Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology.

Background: There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.

Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress.

Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure.

Toward personalized medicine in the neuropsychiatric field.

There are great expectations for the personalized medicine approach to address the therapeutic needs of patients in the twenty-first century. Advances in human genome science and molecular innovations in neuroscience have encouraged the pharmaceutical industry to focus beyond broad spectrum population therapeutics--the driving force behind the "blockbuster" product concept--to personalized medicine. For central nervous system (CNS) therapeutics, repeated failures in converting scientific discoveries to clinical trial successes and regulatory approvals have precipitated a drug pipeline crisis and eroded confidence in the industry.

Modeling treatment-resistant depression.

Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high comorbidity with other psychiatric and somatic disorders. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission.

Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters' perspective.

Innovation is essential for the identification of novel pharmacological therapies to meet the treatment needs of patients with psychiatric disorders. However, over the last 20 yr, in spite of major investments targets falling outside the classical aminergic mechanisms have shown diminished returns. The disappointments are traced to failures in the target identification and target validation effort, as reflected by the poor ability of current bioassays and animal models to predict efficacy and side-effects.

Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat.

Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats.

The effectiveness of multi-target agents in schizophrenia and mood disorders: Relevance of receptor signature to clinical action.

Schizophrenia, bipolar disorder and unipolar depression are multi-dimensional and severely disabling psychiatric diseases with a strong need for improved pharmacotherapies with better adherence, long-term outcome and patient functionality. Progress has been achieved with the emergence of tailored multi-target agents (MTAs), such as second-generation antipsychotics for schizophrenia, with expanding clinical utility in bipolar disorder and depression. Better understanding of how these MTAs exert their beneficial and undesirable clinical effects in terms of receptor interaction remains an area for further elucidation, which may provide insight towards a new generation of individualized, and optimized therapies.

Repeated effects of asenapine on adrenergic and cholinergic muscarinic receptors.

Adrenergic (alpha1 and alpha2) and cholinergic muscarinic (M1-M5) receptor binding in rat forebrain was quantified after 4 wk of twice-daily subcutaneous administration of asenapine or vehicle. Asenapine (0.03, 0.

Asenapine effects in animal models of psychosis and cognitive function.

Rationale: Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.

Objectives: The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.

Materials And Methods: Amphetamine-stimulated locomotor activity (Amp-LMA; 1.

Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain.

Asenapine, a new pyschopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has a unique human receptor binding signature with strong affinity for dopaminergic, alpha-adrenergic, and, in particular, serotonergic receptors raising the possibility of interactions with glutamatergic receptors. Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA) receptors and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were quantified after repeated administration of multiple doses of asenapine (0.03, 0.

Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy.

An in vivo binding assay is characterized for [(3)H]M100907 binding to rat brain, as a measure of 5-HT(2A) receptor occupancy. Dose-response analyses were performed for various 5-HT(2A) antagonist reference agents, providing receptor occupancy ED(50) values in conjunction with plasma and brain concentration levels. Ketanserin and M100907 yielded dose-dependent increases in 5-HT(2A) receptor occupancy with ED(50)s of 0.

Asenapine increases dopamine, norepinephrine, and acetylcholine efflux in the rat medial prefrontal cortex and hippocampus.

Atypical antipsychotic drugs, which are more potent direct acting antagonists of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors, preferentially enhance DA and acetylcholine (ACh) efflux in the rat medial prefrontal cortex (mPFC) and hippocampus (HIP), compared with the nucleus accumbens (NAc). These effects may contribute to their ability, albeit limited, to improve cognitive function and negative symptoms in patients with schizophrenia. Asenapine (ASE), a new multireceptor antagonist currently in development for the treatment of schizophrenia and bipolar disorder, has complex serotonergic properties based upon relatively high affinity for multiple serotonin (5-HT) receptors, particularly 5-HT(2A) and 5-HT(2C) receptors.

Differential regional and dose-related effects of asenapine on dopamine receptor subtypes.

Rationale: The novel psychopharmacologic agent, asenapine, has high affinity for a range of receptors including the dopaminergic receptors.

Objective: We examined the long-term effects of multiple doses of asenapine on dopamine receptor subtypes: D(1)-like (D(1) and D(5)), D(2), D(3), and D(4).

Methods: Rats were given asenapine 0.

Multi- and single-target agents for major psychiatric diseases: therapeutic opportunities and challenges.

There is growing pressure to find more effective therapies for major psychiatric disorders, such as schizophrenia and depressive disorder. The repeated disappointments that have been experienced with highly selective, single-target agents have prompted questions about their relative merits. In contrast, a multi-target agent (MTA) approach, discovered either by serendipity or by judicious design, might offer a more rational way to address the complex clinical demands of patients and their co-morbidities.

Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.

Rationale: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.

Materials And Methods: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.

Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987.

Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia.

The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile.

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets.

Reboxetine: functional inhibition of monoamine transporters and nicotinic acetylcholine receptors.

The present study determined whether repeated administration of the antidepressant and selective norepinephrine (NE) uptake inhibitor reboxetine resulted in an adaptive modification of the function of the NE transporters (NETs), serotonin (5-HT) transporters, or dopamine (DA) transporters. Because antidepressants may be effective tobacco smoking cessation agents and because antidepressants have recently been shown to interact with nicotinic acetylcholine receptors (nAChRs), the interaction of reboxetine with nAChRs was also evaluated. Repeated administration of reboxetine (10 mg/kg i.