Introduction:Despite extensive research and numerous available treatments, major depressive disorder (MDD) remains a significant global health issue with limited efficacy from current monoaminergic antidepressants. Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in a subgroup of depressed patients, leading to interest in developing targeted treatments such as vasopressin V1b receptor antagonists. Nelivaptan, a potent V1b antagonist, demonstrated statistically significant antidepressant efficacy in one of two previous Phase 2 trials but was not pursued further. Methods:We reanalyzed the trial data (NCT00358631) using a finite mixture of linear regression model (FMM) to investigate whether antidepressant responses to nelivaptan exhibit a bimodal distribution, suggesting distinct responder subgroups. We analyzed the 17-item Hamilton Rating Scale for Depression (HAMD) scores from baseline to day 56 for patients treated with 250 mg BID nelivaptan (n = 62) versus placebo (n = 63). Results:Our analyses revealed a bimodal response distribution exclusively in the nelivaptan-treated group, characterized by two distinct subpopulations: a high-responder subgroup (mean change: -17.14) and a low-responder subgroup (mean change: -3.85). In contrast, the placebo group displayed a unimodal distribution (mean change: -7.06). Discussion:These findings support the hypothesis that nelivaptan effectively reduces depressive symptoms specifically in a subset of MDD patients, potentially identifiable by underlying HPA axis dysfunction. The confirmation of this hypothesis requires further studies integrating measures of HPA axis activity alongside response to nelivaptan treatment, facilitating precision psychiatry approaches for depression.

Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ 25–35 . In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ 25–35 . It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

Productivity remains a critical issue for the pharmaceutical industry and biomedical research, as illustrated by the low number of new molecular and biological entities that were approved in 2016 (Mullard, 2017). The failure rate in drug discovery programmes is high, and the returns on small-molecule R&D remain below their capital costs (David et al., 2009). The quest for a new paradigm that would radically change the pharmaceutical industry and create a high-performance R&D organization remains a major goal. Many solutions have been proposed to tackle the problem of productivity in pharmaceutical R&D, but it is striking that little attention has been paid to perhaps what can be considered as the primary culprit of the pharma R&D crisis: the lack of scientific creativity. This is particularly annoying in an era of highly innovative medicines, which progressed from the less demanding era of ‘me-too’ or ‘slightly-me-better’ drugs (Swinney and Anthony, 2011). Research in the drug discovery industry is performed by scientists whose creativity and passion for science are the impetus for innovation. In an attempt to understand what drives major differences in productivity, Edwards et al. (2011) and Ringel et al. (2013) identified a core set of behaviours as critical success factors, among which talent, as measured by publication productivity (e.g. h-index; Hirsch, 2005), is strongly correlated with laboratory performance. Talented scientists act as boundary spanners, coupling seemingly disparate fields and extracting new sources of information, and they are proficient at gathering external knowledge. A recent study that explored the pharmaceutical R&D dynamics by examining the publication activities of all R&D laboratories revealed a marked decline in the total number of publications by large firms (Rafols et al., 2014). While this observation confirms the increasing reliance of pharma on external research, it also emphasizes that less (quality?) science is performed in R&D laboratories, perhaps due to a shortage of talent, a phenomenon that further illustrates the decline in big pharma's R&D. Talent is necessary, although it is not sufficient to assure success. Drug discovery research thrives in a creative, flexible, non-autocratic corporate environment (Cuatrecasas, 2006), in which proper managerial strategies, along with fully empowered key research leaders, are employed to guide and inspire scientists. Such an environment includes biotech- or academic-style research projects that ‘put scientists in the driving seat’ (Zhong and Moseley, 2007), while keeping the requirement of experimental rigour, which is more prominent in big pharma (Ehlers, 2016). The (success) stories of the pioneering biotech companies, Genentech and Vertex Pharmaceutical, are probably the best illustration of how great innovation thrives with a mixture of outstanding research leaders (Herbert Boyer and Joshua Boger, respectively), highly focused groups of committed talented young scientists and visionary neck-exposed risk takers (Bob Swanson for Genentech), these latter creating an environment that supports disruptive science. These biotech companies grew spectacularly quickly because they pushed the boundaries of what is possible in medicine and delivered genuine clinical breakthroughs by translating highly innovative scientific research (e.g. recombinant DNA technology, crystal structure for the protease of the hepatitis C virus and rational drug design) into drugs that have brought substantial benefits to patients (human insulin and growth hormone, protease inhibitors). While today these companies are much larger (Genentech is a Roche company), they have kept their unique culture of relentless commitment to science. A recent analysis of R&D productivity in pharma identified Genentech as the most productive company, generating the highest number of successful drugs at a given level of R&D expenditure than any of the other top 20 pharmaceutical firms (Tollman et al., 2016). The R&D productivity of Genentech is also reflected in their number of scientific publications submitted, which is the second highest among biotechs, but more importantly their h-index is the highest of all biotechs (Figure 1). Pharma executives should be aware that the best way to solve the productivity problem is to return power to researchers. This does mean not only disbanding the silos and severing large groups into more functional smaller highly focused groups led by people who are leaders in their scientific fields, but also promoting the development of an accompanying talent strategy for their scientific workforce. As mentioned in a critical opinion article on the big pharma productivity crisis, there are many great scientists in pharmaceutical research organizations just ‘waiting to be unleashed’ (Booth, 2013) and ready to go the extra mile. The author declares no conflicts of interest.

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ 35 S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca 2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1 neo−/− mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.

Memory dysfunctions are thought to play a crucial role both in the development and the maintenance of posttraumatic stress disorder (PTSD). Patients suffering from this condition persistently re-experience the traumatic event particularly when exposed to trauma-related cues and they display memory alterations. The objective of the present study was to investigate the long-term effects of a traumatic stress exposure on defensive behaviors and memory performance in mice confronted with a natural threat (i.e. a rat) in the defense test battery (MDTB), a procedure developed by the Blanchard group in the early nineties. The object recognition task,which addresses certain aspects of episodic memory, was used to assess the long-term consequences of stress on memory function. Mice were exposed to the MDTB followed two weeks later by a re-exposure to the test apparatus, but in the absence of the threat stimulus. Two hours after the second exposure to the MDTB apparatus, mice were exposed to the object recognition task (ORT). Another set of animals was used which were either exposed to the first or to the second MDTB session, before being tested in the ORT. Results showed that MDTB exposure produced long-lasting alterations in some defensive behaviors, such as escape attempts from the apparatus, which were increased during the re-exposure session at day 14 compared to non-exposed control mice.While exposure to the MDTB context only did not affect memory performance in the ORT, confrontation with the threat stimulus in the MDTB on day 1 impaired episodic memory two weeks after the stressful event. Finally, mice confronted both with the rat on day 1 and the MDTB context on day 14 displayed intact episodic memory performance in the ORT. We hypothesize that re-exposure to the context following a stressful event resulted in an increase of arousal, which subsequently led to an improvement in cognitive performance, a phenomenon also described in PTSD patients. The MDTB is a typical example of the tremendous efforts of Blanchard's lab to increase the translatability potential of the behavioral models of central nervous system disorders.

The US remains at the forefront of a global obesity epidemic with a significant negative impact on public health. While it is well known that a balance between energy intake and expenditure is homeostatically regulated to control weight, growing evidence points to multifactorial social, neurobehavioral and metabolic determinants of food intake that influence obesity risk. This review presents factors such as the ubiquitous presence of rewarding foods in the environment and increased salience of such foods that stimulate brain reward motivation and stress circuits to influence eating behaviors. These rewarding foods via conditioned and reinforcing effects stimulate not only metabolic, but also stress hormones, that, in turn, hijack the brain emotional (limbic) and motivational (striatal) pathways, to promote food craving and excessive food intake. Furthermore, the impact of high levels of stress and trauma and altered metabolic environment (e.g. higher weight, altered insulin sensitivity) on prefrontal cortical self-control processes that regulate emotional, motivational and visceral homeostatic mechanisms of food intake and obesity risk are also discussed. A heuristic framework is presented in which the interactive dynamic effects of neurobehavioral adaptations in metabolic, motivation and stress neurobiology may further support food craving, excessive food intake and weight gain in a complex feed-forward manner. Implications of such adaptations in brain addictive-motivational and stress pathways and their effects on excessive food intake and weight gain are discussed to highlight key questions that requires future research attention in order to better understand and address the growing obesity epidemic.

Cognitive impairments are a prominent feature of schizophrenia not addressed by current medications and which contributes significantly to residual disability burden of the disease. Many of these impairments can be traced to functional abnormalities in the prefrontal cortex (PFC). Metabotropic glutamate 2 receptors (mGluR2) are present at high levels in the PFC and human/rodent pharmacology data indicate that their activation improves cognitive deficits. COMPOUND A is a novel and selective positive allosteric modulator of mGluR2 (see companion poster – Sahni et al .). The present study investigated the effects of COMPOUND A in a variety of tests predictive for both positive symptoms and cognitive impairments associated with schizophrenia. COMPOUND A (0.01-1 mg/kg po) was active in a number of schizophrenia-relevant cognition models in mice. Specifically, COMPOUND A reversed deficits in short-term visual episodic memory (MK801-disrupted novel object recognition) and working memory (Y-maze deficits in NR1 knockdown mice). The activity in the cognition models was also seen in clinically relevant translational cognition models (see companion poster – Naimoli et al. ). COMPOUND A was also active in a hallucinogen-induced positive symptom model (DOI-induced head twitch: MED = 3 mg/kg po mouse, 10 mg/kg po rat). Furthermore, pharmacokinetic and pharmacodynamic studies demonstrated that the activity of COMPOUND A in the hallucinogen model was directly related to the brain concentration. However, COMPOUND A had no effects in a battery of dopamine-mediated positive symptom assays. Importantly, no loss of antipsychotic activity was seen in these tests when COMPOUND A was administered in combination with typical or atypical antipsychotic drugs. Additionally, unlike current antipsychotic treatments, COMPOUND A did not produce any sedation or catalepsy. The overall profile of COMPOUND A in these models suggests that COMPOUND A may be effective as an adjunct treatment with existing antipsychotic drugs (cognition improvement as primary endpoint) or as a monotherapy (positive symptoms and cognition improvement).