Abstract: Summary Background In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fi brillation (AF). We aimed to investigate whether the effi cacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio (HR) 0·94, 95% CI 0·77-1·16) and those without (1·44% vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69% vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08). Interpretation There was no evidence that the relative effi cacy and safety of rivaroxaban compared with warfarin was diff erent between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.

Abstract: Patients with Mild Cognitive Impairment (MCI) are at high risk of progression to Alzheimer’s dementia Identifying MCI individuals with high likelihood of conversion to dementia and the associated biosignatures has recently received increasing attention in AD research Different biosignatures for AD (neuroimaging, demographic, genetic and cognitive measures) may contain complementary information for diagnosis and prognosis of AD We have conducted a comprehensive study using a large number of samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to test the power of integrating various baseline data for predicting the conversion from MCI to probable AD and identifying a small subset of biosignatures for the prediction and assess the relative importance of different modalities in predicting MCI to AD conversion We have employed sparse logistic regression with stability selection for the integration and selection of potential predictors Our study differs from many of the other ones in three important respects: (1) we use a large cohort of MCI samples that are unbiased with respect to age or education status between case and controls (2) we integrate and test various types of baseline data available in ADNI including MRI, demographic, genetic and cognitive measures and (3) we apply sparse logistic regression with stability selection to ADNI data for robust feature selection We have used 319 MCI subjects from ADNI that had MRI measurements at the baseline and passed quality control, including 177 MCI Non-converters and 142 MCI Converters Conversion was considered over the course of a 4-year follow-up period A combination of 15 features (predictors) including those from MRI scans, APOE genotyping, and cognitive measures achieves the best prediction with an AUC score of 08587 Our results demonstrate the power of integrating various baseline data for prediction of the conversion from MCI to probable AD Our results also demonstrate the effectiveness of stability selection for feature selection in the context of sparse logistic regression

Abstract: Paliperidone palmitate (PP) is a recently (USA) approved injectable new-generation antipsychotic. This 53-wk, Phase-III double-blind study was designed to assess the non-inferiority of PP to risperidone long-acting injectable (RIS-LAI) in schizophrenia treatment. Acutely symptomatic patients ( n =749), with a Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomly allocated to gluteal injections of either ( a ) PP: 50 mg eq. on days 1 and 8, and flexible dosing [25–100 mg eq. (i.e. 39–156 mg USA dosing)] once-monthly; or ( b ) RIS-LAI: bi-weekly injections of 25 mg on days 8 and 22, and flexible dosing (25–50 mg) starting from day 36, with allowed oral supplementation. Patients ( n =747) were 59% men, 92% white, mean (s.d.) age of 41 (11.95) yr and 45% ( n =339) completed the study. Mean (s.d.) change from baseline to endpoint in PANSS total score was: −11.6 (21.22) PP; and −14.4 (19.76) RIS-LAI (per-protocol analysis set, primary measure); least-squares means difference was −2.6 (95% CI −5.84 to 0.61), with a prespecified 5-point non-inferiority margin. PP's suboptimal dosing regimen (<150 mg eq. initial dose) resulted in lower median plasma levels of the active moiety in PP-treated vs. RIS-LAI-treated patients. Insomnia was the most common treatment-emergent adverse event, with a similar incidence in both groups (15%). PP did not demonstrate comparable efficacy to RIS-LAI, which may be attributable to the initiation dosing strategy employed. Tolerability of both treatments was comparable to previous studies, with no new safety signals detected.

Abstract: BACKGROUND & PURPOSE Loperamide is a selective µ opioid receptor agonist acting locally in the gastrointestinal (GI) tract as an effective anti-diarrhoeal but can cause constipation. We tested whether modulating µ opioid receptor agonism with δ opioid receptor antagonism, by combining reference compounds or using a novel compound (‘MuDelta’), could normalize GI motility without constipation. EXPERIMENTAL APPROACH MuDelta was characterized in vitro as a potent µ opioid receptor agonist and high-affinity δ opioid receptor antagonist. Reference compounds, MuDelta and loperamide were assessed in the following ex vivo and in vivo experiments: guinea pig intestinal smooth muscle contractility, mouse intestinal epithelial ion transport and upper GI tract transit, entire GI transit or faecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil (post-inflammatory). Colonic δ opioid receptor immunoreactivity was quantified. KEY RESULTS δ Opioid receptor antagonism opposed µ opioid receptor agonist inhibition of intestinal contractility and motility. MuDelta reduced intestinal contractility and inhibited neurogenically-mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. Stress up-regulated δ opioid receptor expression in colonic epithelial cells. In stressed mice, MuDelta normalized GI transit and faecal output to control levels over a wide dose range, whereas loperamide had a narrow dose range. MuDelta and loperamide reduced upper GI transit in the post-inflammatory model. CONCLUSIONS AND IMPLICATIONS MuDelta normalizes, but does not prevent, perturbed GI transit over a wide dose-range in mice. These data support the subsequent assessment of MuDelta in a clinical phase II trial in patients with diarrhoea-predominant irritable bowel syndrome.

Abstract: Background Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. Objective To evaluate overall pooled study data to assess the safety profile of ustekinumab through 3 years of treatment. Methods Cumulative safety data were pooled from studies in 3117 ustekinumab-treated patients. Results During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with ustekinumab 45 mg (57.6%), or with ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; ustekinumab 45 mg: 66.0%; and ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. Limitations Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 ustekinumab-treated patients were treated for 2 or more years. Conclusions The safety profile of continued ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.

Abstract: Although epilepsy is associated with substantial role impairment, it is also highly comorbid with other physical and mental disorders, making unclear the extent to which impairments associated with epilepsy are actually due to comorbidities. This issue was explored in the National Comorbidity Survey Replication (NCS-R), a nationally representative household survey of 5692 US adults. Medically recognized epilepsy was ascertained with self-report, comorbid physical disorders with a chronic conditions checklist, and comorbid DSM-IV mental disorders with the Composite International Diagnostic Interview. Lifetime epilepsy prevalence was estimated at 1.8%. Epilepsy was comorbid with numerous neurological and general medical conditions and with a sporadic cluster of mental comorbidities (panic, PTSD, conduct disorder and substance use disorders). Although comorbid disorders explain part of the significant gross associations of epilepsy with impairment, epilepsy remains significantly associated with work disability, cognitive impairment and days of role impairment after controlling comorbidities. The net association of epilepsy with days of role impairment after controlling for comorbidities is equivalent to an annualized 89.4 million excess role impairment days among US adults with epilepsy, arguing that role impairment is a major component of the societal costs of epilepsy per se rather than merely due to disorders comorbid with epilepsy. This estimated burden is likely conservative as some parts of the effects of epilepsy are presumably mediated by secondary comorbid disorders.

Abstract: Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.

Abstract: The objective of this analysis was to develop a semi-mechanistic nonlinear disease progression model using an expanded set of covariates that captures the longitudinal change of Alzheimer's Disease Assessment Scale (ADAS-cog) scores from the Alzheimer's Disease Neuroimaging Initiative study that consisted of 191 Alzheimer disease patients who were followed for 2 years. The model describes the rate of progression and baseline disease severity as a function of influential covariates. The covariates that were tested fell into 4 categories: (1) imaging volumetric measures, (2) serum biomarkers, (3) demographic and genetic factors, and (4) baseline cognitive tests. Covariates found to affect baseline disease status were years since disease onset, hippocampal volume, and ventricular volume. Disease progression rate in the model was influenced by age, total cholesterol, APOE e4 genotype, Trail Making Test (part B) score, and current levels of impairment as measured by ADAS-cog. Rate of progression was slower for mild and severe Alzheimer patients compared with moderate Alzheimer patients who exhibited faster rates of deterioration. In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS-cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations.

Abstract: Purpose To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. Methods This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and April 2008. Trabectedin was administered intravenously as 1 of 3 schedules: 24-hour infusion every 3 weeks (q3wk 24-h; n = 570/2,818 cycles), 3-hour infusion every 3 weeks (q3wk 3-h; n = 258/1,003 cycles), and 3-hour infusion for three consecutive weeks every 4 weeks (qwk 3-h; n = 304/1,198 cycles). Results The majority of patients (90%) had received previous chemotherapy. Patients were given a median of three treatment cycles of trabectedin (range, 1–59). Nausea, fatigue and vomiting were the most common trabectedin-related adverse events, reported in ≥20% of patients. Reversible myelosuppression (mainly neutropenia) and transient reversible transaminase increases were the most common laboratory abnormalities seen with trabectedin, with a very low incidence of relevant clinical consequences. Deaths associated with drug-related adverse events were infrequent, occurring in 19 (1.7%) patients. Conclusion Single-agent trabectedin treatment was reasonably well tolerated. Trabectedin can be administered for prolonged periods to patients with sustained clinical benefit (induction of disease stability or shrinkage) without cumulative toxicities over time.

Abstract: Background Cutaneous sarcoidosis (CS) skin provides relatively noninvasive access to granulomatous sarcoidosis tissue. Objective We sought to explore the role of the T-helper (Th)1 and Th17 pathways in sarcoidosis. Methods We used molecular profiling and gene expression analysis to analyze the Th1 and Th17 pathways and other immune-mediated pathways in CS. Molecular profiles were obtained from sarcoidosis skin lesions (lesional skin [LS]), unaffected skin from patients with CS (non-LS), and the skin of healthy control subjects. Whole blood was collected to compare the molecular profile of sarcoidosis skin lesions and whole blood. Results Twenty participants were enrolled: 15 with active CS and 5 healthy volunteers. Microarray analyses comparing non-LS and healthy volunteer skin with LS showed several thousand genes differentially expressed (≥2-fold change false discovery rate, P Limitations Measurements were made at a single point in time and may not identify mechanisms that may be identified in patients followed up longitudinally. Conclusion These findings provide novel insight into the dysregulated pathways that may be involved in the pathogenesis of sarcoidosis.

Abstract: 30. Chantret I, Lacasa M, Chevalier G, et al. Sequence of the complete cDNA and the 50 structure of the human sucrase-isomaltase gene. Possible homology with a yeast glucoamylase. Biochem J 1992; 285:915–23. 31. Nichols BL, Eldering J, Avery S, et al. Human small intestinal maltaseglucoamylase cDNA cloning. Homology to sucrase-isomaltase. J Biol Chem 1998;273:3076–81. 32. Nichols BL, Avery S, Sen P, et al. The maltase-glucoamylase gene: common ancestry to sucrase-isomaltase with complementary starch digestion activities. Proc Natl Acad Sci U S A 2003;100:1432–7. 33. Quezada-Calvillo R, Robayo-Torres C, et al. Luminal substrate ‘‘brake’’ on mucosal maltase-glucoamylase activity regulates total rate of starch digestion to glucose. J Pediatr Gastroenterol Nutr 2007;45:32–43. 34. Quezada-Calvillo R, Sim L, Ao Z, et al. Luminal starch substrate ‘‘brake’’ on maltase-glucoamylase activity is located within the glucoamylase subunit. J Nutr 2008;138:685–92. 35. Quezada-Calvillo R, Robayo-Torres C, Opekun AR, et al. Contribution of mucosal maltase-glucoamylase activities to mouse small intestinal starch alpha-glucogenesis. J Nutr 2007;137:1725–33. 36. Nichols BL, Quezada-Calvillo R, Robayo-Torres CC, et al. Mucosal maltase-glucoamylase plays a crucial role in starch digestion and prandial glucose homeostasis of mice. J Nutr 2009;139:684–90. 37. Jones K, Sim L, Mohan S, et al. Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase. Bioorg Med Chem 2011;19:3929–34. 38. Eskandari R, Jones K, Rose DR, et al. Selectivity of 30-O-methylponkoranol for inhibition of Nand C-terminal maltase glucoamylase and sucrase isomaltase, potential therapeutics for digestive disorders or their sequelae. Bioorg Med Chem Lett 2011;21:6491–4. 39. Sim L, Willemsma C, Mohan S, et al. Structural basis for substrate selectivity in human maltase-glucoamylase and sucrase-isomaltase N-terminal domains. J Biol Chem 2010;285:1763–70. 40. Sim L, Quezada-Calvillo R, Sterchi EE, et al. Human intestinal maltaseglucoamylase: crystal structure of the N-terminal catalytic subunit and basis of inhibition and substrate specificity. J Mol Biol 2008;375:782–92. 41. Krasilnikoff PA, Gudman-Hoyer E, Moltke HH. Diagnostic value of disaccharide tolerance tests in children. Acta Paediatr Scand 1975; 64:693–8. 42. Perman JA, Barr RG, Watkins JB. Sucrose malabsorption in children: noninvasive diagnosis by interval breath hydrogen determination. J Pediatr 1978;93:17–22. 43. Douwes AC, Fernandes J, Jongbloed AA. Diagnostic value of sucrose tolerance test in children evaluated by breath hydrogen measurement. Acta Paediatr Scand 1980;69:79–82. 44. Lifschitz CH, Irving CS, Gopalakrishna GS, et al. Carbohydrate malabsorption in infants with diarrhea studied with the breath hydrogen test. J Pediatr 1983;102:371–5. 45. Davidson GP, Robb TA. Detection of primary and secondary sucrose malabsorption in children by means of the breath hydrogen technique. Med J Aust 1983;2:29–32. 46. Robayo-Torres CC, Opekun AR, Quezada-Calvillo R, et al. C-breath tests for sucrose digestion in congenital sucrase isomaltase-deficient and sacrosidase-supplemented patients. J Pediatr Gastroenterol Nutr 2009;48:412–8.

Abstract: Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. The pleiotropic effects of histamine are mediated by four G protein-coupled receptors, as follows: Hrh1/H(1)R, Hrh2/H(2)R, Hrh3/H(3)R, and Hrh4/H(4)R. H(4)R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied. In this study, we show that, compared with wild-type mice, animals with a disrupted Hrh4 (H(4)RKO) develop more severe myelin oligodendrocyte glycoprotein (MOG)(35\x{2013}55)-induced experimental allergic encephalomyelitis. Mechanistically, we also show that H(4)R plays a role in determining the frequency of T regulatory (T(R)) cells in secondary lymphoid tissues, and regulates T(R) cell chemotaxis and suppressor activity. Moreover, the lack of H(4)R leads to an impairment of an anti-inflammatory response due to fewer T(R) cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells.

Abstract: The credibility of industry-sponsored clinical research has suffered in recent years, undercut by reports of selective or biased disclosure of research results, ghostwriting and guest authorship, and inaccurate or incomplete reporting of potential conflicts of interest.1,2 In response, many pharmaceutical companies have integrated best practices and recommendations from groups such as the International Committee of Medical Journal Editors (ICMJE), the Good Publication Practice guidelines, the Committee on Publication Ethics, the EQUATOR (Enhancing the QUAlity and Transparency Of health Resources) Network, and the Medical Publishing Insights and Practices (MPIP) initiative into their internal policies and standard operating procedures.3-10 However, a credibility gap remains: some observers, including some journal editors and academic reviewers, maintain a persistent negative view of industry-sponsored studies.11 Given industry's pivotal role in the development of new therapies, further improvements in research conduct and disclosure are needed across the industry-investigator-editor enterprise to restore confidence in industry-sponsored biomedical research. In 2008, the MPIP was founded by members of the pharmaceutical industry and the International Society for Medical Publication Professionals to elevate trust, transparency, and integrity in publishing industry–sponsored studies through education and creation of a discussion forum among industry research sponsors and biomedical journals.12,13 In 2010, the MPIP convened a roundtable of 23 journal editors and industry representatives (see the “Acknowledgments” section for a list of MPIP participants) to characterize the persistent and perceived credibility gap in industry-sponsored research and identify approaches to resolve it. Attendees agreed that there have been important improvements in the conduct and reporting of industry-sponsored studies during the past 5 years, but several opportunities remain for additional improvement. Attendees reached consensus on a top 10 list of recommendations (Table), intended to serve as a call to action for all stakeholders—authors, journal editors, research sponsors, and others—to enhance the quality and transparency of industry-sponsored clinical research reporting. Although framed in the context of industry sponsorship, many of these recommendations would enhance the credibility of clinical research publications in general, regardless of the funding source. TABLE Top 10 Recommendations for Closing the Credibility Gap in Reporting Industry-Sponsored Clinical Research

Abstract: Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency ‘Scientific Discussions’; and the US Food and Drug Administration ‘Pharmacology/Toxicology Reviews’ and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.

Abstract: Background In patients with psoriasis and inadequate response (IR) to tumor necrosis factor-α antagonist treatment, the incremental benefit of switching to another tumor necrosis factor-α antagonist is unknown. Objective We sought to evaluate the clinical response to an etanercept-to-infliximab switch in patients with psoriasis and IR to etanercept. Methods Adults with moderate-to-severe plaque psoriasis and IR to etanercept (≥4 months) were eligible for this open-label study (called PSUNRISE). Patients had a Physician Global Assessment (PGA) score of at least 2 (mild) on a 5-point scale with etanercept, with or without concomitant oral systemic methotrexate or cyclosporine at baseline and during the study. Patients received intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, 14, and 22. PGA was used to evaluate efficacy at week 10 (primary end point) and week 26 (durability). Safety was evaluated through the end of the study. Results Of 215 patients, only 10 received concomitant immunomodulators. At week 10, 65.4% of patients (138 of 211; 95% confidence interval 58.6%-71.8%) achieved a PGA score of clear (0) or minimal (1) (primary end point). This response was durable through week 26, at which time 61.3% (122 of 199; 95% confidence interval 54.2%-68.1%) achieved a PGA score of clear (0) or minimal (1). There were no unexpected side effects or safety concerns. Limitations This was an open-label, 26-week study; an incremental change of 1 PGA point, even mild to minimal, was considered clinically significant, as most psoriasis practitioners seek to achieve minimal psoriasis or clear skin. Conclusion After switching to infliximab, a substantial proportion of patients with psoriasis and IR to etanercept experienced rapid and durable improvement.

Abstract: Lysophosphatidic acid (LPA) is a bioactive lipid acting on the nervous system through at least 6 different G protein-coupled receptors. In this study, we examined mice lacking the LPA5 receptor using an extensive battery of behavioral tests. LPA5-deficient mice showed decreased pain sensitivity in tail withdrawal, faster recovery in one inflammatory pain procedure (complete Freund's adjuvant-induced inflammation) and attenuated responses under specific neuropathic pain conditions. Notably, deletion of LPA5 also induced nocturnal hyperactivity and reduced anxiety in the mutant mice. Several exploratory tasks revealed signs of reduced anxiety in LPA5 knockout mice including increased visits to the arena center and reduced thigmotaxis in the open field, and more open arm entries in the elevated plus maze. Finally, LPA5 knockout mice also displayed marked reduction in social exploration, although several other tests indicated that these mice were able to respond normally to environmental stimuli. While learning and memory performance was not impaired in LPA5-deficient mice, we found differences, e.g., targeted swim strategy and reversal learning, as well as scheduled appetitive conditioning that might indicate differential motivational behavior. These results imply that LPA5 might be involved in both nociception and mechanisms of pain hypersensitivity, as well as in anxiety-related and motivational behaviors. These observations further support the proposed involvement of LPA signaling in psychopathology.