Advances in Drug Discovery and Development in Geriatric Psychiatry.

PURPOSE OF REVIEW: This article reviews recent advances in drug discovery and development for geriatric psychiatry. Drug discovery for disorders of the central nervous system is a long and challenging process, with a high attrition rate from the preclinical stages through to marketing a compound. Developing drugs for geriatric neuropsychiatric conditions presents additional challenges, due to the complexity of the symptoms, comorbid diagnoses, and the variability of the population. Despite there being limited success over the past two decades, a number of new approaches have identified potential targets for preclinical development and ultimately clinical testing. RECENT FINDINGS: Recent approaches have tried to address specific mechanisms that relate to the disease progression. These approaches include combining a number of ligands into to multi-target compounds, or targeting specific types of cells such as protein kinases or myeloid cells. In addition, the increased use of induced pluripotent stem cell cultures has enabled new compounds to be tested on disease-specific tissues, increasing the success rate of the lead compounds going through the preclinical stages. New pharmacological agents designed with advanced screening techniques and the shift towards systems pharmacology is changing the landscape of drug discovery in geriatric psychiatry. There is potential for these new agents to produce targeted effects in the framework of disorders that have long been untreatable.

A Critical Commentary on the 2017 AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology.

In 2004, 2011, and 2017, the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP), a group of German-speaking psychiatric researchers and psychiatrists, published successive versions of therapeutic drug monitoring (TDM) expert group consensus guidelines. The 2017 version has as a major strength its encyclopedic nature, including 1358 references. The guideline has 3 major sections: 1) theoretical aspects of TDM, 2) drug concentration levels in blood to guide neuropsychopharmacotherapy, and 3) practical aspects of TDM in psychiatry and neurology. The writer hopes the time is right for a TDM guideline in psychiatry, which is indicated for: 1) psychiatric researchers ready to value how TDM can contribute to moving psychopharmacology forward, 2) flexible clinicians ready to improve their patient care by personalizing dosing, and 3) today's psychiatry residents prepared as a new generation ready to be trained in TDM and willing to continue incorporating TDM as new psychiatric drugs are marketed.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Clinical Pharmacopsychology: Conceptual Foundations and Emerging Tasks.

The aim of this critical review was to outline emerging trends and perspectives of clinical pharmacopsychology, an area of clinical psychology that is concerned with the psychological effects of medications. The historical development of clinical pharmacopsychology is outlined, with discussion of its most representative expressions and reference to current challenges of clinical research, with particular reference to clinimetrics. The domains of clinical pharmacopsychology encompass the clinical benefits of psychotropic drugs, the characteristics that predict responsiveness to treatment, the vulnerabilities induced by treatment (side effects, behavioral toxicity, iatrogenic comorbidity), and the interactions between drug treatment and psychological variables. Its aim is to provide a comprehensive assessment of the clinical important changes that are concerned with (a) wanted and expected treatment effects, (b) treatment-induced unwanted side effects, and (c) the patient's own personal experience of a change in terms of well-being and/or quality of life. Clinical pharmacopsychology offers a unifying framework for the understanding of clinical phenomena in medical and psychiatric settings. Research in this area deserves high priority.

Update Psychopharmacotherapy. / Aktuelles zur Psychopharmakotherapie.

Despite unmet meeds regarding efficacy, tolerability and time of onset and the high importance of mental disorders very few new psychotropics have been introduced in Germany recently. Lurasidon and the new multimodal antidepressant vortioxetine demonstrating clinical efficacy in the improvement of cognition have been withdrawn from the German market due to economic reasons based on an official committee judgement "missing additional benefit". Among new substances introduced are the selective opioid modulator nalmefene for reduction of alcohol consumption, the selective alpha-2-receptor agonist guanfacine for ADHS treatment in child and youth psychiatry, the older antidepressant milnacipran and the glucagon-like-peptide-1-receptor agonist liraglutide for treatment of adipositas. In the USA the atypical antipsychotics cariprazine and brexpiprazole have been released. The introduction of the long acting depot antipsychotics aripiprazole (1 month) and paliperidone (3 months) can be seen as major progress in the treatment of schizophrenia. Loxapine is available as inhalative antipsychotic for rapid treatment of agitation in schizophrenia and mania. Atypical antipsychotics like quetiapine are recommended now as add-on treatment for therapy-resistant depressions. Ketamine and botulinum toxin are in experimental use as antidepressants. The development of psychotropics is long lasting and costly and made even more difficult by negative medial attitudes additionally. Constructive resolving attempts are needed urgently to avoid a standstill in the development of psychotropic drugs.

Pharmacotherapy in Psychiatric Disorders of Children: Current Evidence and Trends.

Pharmacotherapeutic interventions are available for most psychiatric disorders in children. Evidence for these interventions varies, depending on the targeted disorders. For attention-deficit/hyperactivity disorder, a sound database on efficacy and safety of medication exists. For other common disorders or psychopathological phenomena like disruptive behavior, anxiety disorders, depressive disorders, or autism, data on efficacy and safety are much scarcer. This selective review aims to provide an overview about current psychopharmacological interventions in child and adolescent psychiatry. The literature indicates either a lower efficacy than other interventions or less beneficial effects compared to possible adverse events in these cases. Most guidelines recommend psychopharmacotherapy in children to be embedded in a psychosocial or therapeutic intervention plan. Decision for medication depends on the severity of symptoms, chronicity, and, most important, impairment of the child in academic performance, family relationships, and everyday life. The high rates of off-label use in the age group of children are often due to a lack of market authorization studies less indicative of low efficacy. As adverse events need to be monitored closely, pharmacotherapy should mainly be restricted to experienced mental health care providers.

A New Nomenclature for Psychotropic Drugs.

INTRODUCTION: Current classifications of psychotropic drugs, developed in the 1960s, are based on beliefs about clinical effectiveness. This article evaluates the scientific validity of current drug terms and possible alternative classifications. METHODS: A historical, conceptual, and empirical review of the psychopharmacology literature is provided. Consistency of classification is examined by 3 major categories: chemical structure, pharmacodynamic mechanism, and clinical efficacy. RESULTS: Current drug terms based on clinical effectiveness are not valid scientifically, either claiming efficacy which is disproven or ignoring other areas of clinical efficacy. Hence, clinical efficacy is not a consistent and scientifically valid way of classifying psychotropic drugs. Chemical structures are also heterogeneous for drugs with similar clinical efficacy. The most consistent way to define drug classes is pharmacodynamic mechanism. Specific drug groups identified are: monoamine agonists ("antidepressants" and "stimulants"), dopamine blockers ("antipsychotics"), second messenger modifiers ("mood stabilizers), and gabaergic agonists ("anxiolytics" or "hypnotics"). CONCLUSIONS: Consistent with a recent proposal of psychopharmacology organizations, this article proposes a new nomenclature based mainly on biological pharmacodynamic mechanisms. Specific terms that are scientifically valid and clinically practical are suggested. It is hoped that this new language would allow for more meaningful and accurate communication between clinicians and patients.

Trends in psychopharmacologic treatment of tic disorders in children and adolescents in Germany.

Data on medical treatment of children and adolescents with tic disorders are scarce. This study examined the administrative prevalence of psychopharmacological prescriptions in this patient group in Germany. Data of the largest German health insurance fund were analysed. In outpatients aged 0-19 years with diagnosed tic disorder, psychotropic prescriptions were evaluated for the years 2006 and 2011. In 2011, the percentage of psychotropic prescriptions was slightly higher than in 2006 (21.2 vs. 18.6%). The highest prescription prevalence was found in Tourette syndrome (51.5 and 53.0%, respectively). ADHD drugs were most frequently prescribed, followed by antipsychotics. In 2011, prescriptions of second generation antipsychotics (SGA) were higher and prescriptions of first generation antipsychotics (FGA) lower than in 2006. Concerning prescribed antipsychotic substances, in 2011 risperidone prescriptions were higher and tiapride prescriptions lower. Paediatricians issued 37.4%, and child and adolescent psychiatrists issued 37.1% of psychotropic prescriptions. The FGA/SGA ratio was highest in GPs (1.25) and lowest in child and adolescent psychiatrists (0.96). From 2006 to 2011, there was only a slight increase in psychotropic prescriptions for children and adolescents with a diagnosis of tic disorder in Germany, which stands in contrast towards the significant increase in psychotropic prescriptions in other child and adolescent psychiatric disorders (e.g. ADHD). There were marked differences in treatment patterns by tic disorder subgroups, with Tourette syndrome patients receiving most frequently psychopharmacotherapy. Risperidone prescriptions increased, probably reflecting a switch in prescribing practice towards up-to-date treatment guidelines. In primary care physicians, dissemination of current tic disorder treatment guidelines might constitute an important educational goal.

[The problem of small "n" and big "P" in neuropsycho-pharmacology, or how to keep the rate of false discoveries under control]. / A kis "n", nagy "P" probléma a neuropszichofarmakológiában, avagy hogyan kontrolláljuk a hamis felfedezések arányát.

One of the characteristics of many methods used in neuropsychopharmacology is that a large number of parameters (P) are measured in relatively few subjects (n). Functional magnetic resonance imaging, electroencephalography (EEG) and genomic studies are typical examples. For example one microarray chip can contain thousands of probes. Therefore, in studies using microarray chips, P may be several thousand-fold larger than n. Statistical analysis of such studies is a challenging task and they are refereed to in the statistical literature such as the small "n" big "P" problem. The problem has many facets including the controversies associated with multiple hypothesis testing. A typical scenario in this context is, when two or more groups are compared by the individual attributes. If the increased classification error due to the multiple testing is neglected, then several highly significant differences will be discovered. But in reality, some of these significant differences are coincidental, not reproducible findings. Several methods were proposed to solve this problem. In this review we discuss two of the proposed solutions, algorithms to compare sets and statistical hypothesis tests controlling the false discovery rate.

[Research in Psychopharmacology]. / La investigación en psicofarmacología.

Research in psychopharmacology began around 1950 with the description of antipsychotic effect of chlorpromazine followed shortly later with the mechanism of action of antidepressants. In these initial phases, pharmacy industry was open to knowledge and made efforts tending to the development to new drugs that showed efficacy and good safety profiles. In parallel development of theories attempting to find the etiology of psychiatric disorders acquired impulse. This review summarizes the new drugs for the treatment of psychiatric disorders currently under development and also presents a short list of the main biomarkers proposed for the diagnosis or the comprehension of the etiopathogeny in Psychiatry. Several questions arose when brain structures, biochemical pathways, proteins and genes began to be identified in the search for a better comprehension of etiopathogeny of mental disorders. Pharmaceutical industry virtually moved away from this field of research. Epistemological and methodological obstacles in psychopharmacological investigation together with the lack of priority given by industry to this field allow us to predict few advances for the treatment in Psychiatry in the short term.

Problems and solutions to filling the drying drug pipeline for psychiatric disorders: a report from the inaugural 2012 CINP Think Tank.

The inaugural Collegium Internationale Neuro-Psychopharmacologicum (CINP) Think Tank, a small open meeting sponsored by the CINP, discussed impediments to developing new drugs for psychiatric disorders and approaches to overcome these impediments. Whilst neuropsycharmacology has a rich pharmacopeia (current treatments benefiting many individuals), issues of treatment resistance, sub-optimal response and unwanted side effects remain problematic. Many scientific, economic and social issues are impeding the development of drugs (e.g. higher risk of failure, placebo effects, problematic regulatory environments, pressures imposed by patent protection, downward pressure on reimbursements and financial, legal and social risk aversion). A consensus of the meeting was that efforts to understanding the core pathophysiology of psychiatric disorders are fundamental to increasing the chance of developing new drugs. However, findings from disorders such as Huntington's chorea, have shown that knowing the cause of a disorder may not reveal new drug targets. By contrast, clinically useful biomarkers that define target populations for new drugs and models that allow findings to be accurately translated from animals to humans will increase the likelihood of developing new drugs. In addition, a greater accent on experimental medicine, creative clinical investigations and improved communication between preclinical neuropsychopharmacologists, clinicians committed to neuropsychopharmacological research, industry and the regulators would also be a driver to the development of new treatments. Finally, it was agreed that the CINP must continue its role as a conduit facilitating vibrant interactions between industry and academia as such communications are a central component in identifying new drug targets, developing new drugs and transitioning new drugs into the clinic.

TDM in Saxonia (Germany).

Conca et al. complain insufficient TD use in Italy. This survey suggests that the situation and possibly also the reasons are similar in the German Federal Republic.