Can brexpiprazole be switched safely in patients with schizophrenia and dopamine supersensitivity psychosis? A retrospective analysis in a real-world clinical practice.

BACKGROUND: Several studies have reported that a switch to the dopamine partial agonist (DPA) aripiprazole (ARP), especially when the switch is abrupt, is likely to fail and sometimes worsen psychosis in schizophrenia patients already under high-dose antipsychotic treatment. Such a switching failure is speculated to be related to be the dopamine supersensitivity state. The risks of switching to the DPA brexpiprazole (BREX) have not been reported. AIMS AND METHODS: We retrospectively analyzed the cases of 106 patients with schizophrenia to identify any factors related to the success or failure of switching to BREX. RESULTS: The comparison between the patients with dopamine supersensitivity psychosis (n = 44) and those without (n = 62) revealed no significant difference in the switching failure judged at the sixth week. A comparison of the patients with successful switching (n = 80) and those who failed (n = 26) revealed that patients with treatment-resistant schizophrenia (TRS) were significantly more likely to fail. A logistic regression analysis also revealed that patients with past failure of switching to ARP are likely to succeed in switching to BREX. The 2-year follow-up of the patients with successful switching to BREX suggested that the patients who were treated with BREX, even temporarily, experienced some improvement in their Global Assessment of Functioning and Clinical Global Impression-Severity scores. CONCLUSIONS: Overall, the results indicate that patients with schizophrenia can be switched more safely to BREX compared to ARP. However, the failure of switching to BREX could be higher in patients with TRS, and thus, starting BREX treatment in refractory patients warrants careful monitoring.

Molecular characterization of oriental eyeworm (Thelazia callipaeda) detected from raccoon (Procyon lotor) and Japanese raccoon dog (Nyctereutes viverrinus) in Kanto region, Japan.

BACKGROUND: The oriental eyeworm Thelazia callipaeda (Spirurida: Thelaziidae) is an emerging parasitic ocular nematode of carnivores and humans. In domestic animals and humans, the infection causes varying degrees of inflammation and lacrimation, and wild carnivores represent an important reservoir. In this study we examined the infection status and molecular characterization of T. callipaeda in two urban carnivores, raccoons Procyon lotor and wild Japanese raccoon dogs Nyctereutes viverrinus, in the Kanto region of Japan. METHODS: From January 2020 to December 2021, 193 carcasses including 178 raccoons and 15 raccoon dogs were examined for the presence of worms in the eye. The worms from infected animals (one worm per host) were morphologically identified as T. callipaeda. Worms (1-5 worms per host) were subjected to genetic analysis using mitochondrial cytochrome c oxidase subunit I gene sequences. RESULTS: The prevalence of T. callipaeda in raccoons and Japanese raccoon dogs was 20.2% (36/178) and 13.3% (2/15), respectively. The cox1 sequences from 56 worms from 38 animals revealed three haplotypes (h9, h10, and h12). Analysis of multiple worms for five raccoons showed co-infection of two different haplotypes (h9 and h10) in a single host. Comparing our data with published sequences, three sequences obtained from raccoons and raccoon dogs shared the same haplotypes as those reported in humans, dogs, and cats in Japan. CONCLUSIONS: Our findings show a high prevalence of T. callipaeda in raccoons, suggesting that this invasive carnivore species serves as an important natural reservoir of T. callipaeda in the Kanto region of Japan, an area with the highest human population of the country.

Dopamine supersensitivity psychosis and delay of clozapine treatment in patients with treatment-resistant schizophrenia.

Both the underutilization of clozapine and treatment resistance of patients to clozapine are serious problems worldwide. Identifying clinical markers predicting response to clozapine would help clinicians more effectively utilize clozapine treatment. The present study retrospectively assessed dopamine supersensitivity psychosis (DSP) in addition to other measures such as age at disease onset and delay of clozapine introduction for a total of 47 treatment-resistant schizophrenia (TRS) patients. The response to clozapine was judged with CGI-C at 1 and 2 years from clozapine introduction. Results revealed that the DSP group tended to have a longer delay between designation of TRS and introduction of clozapine and continued to have slightly more severe psychopathology after treatment with clozapine, showing only slight improvement. The logistic regression analysis showed that the age at disease onset was the only significant indicator, predicting responsiveness to clozapine: patients with an onset age <20 years had a significantly better response to clozapine than patients with an onset age ≥20 years. The present study suggests that DSP might be related to a longer delay in clozapine introduction and the persistence of refractory symptoms despite clozapine treatment, whereas early age of disease onset might be related to a better response to clozapine.

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia.

Background: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. Patients and methods: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). Results: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. Conclusion: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia.

BACKGROUND: GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. METHODS AND RESULTS: In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. CONCLUSIONS: Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.

Body Length and Craniometrics of Non-Native Raccoons in Two Regions in Middle Japan during Early Invasion Stages.

Although the genetic distribution of introduced raccoons (Procyon lotor) in recent years is well known, few studies have examined their morphometrics, especially the relationships between sex and age in the introduced populations. The aim of this study was to describe the morphological characteristics of raccoons from parts of eastern and western Japan during their early invasion stages, focusing on the relationships between body length and the principal component of craniometrics, with region, sex, age class, body length, and body mass index using a regression model. The body length increased more in males than females and in the older age class, supporting the association with intrasexual selection and competition for food resources. Positive relationships for body length and body mass index were found in craniometric analyses, particularly regarding cranial size components, in addition to age class for both sexes, while cranial size also differed between regions for females. The relationship between body length and craniometrics was inconsistent with that of subspecies originating in North America. Given the sympatric distribution of haplotypes of multiple subspecies without reproductive-isolating barriers in North America and in several introduced areas, hybridization must have occurred prior to the introduction or naturalization of this species.

Prevalence and Molecular Characterization of the Zoonotic Enteric Protozoans Cryptosporidium spp., Enterocytozoon bieneusi, and Blastocystis from Pallas's Squirrels (Callosciurus erythraeus) in Kanagawa Prefecture, Japan.

Pallas's squirrel (Callosciurus erythraeus) was introduced in Japan in the 1930s and has since established itself in several areas across the country. Although wild Sciuridae populations have been demonstrated to be potential reservoirs for zoonotic enteric protozoa, epidemiological studies of such pathogens in Japan are scarce. Here, we examined 423 fecal samples from Pallas's squirrels captured in Kanagawa Prefecture, Japan, using PCR and DNA sequencing to determine the occurrence of Cryptosporidium spp., Enterocytozoon bieneusi, and Blastocystis. The overall prevalence of Cryptosporidium spp., E. bieneusi, and Blastocystis was 4.3% (18/423 samples), 13.0% (55/423 samples), and 44.0% (186/423 samples), respectively. The prevalence of Blastocystis and E. bieneusi was significantly higher in spring (60.1% and 17.4%, respectively) than in winter (27.6% and 8.6%, respectively [P < 0.01]). Sequence analysis of Cryptosporidium spp., targeting the partial small subunit ribosomal RNA gene (SSU rDNA), showed 100% identity (541/541 bp) to Cryptosporidium ubiquitum, and analysis of the gp60 gene showed 99.76% (833/835 bp) identity to C. ubiquitum subtype XIIh. The sequences of the ribosomal internal transcribed spacer region of E. bieneusi and the partial SSU rDNA of Blastocystis were identified as E. bieneusi genotype SCC-2 and Blastocystis subtype 4, respectively. This study confirmed the presence of C. ubiquitum, E. bieneusi, and Blastocystis in Pallas's squirrels in Kanagawa Prefecture. Because Pallas's squirrels inhabit urban areas, living close to humans, the species may serve as a potential source of infection in human populations. IMPORTANCE Pallas's squirrel is designated a "regulated organism" under the Invasive Alien Species Act in Japan, and municipal authorities are introducing control measures to reduce its populations. It has been suggested that wild mammals may play a role in contaminating the environment with zoonotic pathogens. The present study detected the enteric pathogens Cryptosporidium ubiquitum, Enterocytozoon bieneusi, and Blastocystis in the feces of Pallas's squirrels inhabiting Kanagawa Prefecture, Japan. These pathogens persist in the environment and contaminate soils and water, which may potentially infect humans. Because Pallas's squirrels in Kanagawa Prefecture are found in urban areas, where they are in close contact with human populations, continued monitoring of zoonotic diseases among squirrel populations will be important for evaluating the significance of wildlife in pathogen transmission.

Pharmacological profiles of the novel analgesic M58996 in rat models of persistent and neuropathic pain.

We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.

Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats.

M58373, 4-[2-(4-hydroxy-4-{[N-(4-isopropoxyphenyl)-N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1-10 microM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3-10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1-10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10-100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.

Analgesic properties of the novel compound M43068 in rat models of acute and neuropathic pain.

We investigated the effects of 2-(4-hydroxybenzoyl)amino-2-methylpropionic acid (M43068), a novel analgesic agent, in rat models of acute and neuropathic pain. Oral M43068 (10-100 mg/kg) suppressed only the late phase of formalin-induced nociceptive behaviors. In the neuropathic pain model, oral M43068 (10-100 mg/kg) suppressed mechanical allodynia in the nerve-injured paw without affecting normal thresholds. On the other hand, i.v. M43068 (30 mg/kg) mainly suppressed the Abeta-fiber-mediated response with the Neurometer. I.c.v. pretreatment with the alpha1-adrenoceptor antagonist, prazosin, or i.p. pretreatment with the gamma-aminobutyric acid (GABA)B receptor antagonist, saclofen, abolished the M43068-induced antinociception. However, oral M43068 (30-300 mg/kg) had no influence on blood pressure and motor function, unlike the alpha1-adrenoceptor and the GABAB receptor agonists. These data indicate that M43068 shows antinociceptive and anti-allodynic effects with reduced risks of side effects. It is suggested that the descending noradrenergic system is involved in the analgesic effects of M43068.