Showing papers in "Pharmacopsychiatry in 2011"

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

Abstract: 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 fur 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.

Non-medical use of prescription stimulants and illicit use of stimulants for cognitive enhancement in pupils and students in Germany.

Abstract: Introduction The aim of this study was to assess for the first time the prevalence and factors associated with stimulant use exclusively for cognitive enhancement among pupils and university students in Germany. Methods A sample of 1 035 pupils (vocational and grammar schools) in small and big cities and 512 university students of 3 Departments (Medicine, Pharmacy, Economics) completed a questionnaire regarding knowledge and use of stimulants for cognitive enhancement and factors associated with their use. Results Lifetime prevalence for use of prescription stimulants (methylphenidate, amphetamines) for cognitive enhancement in pupils was 1.55% and in students 0.78%. Last-year and last-month prevalence rates were significantly lower. 2.42% of pupils and 2.93% of students reported lifetime illicit use of stimulants (amphetamines, cocaine, ecstasy) for cognitive enhancement with lower last-year and last-month rates. Prevalence was higher in male pupils, pupils from vocational schools and pupils with bad marks. Discussion The illicit use of stimulants for cognitive enhancement is significantly higher than non-medical use of prescription stimulants among pupils and students. Stimulant use is determined by gender, school type, and school marks. The potential risks associated with stimulant use require early awareness and intervention strategies.

Use of coffee, caffeinated drinks and caffeine tablets for cognitive enhancement in pupils and students in Germany.

Abstract: Substance use for cognitive enhancement (CE) is a topic of increasing importance There are only few data about substances, prevalence rates and factors associated with CE The aim of this study was to assess first data about the use of coffee, caffeinated drinks and caffeine tablets for CE at school and university A self-report questionnaire was developed to analyze 1 547 pupils and students about their use of coffee, caffeine tablets, and caffeinated drinks for CE and factors associated with this use Lifetime, past-year, and past-month prevalence for the use of coffee for CE was 532%, 85%, and 63%, for the use of caffeinated drinks 39%, 107%, and 63%, and for the use of caffeine tablets 105%, 38%, and 08% Use of caffeinated substances for CE was influenced by gender and school grades The use of coffee and caffeinated drinks for CE was found to be widespread in the surveyed population Although the use of caffeine tablets was found to be smaller than the above-mentioned means, it still indicates a relatively high disposition for using tablets for purposes of CE

Antipsychotics and venous thromboembolism risk: a meta-analysis.

Abstract: Antipsychotics have been inconclusively implicated in susceptibility to venous thromboembolism (VTE). The aim of this study was to investigate the association between antipsychotic drugs and VTE risk by a meta-analysis. PubMed and EmBASE databases were searched for publications through to 10 October 2010. Statistical analysis was performed using Revman 4.2 and Stata 10.0 software. 7 case-control studies involving 31 095 cases and 143 472 controls were analyzed. The results indicate that antipsychotic exposure confers a 139% increased risk of VTE (odds ratio [OR]=2.39, 95% confidence interval [CI]:1.71–3.35). Pooled estimates by drug type showed that use of low-potency antipsychotics (OR=2.91, 95% CI 1.80–4.71) is the most important risk factor for VTE, followed by atypical (OR=2.20, 95% CI 1.22–3.96), conventional (OR=1.72, 95% CI 1.31–2.24) and high-potency drugs (OR=1.58, 95% CI 1.50–1.67). This meta-analysis suggests that antipsychotics are a risk factor for VTE. Additional studies in large cohorts are required to validate our findings. Future analyses should study potential effect modifications by different doses and durations of antipsychotic exposure in different populations.

Proton Magnetic Resonance Spectroscopy Study of Brain Metabolite Changes after Antipsychotic Treatment

Abstract: INTRODUCTION: Proton magnetic resonance spectroscopy ( 1 H MRS) enables the observation of brain function in vivo. The aim of our study was to evaluate the effects of antipsychotic medication on metabolite levels in the brain of schizophrenic patients based on a 1 H MRS examination. METHODS: We examined 42 patients previously diagnosed with chronic schizophrenia twice: firstly, after the neuroleptic wash-out (baseline) and secondly, under stable medication (follow-up, after treatment). The study had a naturalistic design and several different neuroleptic medications were used during the treatment phase. The clinical evaluation, MRI and MRS procedures were performed. The group of 26 healthy controls were also examined to compare MRS results. RESULTS: We found a significantly lower NAA/Cr (N-acetylaspartate/creatine) ratio in the frontal lobe and thalamus in patients (after the wash-out) as compared to controls. After treatment a significant decrease of the Glx/Cr ratio in the temporal lobe and a trend for an increase of the NAA/Cr ratio in the thalamus were observed. CONCLUSION: >Our results confirm that antipsychotic medication modifies brain metabolism measured by means of 1 H MRS. The pattern of the changes suggests a neuroprotective action of antipsychotic medication in schizophrenia.

Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety.

Abstract: Quantification of serum or plasma concentrations of medications is essential to find out if an adverse drug effect (ADE) is associated with an elevated drug concentration. In former years TDM was therefore often used in pharmacovigilance just to confirm that an ADE that had already occurred was due to an elevated drug plasma concentration without identifying the underlying cause for the surprising high concentration. This old approach of Therapeutic Drug Monitoring (TDM) in pharmacovigilance needs to be revised due to new developments in information technology, new analytical procedures and due to the inclusion of clinical pharmacological expert opinions in the presentation of laboratory medicine results. Today, TDM may be used to prevent ADE, rather than just confirming a suggested cause of an ADE that has happened in the past. This approach means that blood should be drawn for TDM analysis after the pharmacokinetic steady state has been reached (5 times of the elimination half life of the drug) with low to moderate dosages under the intended (poly)medication if the patient is clinically regarded as not belonging to the "normal" patient population. With the availability of reliable automated analytical methods this can be performed at a reasonable price. Funds may be saved to the health care system, because hospitalization will be thereby shortened and expensive diagnoses and treatment of ADE will be avoided. However, this has still to be proven in cross-system studies: Budget will be saved in 2 areas of the health system (hospital stay and drug costs), whereas a much smaller amount of money has to be invested for laboratory analyses in another area. TDM may thus change pharmacovigilance as a tool for monitoring and documentation of ADE to a safety tool in drug therapy for prevention of ADE.

Therapeutic plasma concentrations of antidepressants and antipsychotics: lessons from PET imaging.

Abstract: Therapeutic Drug Monitoring (TDM) of psychotropic drugs is strongly depending on the validity of recommended therapeutic plasma concentration reference ranges. Rational pharmacotherapy is based on the assumption that plasma concentrations are directly related to target occupancy by the respective drug. Here we show that positron emission tomography (PET) of molecular drug targets in the brain (neuroreceptors and transporters) allows for establishment of these relationships, thereby providing guidance for TDM services. Associations between brain target occupancy, plasma concentrations, and clinical effects and adverse reactions will be discussed for the most commonly used antidepressant and antipsychotic drugs.

Stress and Affective Disorders: Animal Models Elucidating the Molecular Basis of Neuroendocrine-Behavior Interactions

Abstract: Profound dysfunctions in several neuroendocrine systems have been described in patients suffering from affective disorders such as major depression. In order to elucidate the mechanisms underlying these functional alterations, animal models including mice genetically modified by either direct gene-targeting or by selective breeding approaches have been used exceedingly, revealing valuable insights into neuroendocrine pathways conserved between rodents and men. This review focuses on altered function and regulation of the hypothalamic-pituitary-adrenocortical axis, including its involvement in emotionality and stress responsiveness. In this context, the corticotropin-releasing hormone system and disturbances in glucocorticoid receptor signaling seem to be of central importance. However, changes in the expression and release patterns of vasopressin, dopamine and serotonin have also been shown to contribute to variation in emotionality, stress coping, cognitive functions and social behaviors. Affective disorders show a high degree of complexity, involving a multitude of molecular, neuroendocrine, and behavioral alterations as well as an intense gene-environment interaction, making it difficult to dissociate the primary causes from secondary consequences of the disease. Thus, interdisciplinary research, as applied in the emerging field of systems biology, involving adequate animal models and combined methodologies can significantly contribute to our understanding regarding the transmission of genetic predispositions into clinically relevant endophenotypes. It is only with deep insight into the mechanisms by which the stress hormone systems are regulated that novel treatment strategies and promising targets for therapeutic interventions can be developed in the future. Such in-depth understanding is ultimately essential to realizing our goal of predictive, preventive, and personalized medicine.

Therapeutic drug monitoring in child and adolescent psychiatry.

Abstract: Psychopharmacotherapy in children and adolescents is characterized by an increased susceptibility for adverse events and an increased risk of ineffective treatment due to specific age-dependent and developmental characteristics in comparison to adults. Dosing in paediatric psychiatric patients requires careful handling, since the dose recommendations for adults can not simply be extrapolated to minors because of pharmacokinetic and pharmacodynamic differences. In addition, psychopharmacotherapy in children and adolescents is hampered by lack of high quality evidence on efficacy and safety in many indications and subsequently a high degree of off-label use. Therapeutic Drug Monitoring (TDM) is an established and useful tool in psychiatry to individualize and optimize the outcomes (efficacy/safety balance) of psychopharmacological drug treatment in the individual patient by dose adjustments based upon measured serum concentrations. In children and adolescents the administration of psychotropic drugs is a general indication for performing TDM. However, TDM studies specific in these age groups are necessary to identify age and indication specific therapeutic ranges of serum concentrations. Systematic collection of data on drug exposure, serum concentrations and clinical characteristics as well as outcomes can generate such practice-based evidence. A German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry using a multi-centre internet-based data infrastructure was founded to document and collect demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents (further information: www.tdm-kjp.com).

Body Mass Index Increase, Serum Leptin, Adiponectin, Neuropeptide Y and Lipid Levels during Treatment with Olanzapine and Haloperidol

Abstract: Body mass index (BMI) increase is an undesired effect associated with antipsychotics, and crucial for patients’ global health and treatment compliance. We aimed to investigate the relation between BMI during olanzapine or haloperidol treatments and leptin, neuropeptide Y (NPY), adiponectin and lipid serum levels. In this 9-month, randomized and naturalist study, 34 male patients, 18 on olanzapine and 16 on haloperidol group were enrolled, all were under monotherapy. Patient outcome was evaluated with positive and negative syndrome scale (PANSS) at every 3-month period. In each visit, BMI, leptin, NPY, lipid, olanzapine or haloperidol levels were also monitored. Leptin levels positively correlated with BMI in olanzapine (r=0.64, p Antipsychotics probably interfere on leptin and NPY signalling ways and disturb these hormones in eating behaviour control.

Usefulness of atypical antipsychotics and choline esterase inhibitors in delirium: a review.

Abstract: Delirium is characterized by disturbances of consciousness, attention, cognition, perception, emotions, sleep, and psychomotor activity. Management of delirium involves ensuring safety, improving functioning, identifying and treating the illness underlying the delirium, and use of antipsychotics or benzodiazepines to control behavioural symptoms and prevent mortality. Haloperidol continues to be the most commonly used antipsychotic in delirium. However, in recent times data have emerged which suggest that atypical antipsychotics may be as efficacious as haloperidol in the treatment of delirium. This review intends to review the data with respect to usefulness of atypical antipsychotics in the treatment of delirium. Besides atypical antipsychotics, data with respect to another group of medications - cholinesterase inhibitors are also reviewed. Electronic and manual searches were conducted to identify all the relevant studies and case reports/case series. Evidence suggests that risperidone, olanzapine and quetiapine are as efficacious as haloperidol in the treatment of delirium but have lesser side effects. Data for other atypical antipsychotics are scarce. The data on cholinesterase inhibitors for treatment and prevention of delirium are beginning to accumulate, but do not seem to be convincing. Our review suggests that risperidone, olanzapine and quetiapine are good alternatives to haloperidol in the treatment of delirium.

Affective disorders as complex dynamic diseases--a perspective from systems biology.

Abstract: Understanding mental disorders and their neurobiological basis encompasses the conceptual management of "complexity" and "dynamics" For example, affective disorders exhibit several fluctuating state variables on psychological and biological levels and data collected of these systems levels suggest quasi-chaotic periodicity leading to use concepts and tools of the mathematics of nonlinear dynamic systems Regarding this, we demonstrate that the concept of "Dynamic Diseases" could be a fruitful way for theory and empirical research in neuropsychiatry In a first step, as an example, we focus on the analysis of dynamic cortisol regulation that is important for understanding depressive disorders In this case, our message is that extremely complex phenomena of a disease may be explained as resulting from perplexingly simple nonlinear interactions of a very small number of variables Additionally, we propose that and how widely used complex circuit diagrams representing the macroanatomic structures and connectivities of the brain involved in major depression or other mental disorders may be "animated" by quantification, even by using expert-based estimations (dummy variables) This method of modeling allows to develop exploratory computer-based numerical models that encompass the option to explore the system by computer simulations (in-silico experiments) Also inter- and intracellular molecular networks involved in affective disorders could be modeled by this procedure We want to stimulate future research in this theoretical context

Therapeutic drug monitoring in Italian psychiatry.

Abstract: Therapeutic drug monitoring (TDM) aims to optimize pharmacotherapy treatment. Knowledge, availability and use of TDM for psychiatric patients, however, differ between countries. In this survey we analysed the practice in Italy of TDM for psychoactive drugs. A semi-structured questionnaire was sent out to 211 mental health centres (centro di salute mentale) and 10 university hospitals from each region in Italy. Feedback was obtained from 44 centres. Information collected by the questionnaires indicated that in Italian psychiatry TDM is used for lithium, valproic acid and carbamazepine. With regard to clozapine, TDM was regarded as the blood cell counting which is obligatory when prescribing this drug. TDM was not employed for antidepressant or antipsychotic drug prescribing. Moreover, it appeared that only a few laboratories in Italy offer TDM services for psychiatric patients. Nevertheless, interest was expressed about receiving further information about TDM in psychiatry and participating in training programmes. This nationwide survey revealed that in Italy, TDM of psychoactive drugs is restricted to only a few drugs. In response to interest expressed, mental health workers should be educated about TDM and more laboratories should be encouraged to establish TDM services for psychotropic drugs.

Impact of duration of antidepressant treatment on the risk of occurrence of a new sequence of antidepressant treatment.

Abstract: Introduction: Despite the recommendation that antidepressant treatment should be con- tinued for several months to reduce the risk of relapse / recurrence of depression, early discon- tinuation is frequent in naturalistic conditions. The study was aimed at exploring the impact of early discontinuation of antidepressant treat- ment on the risk of antidepressant re-initiation. Methods: A follow-up study of persons (n = 35 053) starting antidepressant treatment was performed using a representative sample of the French Social Security Insurance national database. Results: The risk of re-initiation of antidepres- sant treatment was higher if the duration of the index episode of antidepressant treatment was ≥ 6 months (hazard ratio (HR) = 2.35; 95 % CI 2.25 - 2.45) or 2 - 5 months (HR = 1.65; 95 % CI 1.59 - 1.71) compared to ≤ 1 month. The other characteristics independently associated with re-initiation of treatment were older age, female gender, low income, serious chronic illness, index prescription by a specialist and co-prescription of other psychotropic drugs. Conclusions: The lower risk of re-initiation of antidepressant treatment in persons with shorter-than-recommended duration of antide- pressant treatment might be explained by over- prescription of antidepressants in persons with sub-threshold symptoms.

Bursts and the efficacy of selective serotonin reuptake inhibitors.

Abstract: We present a new hypothesis for the efficacy of selective serotonin reuptake inhibitors (SSRIs). We propose that SSRIs bring the response to the phasic firing of raphe nucleus cells back to normal, even though the average extracellular 5HT concentration remains low. We discuss burst firing in the raphe nuclei and use mathematical models to argue that tonic firing and phasic firing may be decoupled and may come from different mechanisms. We use a mathematical model for serotonin synthesis, release, and reuptake in terminals to illustrate the responses in terminal regions to bursts in a normal individual and in an individual with low vesicular serotonin. We then show that acute doses of SSRIs do not bring the response to bursts back to normal, but that chronic doses do return the response to normal. These model results need to be confirmed by new electrophysiological and pharmacological experiments.

Clozapine plasma level monitoring for prediction of rehospitalization schizophrenic outpatients.

Abstract: INTRODUCTION: The aim of this naturalistic exploratory study was to examine whether blood antipsychotic drug concentrations can predict rehospitalizations in chronically medicated patients. METHODS: The study included schizophrenic outpatients under clozapine (CLZ) maintenance treatment, supervised by therapeutic drug monitoring (TDM). Patients were observed for a period of 21 months. Their on average monthly measured plasma levels and the date of rehospitalizations were recorded. The variability of the first 3 CLZ plasma levels, measured in 3.6 months, was compared between patients with and without rehospitalization. RESULTS: 23 patients participated of which 6 patients were rehospitalized. Mean plasma concentrations of CLZ were similar in patients without (471 ± 180 ng/mL) and with rehospitalization (446 ± 266 ng/mL). However; coefficients of variation (CV) of plasma concentrations in the first 3 blood samples differed significantly between the rehospitalized and non-rehospitalized groups (37.1% vs. 13.0%, respectively, P = 0.012). A CV ≥ 19.8% was predictive for later rehospitalization with 100% sensitivity and 70.6% specificity. DISCUSSION: Variability in CLZ plasma concentrations may be useful in identifying patients at risk of relapsing under maintenance therapy. Because of the small number of patients the findings need to be confirmed in a larger study.

An open randomized pilot trial on the differential effects of aripiprazole versus risperidone on anhedonia and subjective well-being.

Abstract: Introduction: Negative symptoms of schizophrenia often predict an unfavorable clinical outcome. Disturbed dopamine transmission in different brain parts may underlie different aspects of negative symptoms, and the effect of antipsychotics on them may also differ. This pilot study investigated the potentially therapeutic effects of the partial dopamine agonist aripiprazole on different negative symptoms. Methods: This pilot study randomly assigned patients with schizophrenia (N=40) to either aripiprazole or risperidone. After 6 weeks of treatment, the severity of negative symptoms was determined by the PANSS. Subscales of self-report questionnaires were used to assess differences in initiative, anhedonia, social functioning and subjective well-being. Results: Patients treated with aripiprazole showed a significant improvement on measures for anhedonia and subjective wellbeing. Negative symptoms in general, lack of initiative and social inhibition were also lower in the aripiprazole treated group, but without reaching statistical significance. Discussion: According to this pilot study, aripiprazole appears to specifically improve anhedonia and subjective wellbeing compared to risperidone. This may be caused by a specific effect of aripiprazole on the limbic branch of the dopamine system. Future studies should replicate this finding with a larger sample size.

Predicting response to psychopharmacological treatment: survey of recent results

Abstract: Treatment with antidepressants and antipsychotics, though effective, is unspecific as agents that differ greatly in their biochemical and pharmacological actions have virtually the same efficacy. Half of the patients with initial improvement show incomplete response, while a large proportion of patients exhibit a refractory clinical picture which is resistant to all treatment modalities. Our analyses were based on a reference study of 2 848 depressive inpatients under monotherapeutic treatment with 7 different antidepressants or placebo, along with a naturalistic study of depressive and schizophrenic patients (296 inpatients, 363 outpatients) under today’s “standard” polypharmaceutic treatment regimens. The empirical data suggested the following predictors of response: (1) severity at baseline, (2) early onset of improvement, (3) unwanted side-effects, and (4) medical comorbidity. A combination of these predictors with Therapeutic Drug Monitoring (TDM) methods has direct clinical relevance. Evidence-based approaches to personalized treatment help improving the unsatisfactory situation patients and clinicians are faced with, given today’s incomplete treatments and the fact that the mechanisms by which antidepressants and antipsychotics ultimately exert their therapeutic effects are only marginally understood.

Increased brain membrane fluidity in schizophrenia.

Abstract: Recent findings showing significant correlations between phospholipase A2 (PLA2) activity and structural changes in schizophrenic brains contribute to the membrane hypothesis of schizophrenia, which was hampered because a clean functional link between elevated PLA2 activity and brain structure was missing (Neuroimage, 2010; 52: 1314-1327). We measured membrane fluidity parameters and found that brain membranes isolated from the prefrontal cortex of schizophrenic patients showed significantly increased flexibility of fatty acid chains. Our findings support a possible link between elevated PLA2 activity in cortical areas of schizophrenic patients and subsequent alterations of the biophysical parameters of neuronal membranes leading to structural changes in these areas.

Partial status epilepticus after electroconvulsive therapy and medical treatment with bupropion.

Abstract: Electroconvulsive therapy (ECT) is the most effective treatment for therapy-refractory depression. Usually, prior antidepressant medication will be continued during ECT. However, the seizure threshold may be influenced by psychotropic drugs. We report a patient who received right unilateral ECT under concomitant treatment with bupropion, a selective noradrenaline- and dopamine-reuptake inhibitor. After the fourth session, a focal status epilepticus occurred, which was pharmacoresistant for the duration of 12 days. We assume that the induction of a status may be facilitated by a lowering of the seizure threshold due to bupropion. An evaluation of drug therapy and control of EEG before and during ECT are recommended, especially when the drug treatment has an influence on the seizure threshold.

Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders.

Abstract: Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD.

Completed suicides in 47 psychiatric hospitals in Germany--results from the AGATE-study.

Abstract: There is an ongoing debate about a possibly enhanced risk of suicidal behaviour in some psychiatric patients due to psychopharmacotherapy. Our retrospective study aimed at analyzing the psychopharmacotherapy of 133 inpatient suicides and 133 controls by a matched pair design. We analyzed all suicides (n=133) reported in the AGATE study from 1991 to 2008. Besides evaluation of sociodemographic variables and suicide methods, we compared psychopharmacotherapy of suicides with schizophrenia (n=59) and affective disorders (n=59) to that of a matched control group. Most suicides (n=102, 76.7%) were judged not to be related to psychopharmacotherapy. In general, more psychopharmacological drugs were prescribed for suicides than for controls. Schizophrenic suicides received more low potency FGAs than their controls. More suicides with affective disorders than controls were treated with NASSAs, SNRIs, and high or low potency FGAs. In contrast to their controls, none of the suicides with affective disorders received lithium. NASSAs, SNRIs, and high or low potency FGAs predicted suicide in regression analysis for inpatients with affective disorders. Differences in psychopharmacotherapy might mainly result from a recognized risk of suicide or a more severe degree of illness. However, the underrepresentation of lithium in the suicide groups is noticeable.

Use of anticholinergic drugs in patients with schizophrenia in Asia from 2001 to 2009.

Abstract: Objective The aim of this study was to survey the use of anticholinergic medication (ACM) in Asia between 2001 and 2009 and examine its demographic and clinical correlates. Method A total of 6 761 hospitalized schizophrenia patients in 9 Asian countries and territories were examined between 2001 and 2009. The patients' socio-demographic and clinical characteristics and the prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. Results The frequency of ACM prescription decreased from 66.3% in 2001, to 52.8% in 2004 and 54.6% in 2009, with wide inter-country variations at each time period. Multiple logistic regression analysis of the whole sample showed that patients taking ACM presented with more severe positive, negative, and extrapyramidal symptoms. They were also more likely to receive first-generation and depot antipsychotics and antipsychotic polypharmacy, and less likely to receive second-generation ones. Conclusions The wide variation in ACM prescription across Asia suggests that a combination of clinical, social, economic and cultural factors play a role in determining the use of these drugs. Regular reviews of ACM use are desirable to reveal the discrepancy between treatment guidelines and clinical practice.

The aims of systems biology: between molecules and organisms.

Abstract: The systems approach to biology has a long history. Its recent rapid resurgence at the turn of the century reflects the problems encountered in interpreting the sequencing of the genome and the failure of that immense achievement to provide rapid and direct solutions to major multi-factorial diseases. This paper argues that systems biology is necessarily multilevel and that there is no privileged level of causality in biological systems. It is an approach rather than a separate discipline. Functionality arises from biological networks that interact with the genome, the environment and the phenotype. This view of biology is very different from the gene-centred views of neo-Darwinism and molecular biology. In neuroscience, the systems approach leads naturally to 2 important conclusions: first, that the idea of 'programs' in the brain is confusing, and second, that the self is better interpreted as a process than as an object.

A systems approach to the biology of mood disorders through network analysis of candidate genes.

Abstract: Meta analysis of association data of mood disorders has shown evidence for the role of particular genes in genetic risk. Integration of association data from meta analysis with differential expression data in brains of mood disorder patients could heighten the level of support for specific genes. To identify molecular mechanisms that may be disrupted in disease, a systems approach that involves analysis of biological networks created by these selected genes was employed.Interaction networks of hierarchical groupings of selected genes were generated using the Michigan Molecular Interactions (MiMI) software. Large networks were deconvoluted into subclusters of core complexes by using a community clustering program, GLay. Network nodes were functionally annotated in DAVID Bioinformatics Resource to identify enriched pathways and functional clusters. MAPK and beta adrenergic receptor signaling pathways were significantly enriched in the ANK3 and CACNA1C network. The PBRM1 network bolstered the enrichment of chromatin remodeling and transcription regulation functional clusters. Lowering the stringency for inclusion of other genes in network seeds increased network complexity and expanded the recruitment of enriched pathways to include signaling by neurotransmitter and hormone receptors, neurotrophin, ErbB and the cell cycle. We present a strategy to interrogate mechanisms in the cellular system that might be perturbed in disease. Network analysis of meta analysis- generated candidate genes that exhibited differential expression in mood disorder brains identified signaling pathways and functional clusters that may be involved in genetic risk for mood disorders.

Comparison of polysomnographic variables and their relationship to cognitive impairment in patients with Alzheimer's disease and frontotemporal dementia

Abstract: Polysomnograhic (PSG) studies in Alzheimer’s disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD

Psychological and neuroendocrine responses to social stress and to the administration of the alpha-2-receptor antagonist, yohimbine, in highly trained endurance athletes in comparison to untrained healthy controls.

Abstract: INTRODUCTION: Several clinical studies suggest antidepressive and anxiolytic effects of regular endurance training The mechanisms by which exercise exerts these effects are still unclear It was hypothesized that athletes might show a diminished reaction to psychosocial stress and noradrenergic stimulation METHODS: 12 male athletes and 12 healthy untrained male controls underwent a challenge paradigm on 3 separate days: the alpha-2-receptor antagonist yohimbine (04 mg/kg), placebo or a psychosocial stress test (SST) were administered Responses were measured by psychometric scales, plasma cortisol, blood pressure and heart rate RESULTS: Before testing, psychometric variables and cortisol levels were not different between the 2 groups In comparison to placebo conditions, both the social stress test and the administration of yohimbine were followed by significant increases of anxiety symptoms, plasma cortisol, heart rate and blood pressure in both groups However, these responses were not significantly different between the group of athletes and the control group DISCUSSION: These results do not support the hypotheses that high aerobic fitness is associated with attenuated psychological and neuroendocrine responses to yohimbine or to psychosocial stress

Time perception in patients with major depressive disorder during vagus nerve stimulation.

Abstract: Affective disorders may affect patients’ time perception. Several studies have described time as a function of the frontal lobe. The activating effects of vagus nerve stimulation on the frontal lobe might also modulate time perception in patients with major depressive disorder (MDD). Time perception was investigated in 30 patients with MDD and in 7 patients with therapy-resistant MDD. In these 7 patients, a VNS system was implanted and time perception was assessed before and during stimulation. A time estimation task in which patients were asked “How many seconds have passed?” tested time perception at 4 defined time points (34 s, 77 s, 192 s and 230 s). The differences between the estimated and actual durations were calculated and used for subsequent analysis. Patients with MDD and healthy controls estimated the set time points relatively accurately. A general linear model revealed a significant main effect of group but not of age or sex. The passing of time was perceived as significantly slower in patients undergoing VNS compared to patients with MDD at all time points (T34: t=−4.2; df=35; p VNS is capable of changing the perception of time. This discovery furthers the basic research on circadian rhythms in patients with psychiatric disorders.

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

Abstract: 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.