European Neuropsychopharmacology (v.25, #7)

Contents (OBC).

What regulatory science can bring for CNS drug development by Christine Gispen-de Wied; Violeta Stoyanova-Beninska (967-968).

Cognitive enhancing agents in schizophrenia and bipolar disorder by Annabel Vreeker; Annet H. van Bergen; René S. Kahn (969-1002).
Cognitive dysfunction is a core feature of schizophrenia and is also present in bipolar disorder (BD). Whereas decreased intelligence precedes the onset of psychosis in schizophrenia and remains relatively stable thereafter; high intelligence is a risk factor for bipolar illness but cognitive function decreases after onset of symptoms. While in schizophrenia, many studies have been conducted on the development of cognitive enhancing agents; in BD such studies are almost non-existent. This review focuses on the pharmacological agents with putative effects on cognition in both schizophrenia and bipolar illness; specifically agents targeting the dopaminergic, cholinergic and glutamatergic neurotransmitter pathways in schizophrenia and the cognitive effects of lithium, anticonvulsants and antipsychotics in BD. In the final analysis we conclude that cognitive enhancing agents have not yet been produced convincingly for schizophrenia and have hardly been studied in BD. Importantly, studies should focus on other phases of the illness. To be able to treat cognitive deficits effectively in schizophrenia, patients in the very early stages of the illness, or even before – in the ultra-high risk stages – should be targeted. In contrast, cognitive deficits occur later in BD, and therefore drugs should be tested in BD after the onset of illness. Hopefully, we will then find effective drugs for the incapacitating effects of cognitive deficits in these patients.
Keywords: Schizophrenia; Bipolar disorder; Cognition; Cognitive impairment; Pharmacology; Drug development;

CNS biomarkers: Potential from a regulatory perspective by Maria Isaac; Christine Gispen-de Wied (1003-1009).
Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion.We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators׳ qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer׳s disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification.EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD.The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers.
Keywords: Biomarkers; Qualification advice; Qualification opinion; EMA; FDA;

Early onset APOE E4-negative Alzheimer’s disease patients show faster cognitive decline on non-memory domains by Lieke L. Smits; Yolande A.L. Pijnenburg; Annelies E. van der Vlies; Esther L.G.E. Koedam; Femke H. Bouwman; Ilona E.W. Reuling; Philip Scheltens; Wiesje M. van der Flier (1010-1017).
Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer’s disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5±1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65±8 years, 98(49%) were female and MMSE was 22±4. LMM showed that early onset patients declined faster on executive functioning (β±SE:−0.09±0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β±SE:−0.1±0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β±SE:−0.36±0.1), attention (β±SE:−0.42±0.1), executive (β±SE:−0.41±0.1) and visuo-spatial functioning (β±SE:−0.43±0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains.
Keywords: Alzheimer׳s disease; cognitive neuropsychology in dementia; neuropsychology; cognitive decline; longitudinal design;

Placebo response in antipsychotic trials of patients with acute mania by C.C.M. Welten; M.W.J. Koeter; T. Wohlfarth; J.G. Storosum; W. van den Brink; C.C. Gispen-de Wied; H.G.M. Leufkens; D.A.J.P. Denys (1018-1026).
We examined the role of placebo response in acute mania trials. Specifically, whether placebo response: (1) predicts treatment effect, (2) can be predicted by patient and study characteristics, and (3) can be predicted by a parsimonious model. We performed a meta-analysis of individual patient data from 10 registration studies (n=1019) for the indication acute manic episode of bipolar disorder. We assessed the effect of 14 determinants on placebo response. Primary outcome measures were mean symptom change score (MCS) on the Young Mania Rating Scale (YMRS) and response rate (RR), defined as ≥50% YMRS symptom improvement from baseline to endpoint. The overall placebo response was 8.5 points improvement on the YMRS (=27.9%) with a RR of 32.8%. Placebo response was significantly associated with the overall treatment response. Five determinants significantly (p<0.05) predicted the placebo response. The multivariate prediction model, which consisted of baseline severity, psychotic features at baseline, number of geographic regions, and region, explained 10.4% and 5.5% of the variance in MSC and RR, respectively. Our findings showed that the placebo response in efficacy trials of antipsychotics for acute mania is substantial and an important determinant of treatment effect. Placebo response is influenced by patient characteristics (illness severity and presence of psychotic features) and by study characteristics (study year, number of geographic regions and region). However, the prediction model could only explain the placebo response to a limited extent. Therefore, limiting trials to certain patients in certain geographic regions seems not a viable strategy to improve assay sensitivity.
Keywords: Bipolar mania; Placebo response; Antipsychotics; Predictors;

Regulatory and clinical aspects of psychotropic medicinal products bioequivalence by Ewa Bałkowiec-Iskra; Grzegorz Cessak; Olga Kuzawińska; Katarzyna Sejbuk-Rozbicka; Konrad Rokita; Dagmara Mirowska-Guzel (1027-1034).
Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost, leading to containment of public expenditures on medicinal products reimbursement. The critical assessment of bioequivalence of any reference medicinal product and its counterpart is based on comparison of their rate and extent of absorption. It is assumed that two medicinal products are bioequivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. Bioequivalent medicinal products are declared to be also therapeutically equivalent and can be used interchangeably. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of this article is to provide a description of rules that guide registration of generic medicinal products in the European Union and to analyze specific examples from the scientific literature concerning therapeutic equivalence of reference and generic antidepressant and antipsychotic medicinal products.
Keywords: Bioequivalence; Generic medicinal products; Psychotropic medicinal products; Registration;

Lost interest for existing compounds: New boosts by Lawrence T. Friedhoff; James Dailey (1035-1038).
Development of new drugs is typically thought of as a bottom-up endeavor where basic science identifies a target, various strategies are used to generate drugs that stimulate or inhibit the target, the drugs are first tested for safety and efficacy in animals and finally efficacy and safety are evaluated in a well defined clinical development process. However, this is not the only way that new drug products are developed. Many new products come from re-initiating development of discontinued drugs, finding new uses for existing drugs, creating a new product by obtaining marketing approval in expanded territories, obtaining approvals for new formulations or a single isomer of a previously approved racemic drug, converting products from prescription to over-the- counter use or converting folk medicines or vitamins to modern pharmaceuticals. Based on this long and successful history of contributions to modern therapeutics, these alternative sources of new products should not be neglected.
Keywords: New drug development; Drug approval; New formulation; New indications; Optical isomers; Folk medicine;

Since medicines for psychiatric diseases are often studied in adults first, it would be useful if data from efficacy trials in adults could be extrapolated to children and adolescents. However, it is not sufficient to adapt the adult dosages to achieve systemic exposure levels similar to those effective in adults. This can be done with increasing predictive accuracy but before accepting that the same plasma levels should result in the same efficacy as in adults both the mechanism of action of the drug and the pathophysiology of the disease must be considered. For psychiatric disorders there is often insufficient evidence to support the assumptions for extrapolating efficacy as it is not even always sure that the same diagnostic categories correspond to the same disease in adults and children. Even when the basic biological alteration behind the disorder could be considered the same, the psychodynamic consequences and the role of non-pharmacological approaches to treatment may substantially differ across age groups. These facts, together with the absence of detailed historical data on the actual correlations between paediatric and adult responses for many types of psycho-therapeutic medicines, make it difficult to accept extrapolation as the main proof of efficacy in children and adolescents. A corollary is that since efficacy studies will normally be required, they should not be unduly postponed. For products addressing a medical need with good scientific plausibility, they should be initiated as soon as the anticipated safety concerns can be reasonably managed within the context of a paediatric clinical trial.
Keywords: Extrapolation; Paediatrc drug development; Efficacy clinical trials; Psychopharmacology; Adolescent psychiatry; Child psychiatry;