstrate that mouse in vivo MR imaging is sensitive enough to detect and quantify vascular changes caused by transplant arteriosclerosis.

Changes in gustatory perceptions of patients with major depression treated with vagus nerve stimulation (VNS).

BACKGROUND: Olfactory and gustatory functions were investigated before and during vagus nerve stimulation (VNS) in a group of 9 patients with therapy-resistant depression, implanted with a VNS system. METHODS: Gustation and olfaction were tested using standard sniffing tests. Subjects participated in 2 sessions with the vagal stimulator switched on and off, respectively. RESULTS: Under conditions of stimulation of the VNS, there were statistically significant differences of the threshold of perception, with an intensification of the taste "sweet" (Z = -2.0; p = 0.048) and "bitter" (Z = - 2.5; p = 0.011) compared to the "off-mode". A statistical trend (Z = - 1.7; p=0.098) for increased intensity of the taste "salty" was observed, however, these results would supposedly disappear after correction for multiple testing presumably due to the large number of variables and the small sample size. There were no statistically relevant differences concerning olfactory perception. CONCLUSIONS: The changes of gustatory perception under conditions of vagal nerve stimulation observed in this study show another important central nervous effect of vagal stimulation on the limbic system that might be of importance in the elucidation of mechanisms of action of VNS especially on refractory depression.

[Long-term analysis of disability pensions in survivors of the Holocaust: somatic and psychiatric diagnoses]. / Erwerbsminderung bei Holocaustopfern: eine langzeitkatamnestische Betrachtung somatischer und psychiatrischer Diagnosen unter Berücksichtigung des Gesamtschauaspekts.

OBJECTIVE: Survivors of the Holocaust are known to suffer more often from mental as well as somatic consequential illness. The assessment of the degree of disability and invalidity due to the persecution complies with the interaction of directly Holocaust-related mental and somatic primary injuries as well as physical, psychical and psychosocial disadvantages and illnesses acquired later on. METHODS: The presented descriptive as well as multivariate analyses included complete reports (expertise, medical records, physicians' assessments, witnessed hand-written notes of the patients) of 56 survivors of the Holocaust (36 women and 20 men). RESULTS: The disability pension reports of 56 Holocaust survivors (36 women and 20 men) were analysed referring to the diagnostic groups and socio-demographic aspects. In 92.3 % a psychiatric illness could be diagnosed within the first year after liberation. In a separate analysis of somatic diagnoses, gastrointestinal diseases were statistically significant more often in Holocaust survivors with a degree of disability of more than 30 % (chi-square χ (2) = 4.0; df = 1; p = 0.046). CONCLUSIONS: The question of an aggravation of psychiatrically relevant and persecution-associated symptomatology is mainly the objective of the expert opinion taking into account endogenous and exogenous factors such as so-called life events. Above all, newly acquired somatic diseases seem to be responsible for an aggravation of persecution-associated psychiatric symptoms, at least in the presented sample of Holocaust survivors.

[An exploration of the association between disability pension and psychiatric diseases]. / Frühberentung aufgrund psychiatrischer Erkrankungen. Eine Analyse von 94 Berufsunfähigkeitsgutachten.

OBJECTIVE: The necessity to establish disability and invalidity pensions due to psychiatric diseases has become more and more demanding in recent years. So far there is little knowledge about the aetiology and socio-demographic aspects of this phenomenon. METHODS: The presented explorative analyses included 94 examinations (43 women, 51 men) to address, if a person should be medically certified as partly or permanently unfit for work. The data, including psychiatric diagnosis and socio-demographic data were obtained between 1999 and 2006 in a German specialised psychiatric university unit. RESULTS: The diagnoses of neurotic diseases, stress related and somatoform disorders (ICD-10 F 40 - 48) were the most prevalent group (48 %) within the sample. It was a statistically significant predictive factor in a later declaration of disability and invalidity. In this diagnosis group (F 40 - 48) more participants were female when compared to other diagnosis groups. In general, participants were more likely to be divorced and have a lower education level when compared to the general population. However, the mean level of intelligence was similar to the general population. CONCLUSION: The results of the presented study could be beneficial for a better understanding of the association between disability pensions and psychiatric diseases. The increase of neurotic diseases, stress related and somatoform disorders may justify the development of targeted prevention strategies.

Factors associated with deliberate self-harm among Irish adolescents.

BACKGROUND: Deliberate self-harm (DSH) is a major public health problem, with young people most at risk. Lifetime prevalence of DSH in Irish adolescents is between 8% and 12%, and it is three times more prevalent among girls than boys. The aim of the study was to identify the psychological, life-style and life event factors associated with self-harm in Irish adolescents. METHOD: A cross-sectional study was conducted, with 3881 adolescents in 39 schools completing an anonymous questionnaire as part of the Child and Adolescent Self-harm in Europe (CASE) study. There was an equal gender balance and 53.1% of students were 16 years old. Information was obtained on history of self-harm life events, and demographic, psychological and life-style factors. RESULTS: Based on multivariate analyses, important factors associated with DSH among both genders were drug use and knowing a friend who had engaged in self-harm. Among girls, poor self-esteem, forced sexual activity, self-harm of a family member, fights with parents and problems with friendships also remained in the final model. For boys, experiencing bullying, problems with schoolwork, impulsivity and anxiety remained. CONCLUSIONS: Distinct profiles of boys and girls who engage in self-harm were identified. Associations between DSH and some life-style and life event factors suggest that mental health factors are not the sole indicators of risk of self-harm. The importance of school-related risk factors underlines the need to develop gender-specific initiatives in schools to reduce the prevalence of self-harm.

Cardiac effects of vagus nerve stimulation in patients with major depression.

INTRODUCTION: Changes in the heart rate variability are well known among patients with depression. Amongst others, a modulation of the autonomic nervous system is discussed. An investigation of heart rate variability during terms of stimulation could give some insight in the central nervous effect of vagus nerve stimulation (VNS) and possible cardiac side effects. METHODS: The effects of VNS on heart rate (HR) and heart rate variability were studied (HRV) during stimulation in nine patients with major depression according to ICD-10. RESULTS: When comparing treated depressive patients with a sex- and age-matched healthy control group, the analysis of heart rate revealed significantly (t=2.8; df=16, p=0.012) elevated heart rates during completely switched off conditions, during switched on VNS programme in stimulation-free intervals (5 min period) (t=3.0; p=0.009) and during stimulation conditions (30 s) (t=2.8, Levene corrected, p=0.015). The RMSSD (root mean square of successive differences) as a measure of the HRV increased significantly in switched on conditions during stimulation (30 s) in six patients compared to stimulation-free intervals (t=-4.7; df=5, p=0.006) and baseline. DISCUSSION: Clinically relevant cardiac effects were not observed throughout the study. VNS induces reversible changes in heart rate variability in patients with major depression during stimulation conditions.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

[Pre-, peri- and postpartal depression]. / Prä-, peri- und postpartale Depressivität.

INTRODUCTION: Postpartal affective disorders are with a prevalence between 8 % and 15 % highly frequent maternal diseases after childbirth. An undetected and untreated postpartum depression causes a wide range of negative consequences such as risk of a chronic manifestation of a major depression, social retreat, limitations in the bonding behavior, and behavioral disorders of the child. Therefore, an early detection of pregnant women at risk is warranted. METHODS: Within a prospective study (FRAMES: Franconian Maternal Health Evaluation Studies), 1,100 pregnant women were interviewed with standardized questionnaires at three points of time: Prepartal (U1): from the 30 (th) week of pregnancy onwards, 48 - 72 hours (U2) postpartum (pp) und 6 - 8 months pp (U3). 554 women were included in the substudy Blue FRAMES, where an additional telephone interview at the 10 (th) day pp was conducted with a focus on symptoms relating to Baby Blues such as mood instability, irritability and concentration deficits. The Edinburgh Postnatal Depression Scale (EPDS) and the Hamilton Rating Scale For Depression (HAMD) were used for quantification of depressivity at each point of time. RESULTS: EPDS values differed significantly (Friedman Test; chi (2) = 110.8; df = 2, p < 0,001) between the different examination points (Wilcoxon Test; U1 - U2: Z = -11.0; p < 0.001; U1 - U3: Z = -6.6; p < 0.001; U2 - U3: Z = -4,5; p < 0,001). Regarding EPDS values, higher values were observed prepartum (U1). After a decrease after two to three days postpartum (U2), values increased again. However, EPDS values six months postpartum (U3) were still lower than prepartum (U1). DISCUSSION: The observed EPDS values postpartum are comparable to results of other studies. The higher EPDS values prepartum have a good predictive value. There is a great need and possibility for improved prevention of postpartal disorders, when appropriately addressed in the prepartum period.

Clinical benefits and cost effectiveness of vagus nerve stimulation in a long-term treatment of patients with major depression.

BACKGROUND: To evaluate clinical aspects and cost effectiveness of the treatment with vagus nerve stimulation (VNS), a group of 9 VNS-implanted patients and 9 age- and sex-matched patients suffering from treatment-resistant depression were included in a prospective study. METHODS: The psychopathological ratings over 12 months as well as socio-economic data on the duration of hospitalisation, frequency of outpatient treatment, and subsequent drug treatment were compared with the pre-implantation period. RESULTS: Compared with baseline values in the HAMD scale (mean 23.7; SD 2.4), there was a significant (t=14.5; df=8; p<0.001) improvement in symptoms after 12 months' stimulation (mean 10.2; SD 2.4). The duration of hospitalisation dropped on average by 20 days in the first post-implantation year, the treatment frequency from 33 to 14 visits, and drug treatment from 4 to an average of 3 psychotropic drugs. CONCLUSION: In addition to an improvement in clinical symptoms, the VNS method might enable an amortisation of costs.

Herp mRNA expression in patients classified according to Lesch's typology.

Chronic alcoholism is associated with hyperhomocysteinemia. Herp (homocysteine-induced endoplasmic reticulum [ER] protein) levels are elevated as a response to ER stress prior to mitochondrial dysfunction and cell death. The Lesch classification system has been applied in many studies and has been found useful. This study was undertaken to assess Herp mRNA expression in actively drinking patients with alcoholism who were classified according to Lesch's typology. Herp mRNA expression levels were measured by quantitative PCR in the blood of 76 male alcoholic patients. Patients were classified according to Lesch's typology (type I-IV). With respect to Lesch's typology, a significant difference in Herp mRNA expression regarding the four subtypes could be shown (F[3,72]=2.83, P=.044). In a logistic regression model (dependent variable Herp dichotomized by a median-split; adjusted for age and homocysteine levels) the subtype II differed statistically significant from the others (odds ratio, 5.75; 95% confidence interval, 2.07-15.98; P=.001). Type II alcoholic patients had a statistically significant higher expression of Herp mRNA due to upregulation of the expression of this neuroprotective cell non-chaperone by toxic effects of ethanol. These findings might explain why type II patients do not express severe withdrawal symptomatology (i.e., withdrawal seizures). These findings may be useful in the understanding and treatment considerations of different subtypes of alcohol dependence.

[Quality improvement of multiple choice examinations: in psychiatry, psychosomatic medicine, psychotherapy, and neurology]. / Qualitätsverbesserung von Multiple-Choice-Prüfungen: In Psychiatrie, Psychosomatik, Psychotherapie und Neurologie.

We describe a continuous improvement process in planning, performance, and evaluation of multiple choice examination questions in psychiatry, neurology, psychosomatic medicine, and psychotherapy. We analyzed 640 multiple choice questions of 1,419 students during a period of 4 years. Crucial changes concerned the abolishment of problematic question types, implementation of validated new question formats, extension of case-based questions, elongation of question stems, quantitative evaluation of item difficulty, discriminatory value, and the introduction of a peer review system. Consequences of these improvements were greater item difficulty (average 18%) and discriminatory value (average 67%) and reduced post hoc analysis times. Introduction of peer reviews resulted in longer preparation time, which was however appreciated by the peers due to a clear improvement in item quality.

Differential processing and secretion of Abeta peptides and sAPPalpha in human platelets is regulated by thrombin and prostaglandine 2.

Metabolic and functional studies of the amyloid precursor protein (APP) in platelets have advanced our understanding of Alzheimer's disease (AD). Here we report that human platelets contain Abeta peptides, process and secrete them constitutively. Platelets generate formerly unkown Abeta-species by differential processing of APP. Release of Abeta peptides were also increased by platelet activation with thrombin, indicating the existence of a regulated exocytotic pathway. We showed that Abeta-levels, Abeta-processing patterns and Abeta-release kinetics were regulated by thrombin. In controls, release of Abeta peptide species (Abeta 1-40/42 and 1-37/38/39/) continued for more than 4 h, while thrombin activated cells ceased secretion after 1 h at large. Treatment of platelets with prostaglandine 2 slowed this process down. Intracellular Abeta peptide concentrations decreased steadily until no peptides could be detected after 20 h (control) or after 4 h (thrombin) in cultured platelets.

Ghrelin and eating disturbances in psychiatric disorders.

INTRODUCTION: Appetite and eating behavior are frequently altered in psychiatric patients. The newly discovered gut-derived neuropeptide ghrelin simulates hunger and weight gain. Therefore, it might be involved in appetite regulation during psychiatric disorders. METHODS: In 83 depressed, 42 schizophrenic patients and 46 healthy controls plasma ghrelin levels were measured, and the psychometric scores on the Three-Factor Eating Questionnaire (TFEQ) were assessed. RESULTS: Neither ghrelin levels nor TFEQ scores differed between both patient groups and healthy subjects. However, TFEQ subscale 2 (disinhibition) was predicted by BMI-corrected ghrelin levels, while age, sex, smoking, and medication did not show any influence. DISCUSSION: Ghrelin correlates with factors of eating behavior, specifically with subscale 2 on the TFEQ. Ghrelin might be involved in appetite-regulating pathways during psychiatric disorders. However, its influence is not likely to be displayed as a difference between diagnostic groups. Rather, ghrelin is associated with eating behavior in psychiatric patients meaning susceptibility to eating problems.

Dopamine and N-methyl-D-aspartate receptor expression in peripheral blood of patients undergoing alcohol withdrawal.

The aim of the present pilot study was to explore whether a change in cerebral receptors can be demonstrated in human peripheral blood lymphocytes during alcohol withdrawal. Dopamine (D1 and D2) and NMDA (1 and 2B) receptor expressions of 14 male patients suffering from alcohol-dependency were assessed through quantitative RT-PCR. A significant difference in D1 receptor expression (T = 2.361; p = 0.035) in terms of up-regulation could be shown, though there were no significant changes concerning D2, NMDA1 or NMDA2B receptor expression.

Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma.

Pseudoexfoliation syndrome (PEX) is a systemic disorder characterized by the deposition of an abnormal fibrillar material in ocular and various extraocular tissues. It represents the most common identifiable cause of glaucoma (PEX glaucoma = PEXG). Due to similar pathogenetic mechanisms, glaucoma has been called "ocular Alzheimer's disease". PEXG and Alzheimer's disease share common associations such as the higher prevalence of hyperhomocysteinemia in both disorders. In order to investigate the cause of hyperhomocysteinemia in PEXG, we evaluated B-vitamin levels (folate, B12, B6) and their associations with homocysteine (Hcy) in plasma of 70 PEXG patients and 70 control subjects. Folate, vitamin B12 and B6 levels were significantly decreased and associated with elevated Hcy levels in PEXG. Low B-vitamin levels in PEX might also help explain, at least in part, the higher prevalence of B-vitamin deficiency in disorders associated with PEX such as Alzhemier's disease.

Homocysteine levels in aqueous humor and plasma of patients with primary open-angle glaucoma.

We determined homocysteine (Hcy) levels in aqueous humor (AH) and plasma and their association with B-vitamin levels in patients with primary open-angle glaucoma (POAG) and controls. Both AH Hcy and plasma Hcy levels were significantly increased in POAG, and elevation of AH Hcy and plasma Hcy was a significant risk factor for POAG. In contrast to controls, neither plasma nor AH Hcy of POAG patients demonstrated a significant association with important non-genetic determinants of elevated Hcy such as low B-vitamin levels, increasing age and caffeine consumption. Considering that Hcy is a neurotoxin that induces apoptotic retinal ganglion cell death via stimulation of the N-methyl-D-asparate (NMDA) receptor, increased Hcy concentrations in AH and plasma might contribute to the optic nerve damage in POAG.