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. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.

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. METHODS: Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery. RESULTS: We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities. CONCLUSIONS: We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

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, 0.1, and 0.3 mg/kg) produced increases in [3H]prazosin binding to alpha1-adrenergic receptors in the medial prefrontal cortex (mPFC: 30%, 39%, 57%) and dorsolateral frontal cortex (DFC: 27%, 37%, 53%) and increased [3H]RX821002 binding to alpha2-adrenergic receptors in mPFC (36%, 43%, 50%) and DFC (41%, 44%, 52%). Despite showing no appreciable affinity for muscarinic receptors, asenapine produced regionally selective increases in binding of [3H]QNB to M1-M5 receptors in mPFC (26%, 31%, 43%), DFC (27%, 34%, 41%), and hippocampal CA1 (40%, 44%, 42%) and CA3 (25%, 52%, 48%) regions. These regionally selective effects of asenapine on adrenergic and cholinergic muscarinic receptor subtypes may contribute to its beneficial clinical effects in the treatment of schizophrenia and bipolar disorder.

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. Mismatch between disease biology and how psychiatric diseases are categorized has resulted in clinical trials of highly specific agents in heterogeneous patients, leading to variable treatment effects and failed studies. As drug hunters, one sees the opportunity to overhaul the pharmaceutical research and development (R&D) process. Improvements in both preclinical and clinical translational research need to be considered. Linking pharmacodynamic markers with disease biology should provide more predictive and innovative early clinical trials which in turn will increase the success rate of discovering new medicines. However, to exploit these exciting scientific discoveries, pharmaceutical companies need to question the conventional drug research and development model which is silo-driven, non-integrative across the confines of a company, non-disclosing across the pharmaceutical industry, and often independent from academia. This leads to huge redundancy in effort and lack of contextual learning in real time. Nevertheless, there are signs that drug discovery in the 21st century will see more intentional government, academic and industrial collaborations to overcome the above challenges that could eventually link mechanistic disease biology to segments of patients, affording them the benefits of rational and targeted therapy.

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, 0.1, or 0.3 mg/kg, subcutaneous, twice/day) or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP), and processed for in vitro receptor autoradiography. Four weeks of treatment with 0.03, 0.1, or 0.3 mg/kg of asenapine significantly (P < 0.01) decreased binding of [3H]MK-801 to NMDA/MK-801 modulatory sites in NAc (by 27%, 29%, and 26%, respectively), medial CPu (by 25%, 28%, and 24%), and lateral CPu (by 24%, 31%, and 26%). In contrast, the same doses of asenapine did not alter binding of [3H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [3H]AMPA binding to AMPA receptors was selectively and significantly (P < 0.001) elevated in hippocampal CA(1) (41%) and CA(3) (40%) regions but only at the highest dose tested. These results indicate that chronic treatment with asenapine has region-specific and dose-dependent effects on ionotropic Glu-receptor subtypes in rat forebrain, which might contribute to the unique psychopharmacologic properties of asenapine.

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. Rather than being mutually exclusive, a balanced portfolio of the two approaches may offer a beneficial and synergistic outcome toward identification of novel antipsychotic and antidepressant therapies. With improvements in biomarker technology, translational biology and a growing understanding of psychopathology, there is optimism that the new generation of MTAs will finally shed the stigma of 'dirty drugs' and progress to the concept of intentionally designed and tailored psychopharmacological agents.

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 0.03, 0.1, or 0.3 mg/kg (subcutaneously, twice daily) or vehicle for 4 weeks. Receptor binding was determined by autoradiography from brain sections collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP). RESULTS: Four weeks of asenapine at 0.3 mg/kg significantly (P < 0.05) increased D(1)-like binding in the mPFC (by 26%), NAc (59%), and CPu (55%). Asenapine (0.1 and 0.3 mg/kg) also increased D(2) binding in mPFC (43% and 55%, respectively). All doses of asenapine dose-dependently increased D(2) binding in HIP (by 32%, 45%, and 63%, respectively). In contrast, only 0.3 mg/kg of asenapine significantly (P < 0.05) increased D(2) binding in the NAc (32%) and CPu (41%). Repeated treatment with 0.1 and 0.3 mg/kg of asenapine increased D(4) binding in the NAc (36% and 71%), CPu (27% and 70%), and HIP (48% and 77%). However, asenapine, at the doses tested, did not significantly alter D(3) binding in the brain regions examined in this study. CONCLUSIONS: These results indicate that asenapine has region-specific and dose-dependent effects on dopamine receptor subtypes in rat forebrain, which may contribute to asenapine's unique psychopharmacological properties.

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. RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC. CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

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 0.316 mg/kg and 0.100 mg/kg, respectively. The atypical antipsychotics risperidone, olanzapine, and clozapine dose-dependently inhibited in vivo [(3)H]M100907 binding with ED(50) values of 0.051, 0.144, and 1.17 mg/kg, respectively. In contrast, the typical antipsychotic haloperidol exhibited only 20.1% receptor occupancy at 10 mg/kg despite producing dose-dependent increases in plasma and brain exposure levels. The novel psychopharmacologic agent asenapine dose-dependently occupied 5-HT(2A) receptors in rat brain with an ED(50) of 0.011 mg/kg, demonstrating higher 5-HT(2A) receptor potency compared with the other atypical antipsychotics tested. This enhanced potency was supported by a lower plasma exposure EC(50) of 0.477 ng/ml, compared with risperidone (1.57 ng/ml) and olanzapine (7.81 ng/ml) and was confirmed in time course studies. The validated [(3)H]M100907 rat in vivo binding assay allows for preclinical measurement of 5-HT(2A) receptor occupancy, providing essential data for understanding the pharmacological profile of novel antipsychotic agents. Additionally, the corresponding plasma and brain drug exposure data analyses provides a valuable data set for 5-HT(2A) reference agents by enabling direct comparison with any complementary studies performed in rats, thus providing a foundation for predictive pharmacokinetic/pharmacodynamic models and, importantly, allowing for translation to human receptor occupancy studies using [(11)C]M100907 positron emission tomography.

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. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.

KCNQ channel openers reverse depressive symptoms via an active resilience mechanism.

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.

Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors.

A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.

Application of cross-species PET imaging to assess neurotransmitter release in brain.

RATIONALE: This review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain. OBJECTIVES: Although PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) "Novel Methods leading to New Medications in Depression and Schizophrenia" (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, "Cross-species and neurochemical imaging (PET) methods for drug discovery", commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain. RESULTS: Sharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions. CONCLUSIONS: PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders.

BACKGROUND: Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1(neo-/-)) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. METHODS: Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1(neo-/-) mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery. RESULTS: Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1(neo-/-) mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MS(E) profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus. CONCLUSIONS: Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts.

Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance. METHODS: We take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state. RESULTS: Quantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation. CONCLUSIONS: System state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments.

Asenapine effects on cognitive and monoamine dysfunction elicited by subchronic phencyclidine administration.

PURPOSE: Repeated, intermittent administration of the psychotropic NMDA antagonist phencyclidine (PCP) to laboratory animals causes impairment in cognitive and executive functions, modeling important sequelae of schizophrenia; these effects are thought to be due to a dysregulation of neurotransmission within the prefrontal cortex. Atypical antipsychotic drugs have been reported to have measurable, if incomplete, effects on cognitive dysfunction in this model, and these effects may be due to their ability to normalize a subset of the physiological deficits occurring within the prefrontal cortex. Asenapine is an atypical antipsychotic approved in the US for the treatment of schizophrenia and for the treatment, as monotherapy or adjunctive therapy to lithium or valproate, of acute manic or mixed episodes associated bipolar I disorder. To understand its cognitive and neurochemical actions more fully, we explored the effects of short- and long-term dosing with asenapine on measures of cognitive and motor function in normal monkeys and in those previously exposed for 2 weeks to PCP; we further studied the impact of treatment with asenapine on dopamine and serotonin turnover in discrete brain regions from the same cohort. METHODS: Monkeys were trained to perform reversal learning and object retrieval procedures before twice daily administration of PCP (0.3 mg/kg intra-muscular) or saline for 14 days. Tests confirmed cognitive deficits in PCP-exposed animals before beginning twice daily administration of saline (control) or asenapine (50, 100, or 150 µg/kg, intra-muscular). Dopamine and serotonin turnover were assessed in 15 specific brain regions by high-pressure liquid chromatography measures of the ratio of parent amine to its major metabolite. RESULTS: On average, PCP-treated monkeys made twice as many errors in the reversal task as did control monkeys. Asenapine facilitated reversal learning performance in PCP-exposed monkeys, with improvements at trend level after 1 week of administration and reaching significance after 2-4 weeks of dosing. In week 4, the improvement with asenapine 150 µg/kg (p = 0.01) rendered the performance of PCP-exposed monkeys indistinguishable from that of normal monkeys without compromising fine motor function. Asenapine administration (150 µg/kg twice daily) produced an increase in dopamine and serotonin turnover in most brain regions of control monkeys and asenapine (50-150 µg/kg) increased dopamine and serotonin turnover in several brain regions of subchronic PCP-treated monkeys. No significant changes in the steady-state levels of dopamine or serotonin were observed in any brain region except for the central amygdala, in which a significant depletion of dopamine was observed in PCP-treated control monkeys; asenapine treatment reversed this dopamine depletion. A significant decrease in serotonin utilization was observed in the orbitofrontal cortex and nucleus accumbens in PCP monkeys, which may underlie poor reversal learning. In the same brain regions, dopamine utilization was not affected. Asenapine ameliorated this serotonin deficit in a dose-related manner that matched its efficacy for reversing the cognitive deficit. CONCLUSIONS: In this model of cognitive dysfunction, asenapine produced substantial gains in executive functions that were maintained with long-term administration. The cognition-enhancing effects of asenapine and the neurochemical changes in serotonin and dopamine turnover seen in this study are hypothesized to be primarily related to its potent serotonergic and noradrenergic receptor binding properties, and support the potential for asenapine to reduce cognitive dysfunction in patients with schizophrenia and bipolar disorder.

Attenuation of chronic mild stress-induced 'anhedonia' by asenapine is not associated with a 'hedonic' profile in intracranial self-stimulation.

Chronic mild stress (CMS)-induced 'anhedonia' is a predictive model of antidepressant activity. We assessed the reversal of CMS-induced behavioral changes by asenapine, the antidepressant imipramine, and the atypical antipsychotics olanzapine and risperidone. Secondarily, the ability of these agents to facilitate intracranial self-stimulation (ICSS) was assessed to ensure that any attenuation of CMS-induced anhedonia was not associated with an overt hedonic profile. After 2 weeks of CMS, male Wistar rats were administered asenapine (0.06-0.6 mg/kg), olanzapine (2 mg/kg), risperidone (0.5 mg/kg), or imipramine (10 mg/kg) by intraperitoneal injection over 5 weeks to examine their ability to reverse CMS-induced reductions in the intake of a sucrose solution. For the ICSS study, rats were trained to deliver an electrical stimulus to the ventral tegmental area. The effects of acute doses of subcutaneous asenapine (0.01-0.3 mg/kg), olanzapine (0.3 and 1 mg/kg), risperidone (0.1 and 0.3 mg/kg), and intraperitoneal imipramine (3-30 mg/kg), cocaine (5.0 mg/kg), or amphetamine (1.0 mg/kg) on ICSS were then examined. CMS significantly reduced sucrose intake (P < 0.001). All active agents (0.6 mg/kg asenapine, 2 mg/kg olanzapine, 0.5 mg/kg risperidone, and 10 mg/kg imipramine) reversed the effect of CMS (all P < 0.001). In the ICSS protocol, asenapine (0.01 and 0.03 mg/kg), olanzapine (1 mg/kg), and risperidone (0.3 mg/kg) impaired ICSS performance, whereas positive controls (5 mg/kg cocaine, 1 mg/kg amphetamine) facilitated ICSS. Asenapine reversed CMS-induced anhedonia without facilitating ICSS, providing support for a role of asenapine in treating bipolar disorder and aspects of negative and/or affective symptoms in schizophrenia.

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. This chapter describes how innovations in genomics and translational medicine can impact the future of neuropsychiatry and deconvolute the complexity of psychiatric diseases from symptoms biology. A targeted and consistent investment is needed to restore confidence in translating science into clinical success.

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. In addition, the reason why some individuals respond to SSRIs while others don't are unknown. Here we begin to ask what the basis of treatment resistance is, and propose new strategies to model this phenomenon in animals. We focus specifically on animal models that offer the appropriate framework to study treatment resistance with face, construct and predictive validity.