Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice.

AIM: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. METHODS: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. RESULTS: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). CONCLUSION: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings.

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-µM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.

Chronic social defeat stress increases the amounts of 12-lipoxygenase lipid metabolites in the nucleus accumbens of stress-resilient mice.

Severe and prolonged social stress induces mood and cognitive dysfunctions and precipitates major depression. Neuroinflammation has been associated with chronic stress and depression. Rodent studies showed crucial roles of a few inflammation-related lipid mediators for chronic stress-induced depressive-like behaviors. Despite an increasing number of lipid mediators identified, systematic analyses of synthetic pathways of lipid mediators in chronic stress models have not been performed. Using LC-MS/MS, here we examined the effects of chronic social defeat stress on multiple synthetic pathways of lipid mediators in brain regions associated with stress susceptibility in mice. Chronic social defeat stress increased the amounts of 12-lipoxygenase (LOX) metabolites, 12-HETE and 12-HEPE, specifically in the nucleus accumbens 1 week, but not immediately, after the last stress exposure. The increase was larger in stress-resilient mice than stress-susceptible mice. The S isomer of 12-HETE was selectively increased in amount, indicating the role of 12S-LOX activity. Among the enzymes known to have 12S-LOX activity, only Alox12 mRNA was reliably detected in the brain and enriched in brain endothelial cells. These findings suggest that chronic social stress induces a late increase in the amounts of 12S-LOX metabolites derived from the brain vasculature in the nucleus accumbens in a manner associated with stress resilience.

Prenatal methotrexate injection increases behaviors possibly associated with depression and/or autism in rat offspring; A new animal model for mental disorder, based on folate metabolism deficit during pregnancy.

BACKGROUND: Deficiency of folate, an essential vitamin for DNA synthesis and methylation, is reported as a risk factor for mental disorders. Considering a possibility that folate metabolism deficit during pregnancy may disturb CNS development and increase mental disorders in offspring, we treated pregnant rats with methotrexate (MTX), an inhibitor of folate metabolic enzyme, and evaluated offspring behaviors. METHODS: Saline or MTX was intraperitoneally administered to female SD rats on gestational day 17. Offspring behaviors were evaluated during approximately 6-9 weeks old; prepulse inhibition (PPI), social interaction (SI), locomotor activity (LA), and forced swimming test (FST) for evaluation of schizophrenia, depression, and autism related behaviors; the elevated plus maze (EPM) and the light-dark box (LD) test for evaluation of anxiety. RESULTS: Compared to saline-treated group, MTX-treated group showed decrease of SI and increase of immobility time in FST. In addition, increases of time spent in the light box and shuttling between the light-dark boxes were observed in LD test. On the other hand, no changes were confirmed in EPM, LA, and PPI. CONCLUSION: Decrease of SI and increase of immobility time in FST may suggest association of this animal model with depression and/or autism. Increase of time spent in the light box and shuttling between the light-dark boxes may indicate changes in anxiety or cognitive level to environment, or repetitive behaviors in autism. Although further studies are warranted to characterize this animal model, at least we can say that prenatal MTX exposure, possibly causing folate metabolism deficit, affects offspring behaviors.

Discovery research and development history of the dopamine D2 receptor partial agonists, aripiprazole and brexpiprazole.

Otsuka Pharmaceutical Co., Ltd. successfully developed the first dopamine D2 receptor partial agonist approved for schizophrenia, the antipsychotic aripiprazole (Abilify® ). The drug was approved for this indication in the United States in 2002 and has received approval in the United States, Europe, Japan, and many other countries for several indications including schizophrenia, acute mania, adjunctive treatment of major depressive disorder (MDD), irritability associated with autistic disorder, and Tourette's disorder. Otsuka next developed brexpiprazole (Rexulti® ), another D2 receptor partial agonist, which was granted marketing approval in the United States in 2015 as adjunctive therapy in major depressive disorder and for the treatment of schizophrenia. In Japan, brexpiprazole also received approval as a treatment for schizophrenia in 2018. In this review, we describe Otsuka's research history and achievements over the preceding 40 years in the area of antipsychotic drug discovery for dopamine D2 receptor partial agonists.

[Preclinical pharmacological profiles and clinical efficacy of the novel antipsychotic drug brexpiprazole (REXULTI® Tablets 1†mg, 2†mg)].

Brexpiprazole (Rexulti®) is the second antipsychotic agent in the world with dopamine D2 receptor partial agonist which was developed by Otsuka Pharmaceutical Co. Ltd. It is categorized as 〝Serotonin- dopamine Activity Modulator (SDAM)〟 that regulates both serotoninergic and dopaminergic systems by acting as a partial agonist for serotonin 5-HT1A receptors and D2 receptors and as an antagonist for 5-HT2A receptors. In preclinical pharmacological studies, brexpiprazole showed the equivalent antipsychotic-like effects to those of other atypical antipsychotics. And it was suggested that brexpiprazole has the low potentials to induce extrapyramidal symptoms, hyperprolactinemia and tardive dyskinesia, with improvement effects on cognitive dysfunction. Furthermore, brexpiprazole has the weak effects on histamine H1 receptors which are associated with sedation and weight gain in clinical. In the clinical trials in patients with schizophrenia in both acute and maintenance phase, brexpiprazole showed improvement of antipsychotic effects against placebo, and low incidence of adverse events, e.g., extrapyramidal symptoms, hyperprolactinemia, and weight gain, as suggested in preclinical studies. Furthermore, brexpiprazole showed low incidence of metabolic abnormalities. In particular, brexpiprazole showed relatively low incidences of akathisia, insomnia and agitation which has been commonly reported with aripiprazole. This would be based on the pharmacological features of brexpiprazole that is more potent antagonism at 5-HT2A receptors and D2 receptors partial agonism with lower intrinsic activity compared to those of aripiprazole. In conclusion, brexpiprazole could be one of the antipsychotics with the most rational mechanism of action, and the better efficacy and safety/tolerability profiles would contribute to the treatment of patients with schizophrenia.

Brexpiprazole has a low risk of dopamine D2 receptor sensitization and inhibits rebound phenomena related to D2 and serotonin 5-HT2A receptors in rats.

BACKGROUND: Long-term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D2 receptor sensitization. We evaluated the effects of brexpiprazole on D2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D2 receptors in rats subchronically dosed with another atypical antipsychotic. METHODS: The maximum D2 receptor density (Bmax ) and apomorphine (a D2 receptor agonist)-induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for Bmax , 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine-induced hyperlocomotion and (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI: a 5-HT2A receptor agonist)-induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days. RESULTS: Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED50 of anti-apomorphine-induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the Bmax and apomorphine-induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine-induced hyperlocomotion and also DOI-induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine-induced hyperlocomotion. CONCLUSION: Brexpiprazole has a low risk of D2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D2 and 5-HT2A receptors after a repeated administration of risperidone.

Increased BDNF-TrkB signaling in the nucleus accumbens plays a role in the risk for psychosis after cannabis exposure during adolescence.

Although epidemiological data suggest that repeated use of cannabis during adolescence may increase the risk for psychosis, its precise molecular mechanisms remain undetermined. In this study, we examined whether brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling plays a role in the risk for psychosis after exposure of cannabinoid (CB) receptor agonist during adolescence. Repeated administration of the CB receptor agonist WIN55,212-2 (2 mg/kg/day) during adolescence (P35 - P45) significantly increased methamphetamine (METH: 1 mg/kg)-induced hyperlocomotion in adulthood (P70 - P74) compared with vehicle-treated mice. Western blot analysis showed that BDNF-TrkB signaling in the nucleus accumbens (NAc) of WIN55,212-2-treated mice were significantly higher than that of vehicle-treated mice. Interestingly, an increase in the METH-induced locomotion in WIN55,212-2-treated mice was significantly attenuated by subsequent repeated administration of the TrkB antagonist ANA-12 (0.5 mg/kg/day from P70 to P83). Furthermore, increased BDNF-TrkB signaling in the NAc from WIN55,212-2-treated mice was also significantly attenuated after subsequent repeated administration of ANA-12. These findings suggest that increased BDNF-TrkB signaling in the NAc plays an important role in the increase in METH-induced locomotion in adulthood after repeated WIN55,212-2 administration during adolescence. Therefore, TrkB antagonists would be potential prophylactic and therapeutic drugs for psychosis in adult with cannabis use during adolescence.

Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine.

RATIONALE: Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. OBJECTIVES: The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. METHODS: The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. RESULTS: A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. CONCLUSIONS: These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.

Antidepressant effects of combination of brexpiprazole and fluoxetine on depression-like behavior and dendritic changes in mice after inflammation.

RATIONALE: Addition of low doses of atypical antipsychotic drugs with selective serotonin reuptake inhibitors (SSRIs) could promote a rapid antidepressant effect in treatment-resistant patients with major depression. Brexpiprazole, a new atypical antipsychotic drug, has been used as adjunctive therapy for the treatment of major depression. OBJECTIVES: The present study was undertaken to examine whether brexpiprazole could augment antidepressant effects of the SSRI fluoxetine in an inflammation model of depression. METHODS: We examined the effects of fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or the combination of the two drugs on depression-like behavior, alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling, and dendritic spine density in selected brain regions after administration of lipopolysaccharide (LPS) (0.5 mg/kg). RESULTS: Combination of brexpiprazole and fluoxetine promoted a rapid antidepressant effect in inflammation model although brexpipazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved LPS-induced alterations in the BDNF - TrkB signaling and dendritic spine density in the prefrontal cortex, CA3 and dentate gyrus, and nucleus accumbens. CONCLUSIONS: These results suggest that add-on of brexpiprazole to fluoxetine can produce a rapid antidepressant effect in the LPS inflammation model of depression, indicating that adjunctive therapy of brexpiprazole to SSRIs could produce a rapid antidepressant effect in depressed patients with inflammation.

Adjunctive treatment of brexpiprazole with fluoxetine shows a rapid antidepressant effect in social defeat stress model: Role of BDNF-TrkB signaling.

Addition of low doses of the atypical antipsychotic drug brexpiprazole with selective serotonin reuptake inhibitors (SSRIs) could promote antidepressant effect in patients with major depressive disorder although the precise mechanisms underlying the action of the combination are unknown. Combination of low dose of brexpiprazole (0.1 mg/kg) and SSRI fluoxetine (10 mg/kg) could promote a rapid antidepressant effect in social defeat stress model although brexpiprazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling and dendritic spine density in the prefrontal cortex, hippocampus, and nucleus accumbens in the susceptible mice after social defeat stress. Interestingly, TrkB antagonist ANA-12 significantly blocked beneficial effects of combination of brexpiprazole and fluoxetine on depression-like phenotype. These results suggest that BDNF-TrkB signaling plays a role in the rapid antidepressant action of the combination of brexpiprazole and fluoxetine.

Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is a severe and debilitating psychiatric disorder. However, the precise biological basis remains unknown, hampering the search for novel biomarkers. We performed a metabolomics analysis to discover novel peripheral biomarkers for BD. METHODS: We quantified serum levels of 116 metabolites in mood-stabilized male BD patients (n = 54) and age-matched male healthy controls (n = 39). RESULTS: After multivariate logistic regression, serum levels of pyruvate, N-acetylglutamic acid, α-ketoglutarate, and arginine were significantly higher in BD patients than in healthy controls. Conversely, serum levels of ß-alanine, and serine were significantly lower in BD patients than in healthy controls. Chronic (4-weeks) administration of lithium or valproic acid to adult male rats did not alter serum levels of pyruvate, N-acetylglutamic acid, ß-alanine, serine, or arginine, but lithium administration significantly increased serum levels of α-ketoglutarate. CONCLUSIONS: The metabolomics analysis demonstrated altered serum levels of pyruvate, N-acetylglutamic acid, ß-alanine, serine, and arginine in BD patients. GENERAL SIGNIFICANCE: The present findings suggest that abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism play a role in the pathogenesis of BD.

Palladium-catalyzed enantioselective allylic alkylation of trifluoromethyl group substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic esters with malonate anions.

We examined the palladium-catalyzed allylic alkylation of trifluoromethyl group-substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic benzoate with a malonate anion, and succeeded in obtaining an enantiomerically enriched product in high yields with high ee values through the dynamic kinetic asymmetric transformation (DYKAT). The best result was attained by the [Pd(C3H5)(cod)]BF4/(S)-tol-BINAP in the presence of BSA or DMAP as a base.

Potentiation of neurite outgrowth by brexpiprazole, a novel serotonin-dopamine activity modulator: a role for serotonin 5-HT1A and 5-HT2A receptors.

Brexpiprazole, a novel atypical antipsychotic drug, is currently being tested in clinical trials for treatment of psychiatric disorders, such as schizophrenia and major depressive disorder. The drug is known to act through a combination of partial agonistic activity at 5-hydroxytryptamine (5-HT)1A, and dopamine D2 receptors, and antagonistic activity at 5-HT2A receptors. Accumulating evidence suggests that antipsychotic drugs act by promoting neurite outgrowth. In this study, we examined whether brexpiprazole affected neurite outgrowth in cell culture. We found that brexpiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration dependent manner. The selective 5-HT1A receptor antagonist, WAY-100,635, was able to block the effects of brexpiprazole on neurite outgrowth, unlike the selective dopamine D2 receptor antagonist, raclopride. Furthermore, the selective 5-HT2A receptor antagonist M100907, but not DOI (5-HT2A receptor agonist), significantly potentiated NGF-induced neurite outgrowth. Moreover, xestospongin C and 2-aminoethoxydiphenyl borate (2-APB), both specific inhibitors of inositol 1,4,5-triphosphate (IP3) receptors, significantly blocked the effects of brexpiprazole. These findings suggest that brexpiprazole-induced neurite outgrowth is mediated through 5-HT1A and 5-HT2A receptors, and subsequent Ca(2+) signaling via IP3 receptors.

Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin-dopamine activity modulator.

Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin-dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine). Dosing with dizocilpine (0.1mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1mg/kg, p.o.) significantly ameliorated dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03mg/kg, p.o.) nor olanzapine (0.03mg/kg, p.o.) altered dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve dizocilpine-induced social recognition deficits via 5-HT1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders.

Effects of brexpiprazole, a novel serotonin-dopamine activity modulator, on phencyclidine-induced cognitive deficits in mice: a role for serotonin 5-HT1A receptors.

Brexpiprazole, a serotonin-dopamine activity modulator, is currently being tested in clinical trials as a new therapy for a number of neuropsychiatric diseases, including schizophrenia and major depressive disorder. Accumulating evidence suggests that 5-hydroxytryptamine (5-HT)1A receptors play a role in cognition. This study was undertaken to examine whether brexpiprazole, a novel drug with 5-HT1A receptor partial agonism, could improve cognitive deficits in mice, induced by repeated administration of the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP). Subsequent subchronic (14 days) oral administration of brexpiprazole (0.3, 1, or 3mg/kg/day) significantly attenuated PCP (10mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose-dependent manner. The effects of brexpiprazole (3mg/kg) were significantly antagonized by co-administration of the selective 5-HT1A receptor antagonist, WAY-100,635 (1.0mg/kg), although WAY-100,635 alone was not effective in this model. These findings suggest that brexpiprazole can ameliorate PCP-induced cognitive deficits in mice via 5-HT1A receptors. Therefore, brexpiprazole could ameliorate cognitive deficits as seen in schizophrenia and other neuropsychiatric diseases.

Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

Prenatal immune activation and subsequent peripubertal stress as a new model of schizophrenia.

Epidemiological studies show that maternal viral infection during pregnancy plays a key role in the etiology of neurodevelopmental disorders, such as schizophrenia and autism. Prenatal maternal immune activation and peripubertal psychological stress are key environmental risk factors for neurodevelopmental disorders. Viral mimic polyriboinosinic-polyribocytidylic acid is known to act as a Toll-like receptor-3 agonist. Polyriboinosinic-polyribocytidylic acid has been typically used to establish this rodent model of prenatal immune activation. Recently, Giovanoli et al. reported on a new neurodevelopmental model of schizophrenia based on combined prenatal immune activation and peripubertal stress. In this report, we place these findings into context and discuss their significance.

Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration.

Accumulating evidence suggests that inflammation may play a role in the pathophysiology of major depressive disorder (MDD). Antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), possess anti-inflammatory effects in vitro. Here, we examined the effects of SSRIs and SNRIs on lipopolysaccharide (LPS)-induced inflammation and depressive-like behavior in male mice. A single administration of LPS (0.5mg/kg, i.p.) increased serum levels of the pro-inflammatory cytokine, tumor necrosis factor-α (TNFα) and the anti-inflammatory cytokine, interleukin-10 (IL-10) in mice. Pretreatment with SSRIs (fluoxetine and paroxetine), SNRIs (venlafaxine and duloxetine), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin, attenuated LPS-induced increases in TNFα, whereas it increased serum levels of IL-10, in mice treated with LPS. In the tail suspension test (TST), LPS increased the immobility time without affecting spontaneous locomotor activity, suggesting that LPS induced depressive-like behavior in mice. Treatment with fluoxetine (30 mg/kg) or paroxetine (10mg/kg) significantly shortened LPS-induced increases of immobility time. These results suggested that antidepressants exert anti-inflammatory effects in vivo, and that the serotonergic system may partially mediate these effects. In addition, the anti-inflammatory effects of antidepressants may help alleviate the symptoms of LPS-induced depression in mice.

Aripiprazole attenuates established behavioral sensitization induced by methamphetamine.

Psychostimulant-induced behavioral sensitization is an experimental model of the stimulant psychosis and the vulnerability to relapse in schizophrenia. This study investigated the effects of aripiprazole, an antipsychotic drug that has dopamine D2 receptor partial agonist activity, on established sensitization induced by methamphetamine (MAP) in mice. Repeated treatment with MAP (1.0mg/kg, s.c.) for 10 days progressively increased the ability of MAP to increase locomotor activity. The enhanced locomotion induced by a challenge dose of MAP (0.24 mg/kg, s.c.) also occurred after withdrawal from MAP pretreatment. Repeated treatment with aripiprazole from days 10 to 14 during withdrawal from MAP administration attenuated the effect of MAP pretreatment, enhancing the motor response to a challenge dose of stimulant 3 days after the aripiprazole preparation. In contrast, sulpiride, a dopamine D2 receptor specific antagonist, and risperidone, a serotonin 5-HT2 and dopamine D2 receptor antagonist, did not show effects similar to aripiprazole. The attenuation effect of aripiprazole was blocked by pretreatment with the specific serotonin 5-HT1A antagonist WAY100635. These results of aripiprazole suggest that the attenuation effect of aripiprazole was mediated by 5-HT1A receptors and imply that aripiprazole may have therapeutic value in treating drug-induced psychosis and schizophrenia.