Safety, pharmacokinetics and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects.

AIMS: TAK-071 is a muscarinic M1 receptor positive allosteric modulator designed to have low cooperativity with acetylcholine. This was a first-in-human study to evaluate the safety, pharmacokinetics, and pharmacodynamics of TAK-071. METHODS: TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers alone and in combination with donepezil. Laboratory, electrocardiogram (ECG) and electroencephalogram (EEG) evaluations were performed. Cerebrospinal fluid and blood samples were taken to evaluate the pharmacokinetics (PK), relative bioavailability and food effect. RESULTS: TAK-071 was safe and well tolerated, and no deaths or serious adverse events occurred. TAK-071 demonstrated a long mean (% coefficient of variation) half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. Coadministration with donepezil had no impact on the PK of either drug. There was no food effect on systemic exposure. Quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition. CONCLUSIONS: PK and safety profiles of TAK-071 were favorable, including those exceeding expected pharmacologically active doses based on preclinical data. When administered without donepezil TAK-071 was largely free of cholinergic adverse effects. Further clinical evaluation of TAK-071 is warranted.

Measuring cognition and function in the preclinical stage of Alzheimer's disease.

The Alzheimer's Association's Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer's disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer's disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Trial, the Alzheimer's Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's to compare current approaches and tools that are being developed.

Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia.

BACKGROUND: Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum. OBJECTIVE: To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes. METHODS: Patient-level longitudinal data from the National Alzheimer's Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon. RESULTS: Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy. CONCLUSION: Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.

The potent BACE1 inhibitor LY2886721 elicits robust central Aß pharmacodynamic responses in mice, dogs, and humans.

BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

Validation of a multiplex assay for simultaneous quantification of amyloid-ß peptide species in human plasma with utility for measurements in studies of Alzheimer's disease therapeutics.

The aim of this study was to validate the INNO-BIA plasma amyloid-ß (Aß) forms assay for quantification of Aß1-40 and Aß1-42 according to regulatory guidance for bioanalysis and demonstrate its fitness for clinical trial applications. Validation parameters were evaluated by repeated testing of human EDTA-plasma pools. In 6 separate estimates, intra-assay coefficients of variation (CV) for repeated testing of 5 plasma pools were ≤9% and relative error (RE) varied between -35% and +22%. Inter-assay CV (n = 36) ranged from 5% to 17% and RE varied from -17% to +8%. Dilutional linearity was not demonstrated for either analyte using diluent buffer, but dilution with immuno-depleted plasma by 1.67-fold gave results within 20% of target. Analyte stability was demonstrated in plasma at 2-8 °C for up to 6 h. Stability during frozen storage up to 12 months and through 3 freeze-thaw cycles at ≤ -70 °C was also demonstrated in 5 of 6 individuals but deteriorated thereafter. Neither semagacestat nor LY2811376 interfered with the assay but solanezumab at 500 mg/L reduced recovery of Aß1-42 by 53%. Specimens from a Phase I human volunteer study of the ß-secretase inhibitor LY2811376 were tested at baseline and at intervals up to 12 h after single oral doses, demonstrating a clear treatment effect. During 1,041 clinical assay runs from semagacestat studies over 10 months, the CV for plasma quality control pools at three levels were ≤15% and RE were <10%. In conclusion, the INNO-BIA plasma assay was successfully validated and qualified for use in clinical research.

Enriching amnestic mild cognitive impairment populations for clinical trials: optimal combination of biomarkers to predict conversion to dementia.

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial.

A 12-month prospective, observational study of treatment regimen and quality of life associated with ADHD in central and eastern europe and eastern Asia.

OBJECTIVES: This prospective, observational, non-randomized study aimed to describe the relationship between treatment regimen prescribed and the quality of life (QoL) of ADHD patients in countries of Central and Eastern Europe (CEE) and Eastern Asia over 12 months. METHODS: 977 Male and female patients aged 6-17 years seeking treatment for symptoms of ADHD were assessed using the Child and Adolescent Symptom Inventory-4 Parent Checklists, and the Clinical Global Impressions-ADHD-Severity scale. QoL was assessed using the Child Health and Illness Profile-Child Edition parent report form. Patients were grouped according to whether they were prescribed psycho- and/or pharmacotherapy (treatment) or not (no/'other' treatment). RESULTS: No statistically significant differences were observed between cohorts (treatment vs. no/'other' treatment) in terms of change in QoL, although there was improvement over 12 months, with a greater improvement experienced by patients in the treatment cohort in both study regions (CEE and Eastern Asia). Psychoeducation/counselling and methylphenidate were the predominant ADHD treatments prescribed. CONCLUSIONS: Although both treatment and no/'other' treatment cohorts showed improvements in mean QoL over 12 months, the difference was small and not statistically significant. A major limitation was the higher than anticipated number of patients switching treatments, predominantly from the no/'other' treatment cohort.

Robust central reduction of amyloid-ß in humans with an orally available, non-peptidic ß-secretase inhibitor.

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-ß peptide (Aß) is critical for Alzheimer's disease (AD) pathogenesis. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound Aß-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aß reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aß reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

A prospective observational study of attention-deficit/hyperactivity disorder in Central and Eastern Europe and Turkey: Symptom severity and treatment options in a paediatric population.

Abstract Objective. This study investigates the relationship between treatment regimen, symptom severity, comorbidities and health outcomes of paediatric patients with attention-deficit/hyperactivity disorder (ADHD) in Central and Eastern Europe (CEE). Methods. Males and females aged 6-17 years with ADHD symptoms participated in this 12-month, prospective, observational, non-randomised study. Symptoms and comorbidities were assessed using the Child and Adolescent Symptom Inventory-4 Parent Checklists (CSI-4; ASI-4, categories L/O), and the Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S). Baseline data are presented. Results. The study included 566 patients from Czech Republic, Hungary, Romania, Slovakia and Turkey. Psychiatrists made all diagnoses using The American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV), World Health Organization International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), and "other" criteria (73, 27 and 0.4%, respectively). Patients were grouped into two cohorts based on whether they were prescribed psycho- and/or pharmacotherapy (n=443) or not (n=123). Patients receiving prescribed treatment were older and demonstrated higher symptom severity scores than those receiving no or "other" treatment. Most patients were prescribed conventional treatment for ADHD at baseline. Conclusions. Continued assessment of this population may aid the treatment and outcomes of ADHD in CEE.

Atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: a 6-week, randomized, placebo-controlled, double-blind trial in Russia.

The objective of the study was to compare the efficacy and tolerability of once-daily atomoxetine (< or =1.8 mg/(kg day) with those of placebo in children and adolescents (aged 6-16 years) with attention-deficit/hyperactivity disorder [ADHD (DSM-IV)]. This randomized, placebo-controlled, double-blind trial was conducted in Russia. The primary efficacy measure was baseline-to-end point changes in Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored (ADHDRS-IV-Parent:Inv) total score. Tolerability measures included treatment-emergent signs and symptoms (TESS), laboratory values and weight. Compared with patients in the placebo group (n = 33), patients treated with atomoxetine (n = 72) with a mean final dose of 1.4 mg/kg showed significantly greater improvement in ADHDRS-IV-Parent:Inv total score (least-squares mean: atomoxetine, -15.8; placebo, -11.4; p = 0.013). The most common TESS in the atomoxetine group included anorexia [atomoxetine, n = 13 (18.1%); placebo, n = 2 (6.1%)], somnolence, n = 11 versus n = 3 (15.3% vs. 9.1%, respectively), abdominal pain n = 9 versus n = 1 (12.5% vs. 3.0%, respectively) and nausea, n = 8 versus n = 1 (11.1% vs. 3.0%, respectively). Seven patients in the atomoxetine group and two in the placebo group experienced clinically important weight loss during the study (> or =7% from baseline; mean change, kg: atomoxetine, -0.6; placebo, 0.1; p = 0.032). Atomoxetine is efficacious in improving ADHD symptoms in children and adolescents. Atomoxetine treatment may be associated with a numerically higher incidence of anorexia, somnolence, abdominal pain and nausea, as well as statistically greater losses in body weight.

Attention-deficit/hyperactivity disorder diagnosis, co-morbidities, treatment patterns, and quality of life in a pediatric population in central and eastern Europe and Asia.

Attention deficit/hyperactivity disorder (ADHD) is often poorly understood, and treatment practices are variable. This 12-month, prospective, observational study provides information about the diagnosis, co-morbidities, treatment patterns, and quality of life (QOL) of patients aged 6-17 years with ADHD symptoms from eastern Asia and central and eastern Europe. Here, we present baseline data for the 1068 enrolled and eligible patients in the study (median age 8 years, 82.2% male). Patients were grouped into two cohorts based on whether they were prescribed psycho- and/or pharmacotherapy (n = 794) or not (n = 274) at study entry. On average, patients receiving treatment were significantly older (9.1 vs. 8.4 years, p < 0.001), more severely ill (Clinical Global Impressions [CGI]-ADHD-S, 4.6 vs. 4.2, p < 0.001; Child Symptom Inventory-4 Parent Checklist (CSI-4) ADHD:C, 35.2 vs. 31.9, p < 0.001), and had significantly higher CSI-4 symptom severity scores relating to various co-morbidities than patients not receiving treatment. At study initiation, patient's health-related QOL was significantly impaired as measured on the Child Health and Illness Profile-Child Edition (CHIP-CE) rating scale, with significantly more impairment in the treated group of patients for the Comfort, Risks Avoidance, and Achievement domains. These results provide a description of ADHD and treatment practices in these regions and establish a baseline for gauging changes over time in the study sample.

Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes.

BACKGROUND: Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. AIMS: To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. METHOD: Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. RESULTS: There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. CONCLUSIONS: The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.

Antipsychotic prescription patterns in outpatient settings: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

This report describes antipsychotic prescription patterns for outpatients with schizophrenia prescribed olanzapine (n=3,222), clozapine (n=236), risperidone (n=1,117), quetiapine (n=189) or haloperidol (n=256) monotherapy at study entry and treated in a naturalistic, clinical practice setting over 24 months. Predictive factors associated with remaining on monotherapy were also identified. Olanzapine patients had significantly greater odds of remaining on their initial monotherapy compared to other treatment groups, while clozapine or risperidone recipients were more likely to remain on monotherapy, compared to haloperidol patients. Switching antipsychotic medication was more common than addition of another antipsychotic agent, and the most common reason for modifying treatment was lack of effectiveness. The odds of modifying antipsychotic prescription due to intolerability were lower for patients treated with olanzapine, compared to patients treated with risperidone or haloperidol (p

Parasitosis, dopaminergic modulation and metabolic disturbances in schizophrenia: evolution of a hypothesis.

Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia. Issues for further research have been suggested. Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance. Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. We believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia.

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.

Failed efficacy of fluoxetine in the treatment of posttraumatic stress disorder: results of a fixed-dose, placebo-controlled study.

A multicenter, double-blind, 12-week, placebo-controlled trial of 411 randomized patients, predominantly women diagnosed with posttraumatic stress disorder, failed to show a difference between either dose of fluoxetine treatment and placebo. The mean changes from baseline (SD) measured by the Clinician-Administered PTSD Scale scores were -42.9 (23.1), -42.8 (27.9), and -36.6 (25.7) in the 20-mg fluoxetine, 40-mg fluoxetine, and placebo arms, respectively. Placebo response rate was substantially higher in this study than in a previously published fluoxetine trial of posttraumatic stress disorder.

Fluoxetine in the acute treatment and relapse prevention of combat-related post-traumatic stress disorder: Analysis of the veteran group of a placebo-controlled, randomized clinical trial.

The efficacy and safety of fluoxetine (20-80 mg) was compared with placebo in 144 veterans [36.2 years], diagnosed with combat-related post-traumatic stress disorder (PTSD) selected from a 12-week acute and 24-week relapse prevention PTSD trial. In the acute phase, improvements were greater with fluoxetine than placebo in the disease-specific outcome measures: Treatment Outcome PTSD (TOP-8) total scores (SE):-9.05 (0.90) and -5.20 (1.23), p = 0.001; Clinician Administered PTSD Scale (CAPS) total scores:-31.12 (2.72) and -16.07 (4.24), p < 0.001; all CAPS subscores; Davidson Trauma Scale (DTS) total scores; and other general outcome measures. In the maintenance phase, fluoxetine was superior to placebo in sustaining improvement in TOP-8 [-1.01 (0.91) and 1.56 (0.95)] and CAPS [-4.93 (3.54) and 5.48 (3.66)]. The risk of relapse in the placebo arm was significantly greater than in the fluoxetine arm (log-rank test chi 2 = 4.090, df = 1, p = 0.048). Fluoxetine was well tolerated at a mean daily dose of 65 mg.

[Three paradigms in the treatment of posttraumatic stress disorder]. / A poszttraumás-stressz zavar gyógyszeres kezelésének három paradigmája.

There are three different approaches in the pharmacological treatment of posttraumatic stress disorder (PTSD) in the published data. The most frequently implemented approach is to treat patients suffering from the diagnosis of PTSD. Both short-term acute and long-term relapse prevention treatments represent a curative paradigm: with an intention to diminish the symptoms associated with the disorder. Data about efficacy of monoamine oxidase inhibitors and selective serotonin reuptake inhibitors (SSRIs) in the treatment of PTSD are heterogeneous. Data are relatively consistent with regards of efficacy of SSRIs in the treatment of civilian, predominantly female population, regardless of the type of trauma: interpersonal or non-interpersonal trauma. Placebo controlled trial data in the treatment of combat-related PTSD are inconclusive or negative. Three recently published studies provide new approaches to the treatment of male patients, suffering from combat-related PTSD. A relatively young, recently traumatized male, combat-related population showed significant improvement for fluoxetine compared to placebo. An adjuvant 5HT2 antagonist profile may improve the SSRI effect in the treatment of PTSD: nefazodone was significantly superior compared to placebo in the treatment of combat-related PTSD, and risperidone treatment add-on to antidepressants showed significant benefits compared to antidepressant monotherapy in the treatment of combat-related PTSD. The goal of sedative paradigm is to minimize the immediate consequences of the traumatic stress, decrease the fear, anxiety and sleeplessness. Data published about benzodiazepines failed to show effectiveness in the acute management of post-traumatic mental consequences. The intention of the third treatment paradigm is characterized by the secondary prevention of PTSD. Benzodiazepines administered shortly after the traumatic event, failed to prevent the mental consequences of traumatic stress. Two small trials with propranolol administration after the trauma have been shown some benefits compared to placebo or no treatment. PTSD represents a complex disregulation of numerous neurotransmitters and neuromodulators, therefore the complex pharmacological treatment has to consider approaches beyond the current treatment regimens characterized by modulation of monoamine neurotransmission.

[Posttraumatic stress disorder (PTSD)]. / A poszttraumás stressz zavar.

The diagnosis of posttraumatic stress disorder (PTSD) has been introduced in 1980. The diagnosis, as construct raises several political, moral, legal, and compensation issues. PTSD is considered as a multisystemic dysregulation, involving the hypothalamic- pituitary - adrenal axis, adrenergic hypersensibility, and serotonergic dysfunction. The prevalence of PTSD is 1-9% in the general population, but substantially higher among victims of traumatic events: 19-70%. Placebo controlled studies provide a body of evidence concerning efficacy of selective serotonin reuptake inhibitors in the treatment of PTSD both in the acute and maintenance treatments. Studies with balanced male-female ratio suggest no gender-related differences in the clinical response, furthermore both civilians and veterans improved significantly for selective serotonin reuptake inhibitor treatment.

Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder.

BACKGROUND: Little is known about the effect of pharmacotherapy in the prevention of post-traumatic stress disorder (PTSD) relapse. AIMS: To assess the efficacy and tolerability of fluoxetine in preventing PTSD relapse. METHOD: This was a double-blind, randomised, placebo-controlled study. Following 12 weeks of acute treatment, patients who responded were rerandomised and continued in a 24-week relapse prevention phase with fluoxetine (n=69) or placebo (n=62). The primary efficacy assessment was the prevention of PTSD relapse, based on the time to relapse. RESULTS: Patients in the fluoxetine/fluoxetine group were less likely to relapse than patients in the fluoxetine/placebo group (P=0.027). There were no clinically significant differences in treatment-emergent adverse events between treatment groups. CONCLUSIONS: Fluoxetine is effective and well tolerated in the prevention of PTSD relapse for up to 6 months.