Psychiatric Drug Development Research Articles

Serendipity in psychotropic drugs: Unearthing the origins

This is a dive into the history of several groundbreaking psychiatric drugs and their discoveries. The article begins by exploring the curious origin of the word “serendipity” following Horace Walpole’s encounter with a fairytale. This captivating emergence of “serendipity” is followed by an account of lithium discovered in 1817. About a century and a half later, lithium would receive FDA approval, becoming a cornerstone in the treatment of mania.The narrative meanders to other drugs that have a similar thread of serendipity woven into their beginnings— chlordiazepoxide, meprobamate, chlorpromazine, finally halting at iproniazid, an anti-tubercular agent that unexpectedly revealed its mood-enhancing potential and paved the way for the development of monoamine oxidase inhibitors as antidepressants.The authors navigate through the intricacies of chance and discovery that have influenced the trajectory of psychiatric drug development, leading to unexpected breakthroughs that have forever left their mark on the undeniably vast landscape that is mental health.

Drug targeting in psychiatric disorders - how to overcome the loss in translation?

In spite of major efforts and investment in development of psychiatric drugs, many clinical trials have failed in recent decades, and clinicians still prescribe drugs that were discovered many years ago. Although multiple reasons have been discussed for the drug development deadlock, we focus here on one of the major possible biological reasons: differences between the characteristics of drug targets in preclinical models and the corresponding targets in patients. Importantly, based on technological advances in single-cell analysis, we propose here a framework for the use of available and newly emerging knowledge from single-cell and spatial omics studies to evaluate and potentially improve the translational predictivity of preclinical models before commencing preclinical and, in particular, clinical studies. We believe that these recommendations will improve preclinical models and the ability to assess drugs in clinical trials, reducing failure rates in expensive late-stage trials and ultimately benefitting psychiatric drug discovery and development.

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms.

The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring inventive mechanisms of action. This paper presents an overview of the ongoing advancements in antipsychotic and antidepressant drug development. Historically, antipsychotics predominantly targeted dopamine receptors, but there is now an escalating interest in drugs that act on alternative receptors, exemplified by the TAAR1 receptor. One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric modulation, respectively. This paper underscores the transformative potential of these novel drug candidates in psychiatric treatment and their ability to address cases that were previously treatment-resistant. By focusing on nonmonoamine receptors and introducing innovative mechanisms, these drugs offer a promising prospect of improved outcomes for individuals suffering from schizophrenia and MDD. Thus, sustained attention and dedication to the development of such drugs are essential to augmenting the therapeutic options available for psychiatric patients.

Advancements in Drug Repurposing: Examples in Psychiatric Medications.

Because there are a limited number of animal models for psychiatric diseases that can be extrapolated to humans, drug repurposing has been actively pursued. This study was aimed at uncovering recent trends in drug repurposing approaches and new technologies that can predict efficacy on humans based on animal models used in psychiatric drug development. Psychiatric drugs that were approved by the FDA between 2002 and 2022 were listed, and the method of how the drug repurposing has been applied was analyzed. Drug repurposing has been increasingly applied to recently approved psychiatric drugs. The development concepts of psychiatric drugs that have been developed through drug repurposing over the past 20 years were found to be divided into six categories: new application exploration, reduction of side effects, improvement of symptom control, improvement of medication compliance, enhancement of drug efficacy, and reduction of drug-drug interactions. All repurposed drugs approved before 2016 used either prodrugs or active metabolites, while all drugs approved in 2021 and beyond used fixed-dose combinations with sophisticated ideas. SmartCube®, which uses artificial intelligence to predict human drug efficacy from animal phenotypes, was developed and produced novel drugs that show clinical efficacy. Well-designed drug repurposing approaches and new technologies for predicting human drug efficacy based off of animal models would contribute to novel psychiatric drug development.

Biomarkers in Psychiatric Drug Development: From Precision Medicine to Novel Therapeutics.

Burden of psychiatric disorders is compounded by their wide prevalence as well as the limited efficacy of currently available treatments and the current approaches for prescribing these treatments. The selection of treatments continues to be subjective and often results in a trial-and-error approach. Emerging research suggests that biological markers (or biomarkers) can be used to develop precision medicine approaches for psychiatric disorders. Furthermore, the biomarkers also promise to elucidate the underlying pathophysiological mechanisms which in turn can be used to develop novel therapeutic treatments. In this chapter we have focused on mood disorders and reviewed studies on electroencephalography (EEG), magnetic resonance imaging (MRI), and blood-based biomarkers that can guide selection of one treatment versus another (treatment-selection biomarker) as well as biomarkers that can guide the development of novel therapeutics. These studies suggest that the use of objective physiological data is poised to alter the landscape of psychiatric diagnosis and treatment. However, practical and economic barriers remain as major hurdles. The key to finding such translational diagnostic and therapeutic biomarkers is a better understanding of the underlying pathophysiology, and despite the tremendous advances in neuroscience, it is clear there remains much left to be elucidated.

Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms.

The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment. Narrative commentary drawing on personal positions in both NIH and Industry devoted to translation of CNS compounds from bench to bedside coupled with specific examples of efforts to improve the selection of compounds to take into large clinical trials. Strategies for increasing R&D productivity in the field of CNS drugs articulated over a decade ago have been implemented over the same period with pre-competitive consortia involved in developing the tools needed to show that before being taken into large trials adequate evidence of postulated brain effects are required. In parallel, the field and the FDA have focused much more on the search for domain specific treatments rather than those depending on traditional measures of efficacy in DSM disorders. NIMH programs such as RDoC and the "Fast-Fail" initiative are provided as efforts which influence and involve partnerships with industry. The evolution of the field over the last decade is such that there is a shared focus across sources of funding in the public sector, especially NIH brain institutes, on the tools needed to de-risk psychiatric drug development to the degree needed to encourage private sector investment in the clinical trials needed to advance potential new treatments for areas of greatest need. Expansion of funding for translational tool development will have the highest impact on delivering novel treatments.

Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development.

Six lessons can be learned from the pivotal registration trials for sublingual dexmedetomidine (SLD) for the treatment of agitation in individuals with bipolar disorder or schizophrenia: (1) Knowing the function of a well-defined circuit in the brain, such as the locus coeruleus (LC), facilitates the development of central nervous system drugs. (2) Agitation can be conceptualized both clinically and physiologically. From both perspectives, agitation can present and escalate along a spectrum from mild, characterized as mainly hyperaroused (possibly only a subjective experience with no observable manifestations in its mildest form), to moderate to severe. In the severe state, the patient poses a potential danger to self and others. The level of agitation a patient is experiencing can determine the most appropriate treatment. Behavioral techniques may be sufficient for the mild state. As agitation progresses beyond mild severity, medication intervention becomes needed. SLD can be effective when agitation is moderate or even more severe. At this stage, patients can recognize and be distressed by their symptoms and participate in treatment. When agitation has escalated to such a severe state that patients can no longer participate in treatment, then intramuscular or intravenous medication may be needed. In quite severe cases, physical restraint as well as medication may be required. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC or PEC), a subscale of the PANSS, is a helpful instrument to assess where an individual is along the agitation spectrum. The PEC has been used in studies of pharmacological treatments for agitation, and it is accepted by the US Food and Drug Administration as the primary rating instrument in pivotal efficacy studies of treatments for agitation. (3) Where the patient is on the agitation spectrum is a function of the activity of the LC, which can be one factor in determining the SLD dose that will optimize the patient's clinical outcome. Clinical outcome is optimized when complete resolution of agitation is rapidly achieved, and adverse effects either do not occur or are not clinically meaningful. The adverse effects of greatest interest with SLD are decreases in resting systolic and diastolic blood pressures, reductions in these blood pressures under orthostatic stress, and lower resting heart rate. (4) To ensure safety, the subjects in 2 healthy volunteer studies were not administered doses equivalent to those used to treat agitated patients. The highest dose which a healthy volunteer tolerated in those studies was 40µg. Agitated patients were treated with 120 and 180µg doses. Thus the difference in doses was 3- to 4.5-fold. Agitated patients could also receive 2 additional half doses with an interval of 2 hours between the first and second administrations. For context, there are other examples of situations in which the dose of a drug that is well tolerated by healthy volunteers is lower than the dose that is well tolerated by patients. For example, it has long been accepted that patients with an acute relapse of schizophrenia can tolerate and need higher doses of D2 antagonists for efficacy than healthy volunteers can tolerate who will generally experience substantial sedation if given what is a clinically effective dose in such patients. (5) Agitation is a state phenomenon that may not recur when it is effectively treated, so that the treatment effect can persist for 24 hours despite the plasma half-life of the drug being 2 to 3 hours. (6) Given the established function of the LC, the fact that the dose response and the time curve of the effect are virtually identical in agitated individuals with bipolar disorder or schizophrenia supports the conclusion that the drug is not treating the syndromic diagnoses of bipolar disorder and schizophrenia but rather the state of being agitated because of overactivity of the LC. These 6 lessons are consistent with the discussions in numerous earlier columns in this series and are critical for both the practice of clinical psychopharmacology and psychiatric drug development.

The doors of precision: Reenergizing psychiatric drug development with psychedelics and open access computational tools.

Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets.

Topologically Guided Prioritization of Candidate Gene Transcripts Coexpressed with the 5-HT1A Receptor by Combining In Vivo PET and Allen Human Brain Atlas Data.

The serotonin-1A receptor (5-HT1AR) represents a viable target in the treatment of disorders of the brain. However, development of psychiatric drugs continues to be hindered by the relative inaccessibility of brain tissue. Although the efficacy of drugs selective for the 5-HT1AR has not been proven, research continues to focus on drugs that influence this receptor subtype. To further knowledge on this topic, we investigated the topological coexpression patterns of the 5-HT1AR. We calculated Spearman’s rho for the correlation of positron emission tomography-binding potentials (BPND) of the 5-HT1AR assessed in 30 healthy subjects using the tracer [carbonyl-11C]WAY-100635 and predicted whole-brain mRNA expression of 18 686 genes. After applying a threshold of r > 0.3 in a leave-one-out cross-validation of the prediction of mRNA expression, genes with ρ ≥ 0.7 were considered to be relevant. In cortical regions, 199 genes showed high correlation with the BPND of the 5-HT1AR, in subcortical regions 194 genes. Using our approach, we could consolidate the role of BDNF and implicate new genes (AnxA8, NeuroD2) in serotonergic functioning. Despite its explorative nature, the analysis can be seen as a gene prioritization approach to reduce the number of genes potentially connected to 5-HT1AR functioning and guide future in vitro studies.

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in thebrain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

Potentially repurposable drugs for schizophrenia identified from its interactome

We previously presented the protein-protein interaction network of schizophrenia associated genes, and from it, the drug-protein interactome which showed the drugs that target any of the proteins in the interactome. Here, we studied these drugs further to identify whether any of them may potentially be repurposable for schizophrenia. In schizophrenia, gene expression has been described as a measurable aspect of the disease reflecting the action of risk genes. We studied each of the drugs from the interactome using the BaseSpace Correlation Engine, and shortlisted those that had a negative correlation with differential gene expression of schizophrenia. This analysis resulted in 12 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for schizophrenia (disorder versus normal). Some of these drugs were already being tested for their clinical activity in schizophrenia and other neuropsychiatric disorders. Several proteins in the protein interactome of the targets of several of these drugs were associated with various neuropsychiatric disorders. The network of genes with opposite drug-induced versus schizophrenia-associated expression profiles were significantly enriched in pathways relevant to schizophrenia etiology and GWAS genes associated with traits or diseases that had a pathophysiological overlap with schizophrenia. Drugs that targeted the same genes as the shortlisted drugs, have also demonstrated clinical activity in schizophrenia and other related disorders. This integrated computational analysis will help translate insights from the schizophrenia drug-protein interactome to clinical research - an important step, especially in the field of psychiatric drug development which faces a high failure rate.

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

Drug repurposing is potentially cost-effective, low risk, and necessary in psychiatric drug development. The availability of large, routine data sets provides the opportunity to evaluate the potential for currently used medication to benefit people with serious mental illness (SMI). To determine whether hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs), L-type calcium channel (LTCC) antagonists, and biguanides are associated with reduced psychiatric hospitalization and self-harm in individuals with SMI. These within-individual cohort studies of patients with SMI compared rates of psychiatric hospitalization and self-harm during periods of exposure and nonexposure to the study drugs, with adjusting for a number of time-varying covariates. Participants included 142 691 individuals from the entire population of Sweden with a diagnosis of bipolar disorder (BPD), schizophrenia, or nonaffective psychosis (NAP) who were 15 years or older and who were treated with psychiatric medication from October 1, 2005, through December 31, 2016. Data were analyzed from April 1 through August 31, 2018. Treatment with HMG-CoA RIs, LTCC antagonists, or biguanides. Psychiatric hospitalizations and self-harm admissions. Among the 142 691 eligible participants, the HMG-CoA RI exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR], 0.86; 95% CI, 0.83-0.89; P < .001), schizophrenia (aHR, 0.75; 95% CI, 0.71-0.79; P < .001), and NAP (aHR, 0.80; 95% CI, 0.75-0.85; P < .001) and reduced self-harm rates in BPD (aHR, 0.76; 95% CI, 0.66-0.86; P < .001) and schizophrenia (aHR, 0.58; 95% CI, 0.45-0.74; P < .001). Exposure to LTCC antagonists was associated with reduced rates of psychiatric hospitalization and self-harm in subgroups with BPD (aHRs, 0.92 [95% CI, 0.88-0.96; P < .001] and 0.81 [95% CI, 0.68-0.95; P = .01], respectively), schizophrenia (aHRs, 0.80 [95% CI, 0.74-0.85; P < .001] and 0.30 [95% CI, 0.18-0.48; P < .001], respectively), and NAP (aHRs, 0.89 [95% CI, 0.83-0.96; P = .002] and 0.56 [95% CI, 0.42-0.74; P < .001], respectively). During biguanide exposure, psychiatric hospitalization rates were reduced in subgroups with BPD (aHR, 0.80; 95% CI, 0.77-0.84; P < .001), schizophrenia (aHR, 0.73; 95% CI, 0.69-0.77; P < .001), and NAP (aHR, 0.85; 95% CI, 0.79-0.92; P < .001), and self-harm was reduced in BPD (aHR, 0.73; 95% CI, 0.62-0.84; P < .001) and schizophrenia (aHR, 0.64; 95% CI, 0.48-0.85; P < .001). This study provides additional evidence that exposure to HMG-CoA RIs, LTCC antagonists, and biguanides might lead to improved outcomes for individuals with SMI. Given the well-known adverse event profiles of these agents, they should be further investigated as repurposed agents for psychiatric symptoms.

Comparative psychopharmacology of autism and psychotic-affective disorders suggests new targets for treatment.

The first treatments showing effectiveness for some psychiatric disorders, such as lithium for bipolar disorder and chlorpromazine for schizophrenia, were discovered by accident. Currently, psychiatric drug design is seen as a scientific enterprise, limited though it remains by the complexity of brain development and function. Relatively few novel and effective drugs have, however, been developed for many years. The purpose of this article is to demonstrate how evolutionary biology can provide a useful framework for psychiatric drug development. The framework is based on a diametrical nature of autism, compared with psychotic-affective disorders (mainly schizophrenia, bipolar disorder and depression). This paradigm follows from two inferences: (i) risks and phenotypes of human psychiatric disorders derive from phenotypes that have evolved along the human lineage and (ii) biological variation is bidirectional (e.g. higher vs lower, faster vs slower, etc.), such that dysregulation of psychological traits varies in two opposite ways. In this context, the author review the evidence salient to the hypothesis that autism and psychotic-affective disorders represent diametrical disorders in terms of current, proposed and potential psychopharmacological treatments. Studies of brain-derived neurotrophic factor, the PI3K pathway, the NMDA receptor, kynurenic acid metabolism, agmatine metabolism, levels of the endocannabinoid anandamide, antidepressants, anticonvulsants, antipsychotics, and other treatments, demonstrate evidence of diametric effects in autism spectrum disorders and phenotypes compared with psychotic-affective disorders and phenotypes. These findings yield insights into treatment mechanisms and the development of new pharmacological therapies, as well as providing an explanation for the longstanding puzzle of antagonism between epilepsy and psychosis.Lay Summary: Consideration of autism and schizophrenia as caused by opposite alterations to brain development and function leads to novel suggestions for pharmacological treatments.

Psychiatric Genomics Consortium: From Gwas Findings To Drug Targets

Genome-wide association studies (GWAS) in psychiatry that reach sufficient sample size for power to detect common variant effect sizes have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next few years. This should lead to hundreds of new findings for common genetic variants across the nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. Using the example of schizophrenia and other psychiatric disorders, I will discuss what evidence there is that existing drugs are indicated by GWAS results and how GWAS can be used to identify novel drug targets and potential drug repositioning opportunities.

The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development

The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development

Nociceptin/orphanin FQ receptor agonists increase aggressiveness in the mouse resident-intruder test

Aggressive behaviors can be considered symptoms of bipolar disorder, schizophrenia, post-traumatic stress, intermittent explosive, and personality disorders. Nociceptin/orphanin FQ (N/OFQ) is a peptide acting as endogenous ligand of the NOP receptor. Preclinical and clinical findings suggest the NOP receptor as an innovative target for the treatment of psychopathologies, such as anxiety, depression, and drug abuse. This study investigated the effects of NOP ligands and the behavioral phenotype of mice lacking the NOP receptor in an animal model of aggressiveness, the resident-intruder test. Mood stabilizers, such as valproate, lithium, and carbamazepine reduced aggressive behaviors of resident mice, while diazepam was inactive. In contrast, para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, increased aggressiveness in mice. Similar to PCPA, the treatment with the NOP agonists Ro 65-6570 and AT-090 also increased aggressive behaviors. The systemic administration of the NOP antagonist SB-612111 did not modify the behavior of resident mice, but it prevented the aggressive behavior of Ro 65-6570. NOP receptor knockout mice did not display any behavioral difference compared to wild-type animals in the resident-intruder test. None of the treatments affected non-agonistic behaviors and spontaneous locomotion. In conclusion, NOP receptor agonists increased aggressiveness, while the pharmacological and genetic blockade of NOP receptor signaling did not modify agonistic behaviors. Ultimately, the aggressive profile of action of NOP agonists should be taken into account in the development of innovative psychiatric drugs targeting the NOP receptor.

Repurposing HMG-CoA Reductase Inhibitors, L-Type Calcium Channel Antagonists and Biguanides in Serious Mental Illness: A Within-Individual Cohort Study in National Swedish Data

Background: Drug repurposing is potentially cost-effective, low-risk and necessary in psychiatric drug development. The availability of large routine datasets provides the opportunity to evaluate the potential for currently used medication to benefit people with severe mental illness (SMI). Methods: We performed several within-individual cohort studies of patients with SMI (bipolar disorder (BPD), schizophrenia or non-affective psychosis (NAP)), in the Swedish population (N=142,691). We compared psychiatric hospitalization and self-harm rates during periods patients were exposed and unexposed to HMG-CoA reductase inhibitors, L-type calcium channel (LTCC) antagonists or biguanides. We adjusted for a number of time-varying covariates. Findings: HMG-CoA reductase inhibitor exposure periods were associated with reduced rates of psychiatric hospitalization in BPD (adjusted hazard ratio [aHR] 0·86, 95% confidence interval [CI] 0·83-0·89), schizophrenia (aHR 0·75, 95% CI 0·71-0·79) and NAP (aHR 0·80, 95%CI 0·75-0·85) and reduced self-harm rates in BPD and schizophrenia (aHR 0·76, 95%CI 0·66-0·86 and aHR 0·58, 95%CI 0·45-0·74). LTCC antagonists were associated with reduced hospitalization and self-harm in all subgroups (aHR 0·92, 95%CI 0·88-0·96 and aHR 0·81, 95%CI 0·68-0·95 in BPD, aHR 0·80, 95%CI 0·74-0·85 and aHR 0·30, 95%CI 0·18-0·48 in schizophrenia, and aHR 0·89, 95%CI 0·83-0·96 and aHR 0·56, 95%CI 0·42-0·74 in NAP respectively). During biguanide exposure psychiatric hospitalization was reduced in BPD (aHR 0·80, 95%CI 0·77-0·84), schizophrenia (aHR 0·73, 95%CI 0·69-0·77) and NAP (aHR 0·85, 95%CI 0·79-0·92) and self-harm was reduced in BPD (aHR 0·73, 95%CI 0·62-0·84) and schizophrenia (aHR 0·64, 95%CI 0·48-0·85). Interpretation We have provided additional evidence that HMG-CoA reductase inhibitor, LTCC antagonist and biguanide exposure might lead to improved outcomes for people with SMI. Given their well-known adverse event profiles, they should be further investigated as repurposed agents for psychiatric symptoms. Funding: Swedish Research Council and UCLH NIHR Biomedical Research Centre. Conflict of Interests: JFH, AL, GL, DPJO and CD report no conflict of interest. ICKW has received research funding from Bristol-Myers Squibb, Pfizer and Janssen outside the submitted work. JFH, GL and DPJO are supported by the NIHR UCLH Biomedical Research Centre. CD is supported by grant 523-2010-1052 from the Swedish Research Council. Ethical Approval Statement: Ethical approval for the study was obtained via the Regional Ethical Review Board in Stockholm.

Mood Stabilizers: Implementing Combined Treatment Regimens in Bipolar Disorder

Patients with bipolar disorders spend a greater proportion of their illness in a depressed or mixed state rather than experiencing either mania or hypomania. Over the past 20 years, most major pharmaceutical companies have either reduced or abandoned the research and development of novel psychiatric drugs, exiting the development of new, safe, efficacious, and tolerable treatment regimens for bipolar disorder. Therefore, optimizing the current treatments available is critical. We review studies of the last 15 years that provide guidance relevant to managing the maintenance phase of bipolar disorders. Based on these data, we provide recommendations for effective treatment planning and implementation, principally for the maintenance phase care of persons with bipolar disorder. We also discuss strategies for implementing medication regimens, differentiating strategies for maintenance phase treatment from those of acute phase treatment. Assessing key symptoms that are sensitive to change is critical for longitudinal assessments and treatment planning for patients with bipolar disorders. In most studies, only a subset of rating scale items differentiate patients with good responses from those without. Identified symptoms include racing thoughts, less need for sleep, hyperactivity, increased activity, and increased energy. We developed a procedure for using Multistate Outcome Analysis of Treatment (MOAT) in bipolar disorders. MOAT integrates efficacy and tolerability data during studies to provide information about the quantity and quality of time spent in distinct mood states. The protocol developed will be useful for assessing treatment strategies in bipolar disorder. This review contains 4 figures, 7 tables and 32 references Key words: bipolar, depression, lithium, mania, mixed, mood stabilizer, survival analysis, symptom domains, valproate

CNS Drug Development: Lessons Learned Part 3: Psychiatric and Central Nervous System Drugs Developed Over the Last Decade-Implications for the Field.

This column reviews the divergence between the approach to drug development in infectious disease, oncology, and immunology versus psychiatry. Between 2009 and 2016, 254 new drugs were approved. Of those, only 9 were for a psychiatric indication; another 5 were labeled to treat central nervous system disorders that are not considered psychiatric per se but are frequently found in individuals with psychiatric illnesses (eg, substantial weight gain). There were 2 additional new products for psychiatric indications that involved either a combination product (Contrave) or a prodrug for the production of aripiprazole (Aristada). The column discusses the reasons behind these different rates of development of psychiatric and/or central nervous system drugs compared with drugs in the areas of infectious disease, oncology, and immunology, and it predicts that this situation will change over the next century as we develop an improved understanding of the neurobiology underlying specific psychiatric illnesses.

Validation of Brain Angiotensin System Blockade as a Novel Drug Target in Pharmacological Treatment of Neuropsychiatric Disorders.

Retreat in psychiatric drug development results in innovative medication decline that might be at least partially overcome by adjunct therapy. New evidence from clinical studies has shown a possible role for brain Renin-Angiotensin System (RAS) in both affective and psychotic disorders. Simultaneously, rapidly accumulating data from basic studies indicate effectiveness of central RAS blockade in much broader range of neuropsychiatric disease. Recent findings implicate brain RAS, especially Angiotensin II (Ang II), in neural pathophysiology of mental disorders through neuroendocrine modulation and effects on neurotransmitter release, mostly noradrenaline, acetylcholine and dopamine. The potential effects of angiotensin-converting-enzyme (ACE) inhibition and angiotensin type 1 receptor (AT1R) blockade on treatment of mental disorders are a matter of considerable interest. This review describes involvement of brain RAS in pathophysiology of neuropsychiatric disorders and an intriguing possibilities of improvement in pharmacological treatment outcome, where using angiotensin-converting-enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB), goes beyond blood pressure control.