Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial.

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Survey of chemotherapy-induced nausea and vomiting in patients with urothelial carcinoma.

Chemotherapy-induced nausea and vomiting (CINV) can cause anorexia, weight loss and deterioration of patient quality of life. It is one of the most unpleasant adverse effects of chemotherapy treatment regimens. For the optimal treatment of gastrointestinal symptoms during urothelial carcinoma chemotherapy, the present study investigated the association between gastrointestinal symptoms and therapeutic effects of gemcitabine plus platinum [cisplatin (GC) or carboplatin (GCa)] therapies. The incidence and frequency of nausea/vomiting with GC split therapy (gemcitabine, 1,000 mg/m2 on days 1 and 8; split-dose cisplatin, 35 mg/m2 on days 1 and 8; 21-day schedule) and GCa therapy [gemcitabine, 750-1,000 mg/m2 on days 1, 8 and 15; carboplatin, area under the blood concentration-time curve=5 mg min/ml (Calvert formula) on day 2; 28-day schedule] were lower compared with those of GC therapy (gemcitabine, 1,000 mg/m2 on days 1, 8 and 15; single-dose cisplatin 70 mg/m2 on day 2; 28-day schedule). However, no differences in therapeutic outcomes were observed among therapies. GCa therapy, regardless of renal function, and GC split therapy demonstrated significant increases compared with GC therapy in alleviating gastrointestinal symptoms associated with cancer chemotherapy in patients with urothelial carcinoma. Overall, these results suggested that split-dose cisplatin administration or the use of carboplatin instead of cisplatin may be useful in patients who experience CINV without compromising treatment effectiveness.

Early postnatal inhibition of GLAST causes abnormalities of psychobehaviors and neuronal morphology in adult mice.

The importance of glutamate transporters in learning, memory, and emotion remains poorly understood; hence, in the present study, we investigated whether deficiency of pharmacological GLAST in neurodevelopmental processes affects cognitive and/or emotional behaviors in mice. The mice were injected with a glutamate transporter inhibitor, dl-threo-ß-benzyloxyaspartate (dl-TBOA), during the early postnatal period. At 8 weeks of age, they showed impairments in cognitive or emotional behaviors; dysfunction of glutamatergic neurotransmission (increased expressions of GLAST, GLT-1, or GFAP protein, and decreased ability of glutamate release) in the cortex or hippocampus; morphological changes (decreased cell size in the cortex and thickness of the pyramidal neuronal layer of the CA1 area in the hippocampus). Such behavioral and morphological changes were not observed in adult mice injected with dl-TBOA. These results suggest that GLAST plays an important role in the regulation of cognitive and emotional behaviors. Early postnatal glutamatergic facilitation by GLAST dysfunction leads to cognitive and emotional abnormalities due to neurodevelopmental abnormalities such as morphological changes.

Functional roles of the glial glutamate transporter (GLAST) in emotional and cognitive abnormalities of mice after repeated phencyclidine administration.

Alterations of the glutamatergic system components, including N-methyl-d-aspartate (NMDA) receptors are relevant to the pathophysiology of schizophrenia. Repeated phencyclidine (PCP) administration induces several schizophrenia-like psychobehavioral abnormalities and decreases extracellular glutamate levels, which are associated with increased levels of glial glutamate and aspartate transporter (GLAST) in the prefrontal cortex (PFC) of mice. In the present study, we investigated the functional roles of GLAST in the emotional and cognitive abnormalities in mice following repeated PCP administration by using GLAST heterozygous (+/-) mice, since GLAST mutant mice are a useful tool for elucidating the contribution of glutamate dysfunction to the pathophysiology of schizophrenia. PCP-administered GLAST wild-type (+/+) mice showed enhancement of immobility in a forced swimming test, impairments of visual recognition memory in a novel object recognition test, decrease in high potassium (K+)-induced extracellular glutamate release, and overexpression of GLAST and S100 proteins in the PFC, compared to saline-administered GLAST+/+ mice. Such behavioral and neurochemical abnormalities were not observed in PCP-administered GLAST+/- mice. In conclusion, these results clearly suggest that genetic GLAST dysfunction and glial activation play important roles in the development of emotional and cognitive abnormalities in PCP-administered GLAST+/+ mice.

Blonanserin ameliorates social deficit through dopamine-D3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia.

Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D3 receptor agonist, and SCH23390, a dopamine-D1 receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI, a serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D3 receptor antagonist and SKF38393, a dopamine-D1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser897 by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of NMDA receptors due to Ser897-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D1 receptor-PKA signaling through dopamine-D3 receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D3 receptors may be useful as a novel treatment strategy and that the dopamine-D3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.

Acute administration of ketamine attenuates the impairment of social behaviors induced by social defeat stress exposure as juveniles via activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

The impairment of social behaviors induced by social defeat stress exposure as juveniles is resistant to some antidepressants and an antipsychotic, although the underlying mechanisms and/or therapeutic target are not yet clear. In this study, we investigated the involvement of the glutamatergic neuronal system in the impairment of social behaviors in this model, as this system is known to be involved in many central pathologies. Acute administration of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and subsequent stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, attenuated the expression of impairment of social behaviors. Lack of the NMDA receptor GluN2A subunit or acute administration of ifenprodil, an NMDA receptor GluN2B subunit antagonist, did not cause an effect. There were no significant changes in NMDA function, as determined by the ratios of phosphorylated NMDA receptor subunits in the prefrontal cortex and hippocampus. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, a selective AMPA receptor antagonist, prevented the effect of ketamine on the expression of impairment of social behaviors. On the contrary, the ratio of phosphorylated AMPA receptor GluA1 subunit in the hippocampus was significantly increased in the non-tested, defeated group. Ketamine increased the level of total protein, but not the ratio of phosphorylated GluA1 in the hippocampus of the non-tested, defeated group. In conclusion, exposure to social defeat stress as juveniles may induce the expression of impairment of social behaviors in adolescents via functional changes in GluA1. Activators of AMPA receptor signaling, such as ketamine, may constitute a novel treatment strategy for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles.

Background: Extensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Methods: Juvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress. Results: Stress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects. Conclusions: These findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis.

Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors.

Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells.

Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100µM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25µM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.

Blonanserin ameliorates phencyclidine-induced visual-recognition memory deficits: the complex mechanism of blonanserin action involving D3-5-HT2A and D1-NMDA receptors in the mPFC.

Blonanserin differs from currently used serotonin 5-HT2A/dopamine-D2 receptor antagonists in that it exhibits higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effects of blonanserin on cognitive impairment in an animal model of schizophrenia. We also sought to elucidate the molecular mechanism underlying this involvement. Blonanserin, as well as olanzapine, significantly ameliorated phencyclidine (PCP)-induced impairment of visual-recognition memory, as demonstrated by the novel-object recognition test (NORT) and increased extracellular dopamine levels in the medial prefrontal cortex (mPFC). With blonanserin, both of these effects were antagonized by DOI (a serotonin 5-HT2A receptor agonist) and 7-OH-DPAT (a dopamine-D3 receptor agonist), whereas the effects of olanzapine were antagonized by DOI but not by 7-OH-DPAT. The ameliorating effect was also antagonized by SCH23390 (a dopamine-D1 receptor antagonist) and H-89 (a protein kinase A (PKA) inhibitor). Blonanserin significantly remediated the decrease in phosphorylation levels of PKA at Thr(197) and of NR1 (an essential subunit of N-methyl-D-aspartate (NMDA) receptors) at Ser(897) by PKA in the mPFC after a NORT training session in the PCP-administered mice. There were no differences in the levels of NR1 phosphorylated at Ser(896) by PKC in any group. These results suggest that the ameliorating effect of blonanserin on PCP-induced cognitive impairment is associated with indirect functional stimulation of the dopamine-D1-PKA-NMDA receptor pathway following augmentation of dopaminergic neurotransmission due to inhibition of both dopamine-D3 and serotonin 5-HT2A receptors in the mPFC.

Plasma dehydroepiandrosterone sulfate levels in patients with major depressive disorder correlate with remission during treatment with antidepressants.

OBJECTIVE: We attempted to investigate whether dehydroepiandrosterone sulfate (DHEA-S) levels are associated with remission of major depressive disorder by assessing scores on the 17-Item Structured Interview Guide for the Hamilton Depression before and after antidepressant treatment. METHODS: Plasma DHEA-S levels in 24 patients diagnosed with major depressive disorder on the basis of Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) before and after antidepressant treatment, and 24 healthy, gender-matched, and age-matched controls were measured using a radioimmunoassay kit. RESULTS: Plasma DHEA-S levels in patients were significantly higher than those in healthy controls. In patients who achieved remission after antidepressant treatment, plasma DHEA-S levels significantly declined compared with the levels before treatment. A significant correlation was observed between changes in DHEA-S levels and Absence of Depressive and Anxious Mood scores, which are calculated from the 2-Item Structured Interview Guide for the Hamilton Depression rating as follows: severity of depressive mood and anxiety in patients before and after antidepressant treatment. CONCLUSIONS: These findings suggest that plasma DHEA-S levels can be used as a putative indicator of the state of remission in patients with major depressive disorder. Copyright © 2014 John Wiley & Sons, Ltd.

Combination of neonatal PolyI:C and adolescent phencyclidine treatments is required to induce behavioral abnormalities with overexpression of GLAST in adult mice.

Cumulative incidences of multiple risk factors are related to pathology of psychiatric disorders. The present study was designed to examine combinative effects of a neonatal immune challenge with adolescent abused substance treatment on the psychological behaviors and molecular expressions in the adult. C57BL/6J mice were neonatally treated, with polyriboinosinic-polyribocytidylic acid (PolyI:C: 5mg/kg) during postnatal days (PD) 2-6, then with phencyclidine (PCP: 10mg/kg) during adolescence (PD35-41). Locomotor activity was analyzed to evaluate sensitivity to PCP on PD35 and PD41. Emotional and cognitive tests were carried out on PD42-48. Neonatal PolyI:C treatment markedly enhanced sensitivity to PCP- and methamphetamine-induced hyperactivity in the adolescent. Mice treated with both neonatal PolyI:C and adolescent PCP (PolyI:C/PCP) showed social deficit and object recognition memory impairment. The expression of glutamate/aspartate transporter (GLAST) in the prefrontal cortex (PFC) was significantly increased in the (PolyI:C/PCP)-treated mice. Infusion of glutamate transporter inhibitor (DL-TBOA: 1 nmol/bilaterally) into the PFC reversed the object recognition impairment in the (PolyI:C/PCP)-treated mice. These results indicate that the combined treatment of neonatal PolyI:C with adolescent PCP leads to behavioral abnormalities, which were associated with increase of GLAST expression in the adult PFC.

Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.

Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.

[Pharmacy students' participation in medicinal education for children].

Over recent years, use of self-medication by patients to help prevent and treat their own medical conditions has become increasingly widespread. However, despite provision of warnings and the taking of precautions, health hazards due to medication have occurred and continue to occur. In order to ward off such incidents, it is necessary for both children and adults to be educated about appropriate drug use. And, it is desirable that pharmacy students participate in this medicinal education as a means of affirming what they have learned and improving their communication skills at an early stage in their professional development. In 2008, we held medicinal education classes for pupils and parents at three elementary schools in Aichi Prefecture with the aim of promoting appropriate drug use. Each class comprised of two parts: an introductory lecture in quiz form, lasting about 30 minutes, and a 30-minute participatory group experiment. Subsequently, the activities carried out in both parts were evaluated across 6 items and 3 items respectively, and scored from Satisfied to Unsatisfied (4-step scale) by the pupils and their parents. We also conducted a questionnaire survey on this activity to the pharmacy students. We achieved successful results, gaining high Satisfied levels (better than 90%) in all items. This activity benefited both the children and the pharmacy students. It not only provided education for the general public regarding the appropriate drug use, but is also helping to foster the development in Japan of well-trained future pharmacists.