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Purpose This study was performed to assess the long-term efficacy, safety, and tolerability of brexpiprazole in elderly Japanese patients with schizophrenia. Methods This is a post hoc analysis of a previous open-label study conducted over 56 weeks which consisted of two consecutive phases: a 4-week switching period and a 52-week open-label period. Mean change in the Positive and Negative Syndrome Scale (PANSS) total score, response rates, number and incidence of treatment-emergent adverse events (TEAEs), and other safety parameters were analyzed using descriptive statistics based on age group (elderly, ≥65 and non-elderly, Results This post hoc analysis included 208 de novo patients of which 33 were elderly. The continuation rate in elderly patients was 54.5%, and the mean daily dose and treatment duration of brexpiprazole in elderly patients at week 56 were similar to those of non-elderly patients. The mean change in the PANSS total score from the baseline to week 56 was -13.8 in elderly patients and this improvement was maintained throughout the open-label phase. This outcome was comparable to that of the non-elderly patients (-9.0). The incidence rate of TEAEs was 97.0% in elderly patients and 82.3% in non-elderly patients. Most of the TEAEs were either mild (75.8%) or moderate (18.2%) in severity in the elderly patients and the incidence of TEAEs leading to discontinuation was lower in elderly (9.1%) than in non-elderly patients (13.1%). The most commonly observed adverse events in elderly patients were nasopharyngitis (30.3%) and worsening of schizophrenia (27.3%). The safety profiles in both groups were similar. Conclusion Brexpiprazole was shown to be safe and effective in the treatment of elderly Japanese patients with schizophrenia.

Takeshi Inoue,1 Hiromi Sano,2 Yoshitsugu Kojima,3 Sakiko Yamada,3 Osamu Shirakawa4 1Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 2Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 3Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan; 4Department of Neuropsychiatry, Kindai University Faculty of Medicine, Osaka, JapanCorrespondence: Sakiko YamadaMedical Affairs, Otsuka Pharmaceutical Co., Ltd., Shinagawa Grand Central Tower, 2-16-4 Konan, Minato-Ku, Tokyo, 108-8242, JapanTel +81 3 6717 1400Fax +81 3 6716 1398Email yamadasa@otsuka.jpPurpose: This study aimed to describe real-world treatment patterns and medication adherence among patients with bipolar disorder (BD) in Japan.Patients and Methods: Adult patients with a BD diagnosis were identified between July 2013 and February 2018, using an employment-based health insurance claims database from the JMDC Inc. Treatment patterns of target drugs (mood stabilizers, antipsychotics) and adherence (measured by the proportion of days covered [PDC]) were assessed during the first- through third-year follow-up. Adherence was also assessed for patient subgroups.Results: The analyzed population included 13,788 patients with BD. They were mostly prescribed sodium valproate, lithium, or aripiprazole (range: 21.1– 27.4%) across 3 years of follow-up, whereas lamotrigine was prescribed to 11.2– 12.8% of patients. Benzodiazepines (70– 87%) and antidepressants (52– 71%) were commonly prescribed during all three follow-up periods. The mean PDC among all patients with BD was 0.51 during the first and increased to 0.61 during the third year. The mean PDC was 0.42 (first year) in patients aged < 30 years and 0.49 in those aged 30– 40 years. The PDC was 0.44– 0.61 (depending on the drug class) in those who were prescribed a single-class target drug and 0.68– 0.83 in those prescribed two drug classes concomitantly.Conclusion: This study documented generally low medication adherence among patients with BD, and those at young age. These patients may require more attention.Keywords: bipolar disorders, treatment patterns, medication adherence, oral antipsychotics, mood stabilizers, claims database

Objectives To determine the long‐term safety of switching to brexpiprazole from aripiprazole or non‐aripiprazole dopamine antagonists. Methods Post‐hoc analysis of 56‐week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4‐week switching period with further titration (1–4 mg/day) allowed during the 52‐week, open‐label period. Major assessment items: total/low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc). Results 84/186 (45.2%) patients (aripiprazole, 32.9%; non‐aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL‐/HDL‐cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non‐aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non‐aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non‐aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval. Conclusions Switching to brexpiprazole is associated with a low long‐term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms.

Vasopressin V1b receptor is specifically expressed in the pituitary and mediates adrenocorticotropin release, thereby regulating stress responses via its corticotropin releasing factor-like action. In the present study we examined catecholamine release in response to two types of stress in mice lacking the V1b receptor gene (V1bR−/− mice) vs. wild-type mice. There were no significant differences in the basal plasma levels of catecholamines between the two genotypes. In response to stress induced by forced swimming, norepinephrine (NE), but not epinephrine (E) or dopamine (DA), was increased in wild-type mice, whereas the increases in NE and DA were not observed in V1bR−/− mice. In wild-type mice, E, but not NE or DA, was increased in response to social isolation stress, whereas the increase in E was not observed in V1bR−/− mice. These results suggest that the V1b receptor regulates stress-induced catecholamine release. Because it has been suggested that arginine-vasopressin (AVP) is related to the development of depression, we also evaluated immobility time in the forced swimming test, and we found no significant change in V1bR−/− mice. Taken together, these findings suggest that, in addition to the previously elucidated effect on the hypothalamic-pituitary-adrenal axis, vasopressin activity via V1b receptors regulates stress-induced catecholamine release.

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated usingseveral pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partialagonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.

We have shown that 48-h fasting suppresses luteinizing hormone (LH) secretion in female rats which is enhanced by an estrogenic milieu and mediated by noradrenergic neurons. A similar fasting protocol yielded a suppression of LH secretion in male rats in a testosterone-dependent manner. In this experiment, we intended to identify specific nuclei in the hypothalamus and caudal brainstem that are activated during fasting for 6, 24, 30 or 48 h in castrated male rats with or without chronic testosterone treatment. Fasting started at 1300 h (lights-off at 1900 h). In testosterone-treated castrates, Fos-like-immunoreactive (FL-ir) cells were significantly increased in the paraventricular nucleus, A2 region of the nucleus of the solitary tract, supraoptic nucleus and amygdala 6 h after the onset of fasting but not 24, 30 or 48 h after the onset. On the other hand, FL-ir cells were not significantly different in those areas among fasted castrates compared with unfasted controls. In the A2 region of testosterone-treated castrates, tyrosine hydroxylase- and dopamine-β-hydroxylase-immunoreactive (TH-ir, DBH-ir) cells did not exhibit Fos-like immunoreactivity (FLI). Our results suggest that the absence of food may activate neurons in discrete hypothalamic and brainstem nuclei in male rats at the beginning of fasting and this activation requires an androgenic milieu. The absence of FLI in TH- or DBH-ir cells in the A2 region would indicate that transmitter systems other than catecholaminergic neurons may be involved during the very early stage of 48-h fasting-induced suppression of LH secretion.

We have previously shown that 48-h fasting profoundly suppresses pulsatile LH secretion in female rats in the presence of estrogen, and that the paraventricular nucleus (PVN) is an estrogen action site mediating this inhibition. The present study determined whether fasting suppresses pulsatile LH secretion in male rats in a testosterone-dependent manner, and whether the PVN is involved in the fasting-induced changes in pulsatile LH release. Mean LH concentrations and baseline levels of LH pulses were significantly reduced by 48-h fasting in castrated males implanted with various length (6, 12, and 24 mm) of subcutaneous testosterone implants. LH pulse frequency was significantly lower in fasted rats with a 24-mm testosterone implant compared with unfasted controls. On the contrary, mean LH levels and the amplitude and baseline of LH pulses were significantly increased by fasting in castrated rats without testosterone treatment. PVN lesions partially blocked the inhibitory effect of fasting on LH release in the testosterone-implanted rat model. In addition, local implantation of testosterone or estradiol into the PVN reversed fasting-induced increase in both mean LH levels and the pulse amplitude in castrated males, but did not cause a further suppression of these pulse parameters. These results suggest that testosterone is required to suppress LH pulses during fasting in the male rat. The PVN may mediate, at least partly, the fasting-induced inhibition of LH secretion, and is not the single steroid feedback site mediating the fasting-induced suppression of LH secretion in the male.

The effect of total subdiaphragmatic vagotomy on estrogen-receptor immunoreactivity (ERIR) in the paraventricular nucleus (PVN) and nucleus of the solitary tract (NTS) was examined in fasted ovariectomized rats to clarify the peripheral inputs mediating fasting-induced increase in ERIR in these two nuclei. Vagotomy abolished the effect of 48-h fasting on the expression of ER in these two areas. The result indicates that the neural signal(s) that increase the expression of ER in the PVN and A2 region of the NTS following 48-h fasting is transmitted through the vagus. The involvement of the vagus in the fasting-induced increase in ER in the PVN and A2 region may also be the same neural pathway involved in the suppression of pulsatile luteinizing hormone secretion in fasted female rats.

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56 nM), the 5-HT(1A) receptor (IC(50)=2.3 nM), and the 5-HT transporter (IC(50)=80 nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27 nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27 mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.

The present study examined the effect of 48-h fasting and 1-h immobilization on estrogen receptor immunoreactivity in selected hypothalamic areas and the nucleus of the solitary tract (NTS) in ovariectomized rats. Fasting induced an increase in ER-immunoreactive cells in the paraventricular nucleus (PVN), periventricular nucleus (PeVN) and NTS compared with the unfasted control group. Similarly, immobilization caused an increase in ER-positive cells in the same areas, PVN, PeVN and NTS, versus the non-immobilized group. There was no significant increase in the number of ER-immunoreactive cells in the preoptic area (POA), arcuate nucleus (ARC) or ventromedial hypothalamic nucleus (VMH) following fasting and immobilization. Our previous work in ovariectomized rats with estrogen microimplants in the brain revealed that the PVN and A2 region of the NTS are the feedback sites of estrogen in activating the neural pathway to suppress pulsatile LH secretion during 48-h fasting. The result in the food-deprived rats suggests that estrogen modulation of the suppression of LH secretion during fasting is partly due to the increase in estrogen receptors in the PVN and A2 region. The physiological significance of the increase in neural ER following immobilization remains to be elucidated.