Drug Development In Psychiatry Research Articles

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials.Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710

Application of GWAS summary data and drug-induced gene expression profiles of neural progenitor cells in psychiatric drug prioritization analysis.

Common psychiatric disorders constitute one of the most substantial healthcare burdens worldwide. However, drug development in psychiatry remains hampered partiallydue to the lack of approaches to estimating drugs that can simultaneously modulate the expression of a nontrivial fraction of disease susceptibility genes. We proposed a new drug prioritization strategy under the framework of our previously proposed phenotype-associated tissues estimation approach (DESE) by investigating the drugs' selective perturbation effect on disease susceptibility genes. Based on the genome-wide association study summary data and drug-induced gene expression profiles of neural progenitor cells, we applied this strategy to prioritize candidate drugs for schizophrenia, depression and bipolar I disorder and identified several known therapeutic drugs among the top-ranked drug candidates. Also, our results revealed that the disease susceptibility genes involved in the selective gene perturbation analysis were enriched with many biologically sensible function terms and interacted with known therapeutic drugs. Our results suggested that selective gene perturbation analysis could be a promising starting point to prioritize biologically sensible drug candidates under the "one drug, multiple targets" paradigm for the drug development of common psychiatric disorders.

Will digital technology address the challenges of drug development in psychiatry?

Will digital technology address the challenges of drug development in psychiatry?

Drug Development in Psychiatry: The Long and Winding Road from Chance Discovery to Rational Development.

Based extensively on tables and figures, this chapter reviews drug development in psychiatry with an emphasis on antidepressants from the 1950s to the present and then looks forward to the future. It begins with the chance discovery drugs and then moves to through their rational refinement using structure activity relationships to narrow the pharmacological actions of the drugs to those mediating their antidepressant effects and eliminating the effects on targets that mediate adverse effects. This approach yielded newer antidepressants which compared to older antidepressants are safer and better tolerated but nevertheless do still not treat the approximately 40% of patients with major depression (MD) which is unresponsive to biogenic amine mechanisms of action. This form of MD is commonly referred to as treatment resistant depression. Esketamine is an antidepressant which has a novel mechanism of action: blockade of the glutamate NMDA receptor. These studies coupled with earlier studies with other NMDA drugs suggest approximately 60% of patient with TRD are rapidly and robustly responsive to this mechanism of action. Thus, there appears to be three forms of MD based on pharmacological responsiveness: (a) 60% responsive to biogenic amine mechanisms of action, (b) 24% (i.e., 40×60%) responsive to NMDA but not to biogenic amine mechanisms of action, and (c) 16% (i.e., 40-24%) not responsive to either of these mechanisms of action. Scientific investigation of these three groups may yield important information about the pathophysiology and/or pathoetiology of these different forms of MD. This information coupled with studies into the neurobiology (e.g., imaging studies, connectomes to name a few approaches being used) and genetics of MD should provide the fundamental knowledge which will permit a rational search for and discovery of newer antidepressant drugs and other somatic and psychotherapeutic approaches to the treatment of patients with different forms of MD based on pathophysiology and pathoetiology. Examples are given of how such discovery and development have occurred in other areas of medicine and even in central nervous system (CNS) space including six novel mechanisms of action CNS drugs which have been successfully developed and marketed over the last 25years.

PET technology for drug development in psychiatry.

Positron emission tomography (PET) is a non‐invasive imaging method to measure the molecule in vivo. PET imaging can evaluate the central nervous system drugs as target engagement in the human brain. For antipsychotic drugs, adequate dopamine D2 receptor occupancy (“therapeutic window”) is reported to be from 65%‐70% to 80% to achieve the antipsychotic effect without extrapyramidal symptoms. For antidepressants, the clinical threshold of serotonin transporter (5‐HTT) occupancy is reported to be 70%‐80% although the relation between the side effect and 5‐HTT occupancy has not yet been established. Evaluation of norepinephrine transporter (NET) occupancy for antidepressant is ongoing as adequate PET radioligands for NET were developed recently. Measurement of the target occupancy has been a key element to evaluate the in vivo target engagement of the drugs. In order to evaluate new drug targets for disease conditions such as negative symptoms/cognitive impairment of schizophrenia and treatment‐resistant depression, new PET radioligands need to be developed concurrently with the drug development.

Future paths in psychopharmacology

Drug development in psychiatry is gradually moving from serendipity to personalized medicine. Some promising paths will be reviewed in this issue.

M90 - FUNCTIONAL CHARACTERIZATION OF PSYCHIATRIC DISEASE-ASSOCIATED CACNA1C VARIANTS THROUGH GENETIC, MOLECULAR AND CELLULAR APPROACHES

Background Despite recent advancements in human genomics and identifying hundreds of risk loci for psychiatric disorders, drug development in psychiatry remains a challenge. While Genome-Wide Association Studies (GWAS) provide us with a great starting point by highlighting risk regions of the genome, translating disease-associated DNA variants to physiological function has been quite sluggish. This is mostly due to polygenic and multifactorial nature of psychiatric diseases which in turn have made development of relevant cellular and in vivo models particularly difficult. One recent GWAS identified over hundred genes that are strongly associated with schizophrenia but contribution of each gene to the disease seems to be small. Each risk gene is identified with tens of SNPs, most of which are common SNPs residing in the intronic regions of DNA. Methods Therefore, establishing cellular models to understand the directionality (loss or gain) and functional defect caused by each risk SNP within each gene can be an enormous undertaking. On the other hand, rare exon variants found in the disease population can serve as a more reliable starting point to understand how the function of a risk gene is affected in the disease. Results Here we examined effects of rare variants reported for CACNA1C, a top schizophrenia GWAS hit, in cellular models. CACNA1C is also linked to bipolar disorder, ADHD, depression and autism where schizophrenia GWAS identified over 160 risk SNPs for this gene. We used linkage disequilibrium information to identify a small number of risk SNPs that have the highest chance of affecting the overall function of CACNA1C gene. We have combined these two approaches, built neuronal functional assays and identified several important disease related phenotypes. Discussion These studies show a proof of concept in the context of the CACNA1C gene but this approach can be used as a platform to characterize other GWAS hits several other disease areas.

Drug Development in Psychiatry: The Long and Winding Road from Chance Discovery to Rational Development.

Based extensively on tables and figures, this chapter reviews drug development in psychiatry with an emphasis on antidepressants from 1950s to the present and then looks forward to the future. It begins with the chance discovery drugs and then moves to through their rational refinement using structure activity relationships to narrow the pharmacological actions of the drugs to those mediating their antidepressant effects and eliminating the effects on targets that mediate adverse effects. This approach yielded newer antidepressants which compared to older antidepressants are safer and better tolerated but nevertheless do still not treat the approximately 40% of patients with major depression (MD) which is unresponsive to biogenic amine mechanisms of action. This form of MD is commonly referred to as treatment resistant depression. Esketamine is an investigational antidepressant which has a novel mechanism of action: blockade of the glutamate NMDA receptor. Positive trials reported this year for esketamine make it likely this drug will be approved next year in the USA. These studies coupled with earlier studies with other NMDA drugs suggest approximately 60% of patient with TRD are rapidly and robustly responsive to this mechanism of action. Thus, there appears to be three forms of MD based on pharmacological responsiveness: (a) 60% responsive to biogenic amine mechanisms of action, (b) 24% (i.e., 40×60%) responsive to NMDA but not to biogenic amine mechanisms of action, and (c) 16% (i.e., 40-24%) not responsive to either of these mechanisms of action. Scientific investigation of these three groups may yield important information about the pathophysiology and/or pathoetiology of these different forms of MD. This information coupled with studies into the neurobiology (e.g., imaging studies, connectomes to name a few approaches being used) and genetics of MD should provide the fundamental knowledge which will permit a rational search for and discovery of newer antidepressant drugs and other somatic and psychotherapeutic approaches to the treatment of patients with different forms of MD based on pathophysiology and pathoetiology. Examples are given of how such discovery and development has occurred in other areas of medicine and even in central nervous system (CNS) space including six novel mechanisms of action CNS drugs which have been successfully developed and marketed over the last 25 years.

Opportunities for New Drug Development in Psychiatry: A Glass Half-Full.

Opportunities for New Drug Development in Psychiatry: A Glass Half-Full.

Special issue on CNS experimental medicine

The past 5 years have seen unprecedented changes in the approach to developing new therapeutic drug treatments. Perhaps the most significant changes have taken place in the area of clinical development with a move away from determining efficacy exclusively in traditional phase II clinical trials in patients, to earlier development phases in which efficacy is inferred from experimental studies with healthy volunteers and/or surrogate patient groups. It is not difficult to identify the drivers for such change. In the last decade the cost of drug development has been subject to double-digit year-onyear inflation while the rate of productivity of new drugs remains stubbornly low at approximately 10 per year and falling (Munos, 2009). Moreover, with the development and opportunity costs of each new drug now in excess of 1 billion (DiMasi et al. 2003; Munos, 2009) and the revenues from highly profitable drugs dwindling due to patent expiry, it is little wonder that the outlook for the pharmaceutical industry is increasingly uncertain and the mood is sombre. Nowhere has this been more profoundly experienced than in psychiatry where two large Pharma companies, GlaxoSmithKline and AstraZeneca, recently announced the closure of their discovery research divisions (Miller, 2010). From a commercial business perspective the reasons for these withdrawals are very clear: the prospect of a significant return on capital invested in the discovery of drugs for psychiatric disorders is too low compared with other therapeutic areas to warrant further investment. Thus, despite significant advances in our understanding of brain chemistry, circuitry and function in the last 20 years, these developments have not been sufficient to enable rational development of drug therapies for psychiatric disorders. Part of the problem stems from the empirical observation that promising effects of novel compounds in animals do not reliably predict efficacious effects in patients (Pangalos et al., 2007). This lack of translation from animal models to clinical efficacy makes it difficult to generate human models of psychiatric disease that provide a stepping stone to the large, expensive phase III patient trials required for drug registration. Ironically, however, just as large Pharma companies are reconsidering their commitment to discovering and developing new treatments for psychiatric disorders new approaches to developing and validating human experimental medicine models of the disorders are finally emerging. In this special issue leading researchers review new advances in experimental medicine models and approaches in the areas of anxiety, depression, schizophrenia, cognitive disorders, drug addiction and sleep disorders. They also provide an evaluation of the latest advances in functional magnetic resonance imaging (fMRI), pharmacofMRI (pfMRI) and electroencephalography (EEG) as well emerging technologies such as magnetoencephalography (MEG). These articles articulate some of the latest theories, techniques and technologies that are now being brought to bear in this challenging area. They also highlight recent advances in areas where real progress has been made and the directions that hold significant promise for future drug development in psychiatry. Progress in the development of experimental medicine approaches is particularly apparent in the area of depression. Approximately 14% of the Western European population have a lifetime history of any mood disorder (Alonso et al., 2004). The extent of this problem is also reflected in the large worldwide sales of antidepressants (more than US$19.4 billion in 2007) (CNS Drug Discoveries: Depression, 2008). They are often less than perfect drugs with a significant side effect burden such as sleep disturbance or sexual dysfunction (Hansen et al., 2005). However, perhaps the greatest problem is that a significant proportion of patients are ‘treatment resistant’: their depression is not significantly relieved by two or more courses of treatment with different antidepressants (Howland et al., 2011). Consequently the need for new treatments is undeniable, but in this area the standard animal models of tail suspension, forced swimming and mild chronic stress lack the precision and sophistication required to model such a complex disorder as depression. The traditional theory of antidepressant drug action postulates that treatment with an antidepressant, e.g. a selective serotonin reuptake inhibitor (SSRI), results in downstream neuroadaptive changes which take some time to occur but eventually lead to an elevation in mood. More recently, Harmer et al. (2011a) have proposed that antidepressants

Mechanistic disease modeling as a useful tool for improving CNS drug research and development

AbstractDespite tremendous advances in the basic understanding of CNS diseases, successful clinical drug development in psychiatry and neurology has been limited, putting huge pressure on remaining CNS R&D programs in pharmaceutical companies. In this report, it is proposed that re‐engineering parts of the pharmaceutical Research and Development process by integrating complex modeling and simulation approaches, similar to the aerospace and micro‐electronics industry, has the potential to increase the clinical predictability of animal models and to reduce the attrition rate in clinical drug development. This report will present top‐down Mechanistic Disease Modeling approaches in relation to bottom‐up Systems Biology with specific emphasis on CNS drug R&D. Both combine basic research data with human clinical outcome, but in contrast to System Biology that generically models intracellular pathways and protein‐protein networks, Mechanistic Disease Modeling models the emergent properties of neuronal cell firing activity in large interacting neuronal networks. Such an outcome is much closer to physiological and behavioral processes that drive actual clinical scales. Also illustrated here are some practical applications in the area of Alzheimer's disease and schizophrenia for CNS Research and Development, such as guiding multitarget drug discovery, evaluating both the harmful and beneficial off‐target human effects of candidate drugs, as well as exploring the effect of co‐medications and functional genotypes on the candidate drug efficacy and sensitivity analysis for responder identification. Drug Dev Res 72: 66–73, 2011. © 2010 Wiley‐Liss, Inc.

The silver lining of recent effectiveness trials

The silver lining of recent effectiveness trials

Drug Development in Psychiatry and Genomics: From E. Coli to Man

Drug Development in Psychiatry and Genomics: From E. Coli to Man

Drug Development in Psychiatry and the Human Genome Project: The Explosion in Knowledge and Potential Targets

Drug Development in Psychiatry and the Human Genome Project: The Explosion in Knowledge and Potential Targets

The Human Genome Project and Modern Drug Development in Psychiatry

The Human Genome Project and Modern Drug Development in Psychiatry

New drugs and the NHS: square pegs and a round hole

Drug development in psychiatry has famously been something of a stop–start process. First, there were no truly effective psychotherapeutic agents, then, in the 1950s, phenothiazines, monoamine oxidase inhibitors and tricyclics all appeared in the space of a few years. Then, virtually nothing: no substantial developments for 25 years. In the mid–1980s the first selective serotonin reuptake inhibitors appeared, heralding a new era in psychopharmacology. Then, in 1990 clozapine was re-introduced, to be followed by other atypical antipsychotics and by drugs such as donepezil and acamprosate for entirely new indications. In addition, research into antidepressant therapy has produced new agents with varied modes of action and new strategies for the treatment of refractory depression.