Magnetic Resonance Spectroscopy in the Ventral Tegmental Area Distinguishes Responders to Suvorexant Prior to Treatment: A 4-Week Prospective Cohort Study.

Background: The ventral tegmental area (VTA; a dopaminergic nucleus) plays an important role in the sleep-wake regulation system including orexin system. In addition to neuronal activity, there is increasing evidence for an important role of glial cells (i.e., astrocytes and microglia) in these systems. The present study examined the utility of magnetic resonance spectroscopy (MRS) for detecting neural and/or glial changes in the VTA to distinguish responders from non-responders before treatment with the orexin receptor antagonist suvorexant. Methods: A total of 50 patients were screened and 9 patients were excluded. The remaining 41 patients with insomnia who have or not a psychiatric disease who were expected to receive suvorexant treatment were included in this study. We compared MRS signals in the VTA between responders to suvorexant and non-responders before suvorexant use. Based on previous reports, suvorexant responders were defined as patients who improved ≥3 points on the Pittsburgh Sleep Quality Index after 4 weeks of suvorexant use. MRS data included choline (reflects non-specific cell membrane breakdown, including of glial cells) and N-acetylaspartate (a decrease reflects neuronal degeneration). Results: Among 41 examined patients, 20 patients responded to suvorexant and 21 patients did not. By MRS, the choline/creatine and phosphorylcreatine ratio in the VTA was significantly high in non-responders compared with responders (p = 0.039) before suvorexant treatment. There was no difference in the N-acetylaspartate/creatine and phosphorylcreatine ratio (p = 0.297) between the two groups. Conclusions: Changes in glial viability in the VTA might be used to distinguish responders to suvorexant from non-responders before starting treatment. These findings may help with more appropriate selection of patients for suvorexant treatment in clinical practice. Further, we provide novel possible evidence for a relationship between glial changes in the VTA and the orexin system, which may aid in the development of new hypnotics focusing on the VTA and/or glial cells.

Psychosis in a primary hyperparathyroidism patient with mild hypercalcemia: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. PATIENT CONCERN: Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). DIAGNOSIS: She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. INTERVENTIONS: Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. OUTCOMES: Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. CONCLUSION: We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

Real-World Preventive Effects of Suvorexant in Intensive Care Delirium: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown. METHODS: A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay. RESULTS: There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013). CONCLUSIONS: The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

Low Serum Levels of Fibroblast Growth Factor 2 in Gunn Rats: A Hyperbilirubinemia Animal Model of Schizophrenic Symptoms.

BACKGROUND: Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons. METHOD: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. RESULTS: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. CONCLUSION: Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.

Parvalbumin-positive GABAergic interneurons deficit in the hippocampus in Gunn rats: A possible hyperbilirubinemia-induced animal model of schizophrenia.

A reduction of GABAergic markers in postmortem tissue is consistently found in schizophrenia. Importantly, these alterations in GABAergic neurons are not global, which means they are more prevalent among distinct subclasses of interneurons, including those that express the calcium binding protein parvalbumin. A decreased expression of parvalbumin in the hippocampus is a consistent observation not only in postmortem human schizophrenia patients, but also in a diverse number of rodent models of the disease. Meanwhile, previously we reported that the congenital hyperbilirubinemia model rats (Gunn rats), which is a mutant of the Wistar strain, showed behavioral abnormalities, for instance, hyperlocomotor activity, deficits of prepulse inhibition, inappropriate social interaction, impaired recognition memory similar with several rodent models of schizophrenia. Several animal studies linked the importance of palvalbumin in relation to abnormal hippocampal activity and schizophrenia-like behavior. Here, we show that parvalbumin positive cell density was significantly lower in the CA1, CA3 and the total hippocampus of Gunn rats (congenital hyperbilirubinemia model rats) compared to Wistar control rats. The correlations between serum UCB levels and loss of PV expression in the hippocampus were also detected. The decreases in the PV-expression in the hippocampus might suggest an association of the behavioral abnormalities as schizophrenia-like behaviors of Gunn rats, compared to the Wistar control rats.

Electroconvulsive shock restores the decreased coverage of brain blood vessels by astrocytic endfeet and ameliorates depressive-like behavior.

BACKGROUND: Although growing evidence indicates that ECT affects astrocytes, the exact mechanisms of the therapeutic effect of ECT are still unknown. Astrocytic endfeet express the water channel aquaporin (AQP) 4 abundantly and ensheath brain blood vessels to form gliovascular units. It has been shown that the coverage of blood vessels by AQP4-immunostained endfeet is decreased in the prefrontal cortex (PFC) of patients with major depression. This study was made to determine whether ECT restores the astrocytic coverage of blood vessels with amelioration of depressive symptoms. METHODS: After electroconvulsive shock (ECS) administration to rats, the forced swimming test (FST) and Y-maze test were performed. Subsequently, immunofluorescence analysis was conducted to measure the coverage of blood vessels by astrocytic endfeet in the PFC and hippocampus by using the endothelial cell marker lectin and anti-AQP4 antibody. We also performed Western blot to examine the effects of ECS on the hippocampal expression of AQP4 and the tight junction molecule claudin-5. RESULTS: Gunn rats showed learned helplessness and impaired spatial working memory, compared to normal control Wistar rats. ECS significantly improved the depressive-like behavior. Gunn rats showed a decrease in astrocytic coverage of blood vessels, that was significantly increased by ECS. ECS significantly increased expression of AQP4 and claudin-5 in Gunn rats. CONCLUSIONS: ECS increased the reduced coverage of blood vessels by astrocytic endfeet in the mPFC and hippocampus with amelioration of depressive-like behavior. Therefore, therapeutic mechanism of ECT may involve restoration of the impaired gliovascular units by increasing the astrocytic-endfoot coverage of blood vessels.

Clostridium butyricum MIYAIRI 588 as Adjunctive Therapy for Treatment-Resistant Major Depressive Disorder: A Prospective Open-Label Trial.

AIM: Up to 60% of depressed patients do not obtain sufficient relief from a course of antidepressant therapy, and these treatment-resistant major depressive disorder (TRD) patients are at increased risk for relapse, chronicity, persistent psychosocial impairments, and suicide. Probiotics actively participate in treatment of neuropsychiatric disorders. However, the role of gut microbiota in brain disorders and depression remains unclear. We performed a prospective study to evaluate the effects of Clostridium butyricum MIYAIRI 588 (CBM588). METHODS: This was an 8-week open-label study to evaluate the efficacy and safety of CBM588 in combination with antidepressants in adult patients diagnosed with TRD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Forty antidepressant-treated inpatients were included. Patients were randomized to adjuvant treatment with CBM588 (n = 20) or control (n = 20). The primary endpoint was the change in the 17-item Hamilton Depression Rating Scale score from baseline to week 8. Secondary end points were changes in the Beck Depression Inventory and the Beck Anxiety Inventory scale scores from baseline to week 8. The Systematic Assessment of Treatment Emergent Events-General Inquiry was used to assess adverse effects. RESULTS: CBM588 (60 mg/d) in combination with antidepressants (flvoxamine, paroxetine, escitalopram, duroxetine, and sertraline) provided significant improvement in depression. All patients completed the trial, and 70% responded to treatment; the remission rate was 35.0%. No serious adverse events occurred. CONCLUSIONS: These preliminary data suggest that CBM588 in combination with antidepressants is effective and well tolerated in the treatment of TRD. Further studies using a larger, double-blind, parallel-group design are warranted to confirm these findings.

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test.

INTRODUCTION: Recent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia-like behavior. METHODS: As it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression-like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium-binding adaptor molecule (Iba) 1 and the astrocytic marker S100B. RESULTS: Both the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression-like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1-positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B-positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats. CONCLUSION: Our findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

Aceruloplasminemia With Psychomotor Excitement and Neurological Sign Was Improved by Minocycline (Case Report).

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin gene. Its prevalence is 1 in 2,000,000 people in Japan. This is a disorder of neurodegeneration with iron accumulation in the brain revealed by MRI. The iron overload induces oxidative stress and generation of reactive oxygen species, which triggers a cascade of pathological events that lead to neuronal death. Intravenous administration of an iron chelator, deferoxamine has been proposed as a method of inhibiting the accumulation of iron.The patient was a 46-year-old Japanese woman. She was diagnosed at the age of 33 years. Deferoxamine was administrated for 6 months but was discontinued due to adverse effects. On admission at the age of 46, psychomotor excitement was acute in onset. The extrapyramidal symptoms reflected iron deposition in the basal ganglia and substantia nigra in the midbrain. Ataxia and a wide-based gate reflected iron deposition in the dentate nuclei of the cerebellum. An antibiotic, minocycline at 150 mg/day successfully ameliorated the clinical symptoms.Minocycline, a second generation tetracycline, has a direct radical scavenging property due to its chemical structure. It has been reported that minocycline is similar to deferoxamine in its ability to chelate iron. Minocycline is also involved in preventing the upregulation of proinflammatory cytokines. The iron-chelating, antioxidant, and anti-inflammatory effects of minocycline were involved in this case.

Treatment of Paroxysmal Perceptual Alteration in Catatonic Schizophrenia by Switching to Aripiprazole from Risperidone: A Case Report.

Paroxysmal perceptual alteration (PPA) is the occurrence of brief and recurrent episodes of perceptual changes. It is mainly caused by the treatment of schizophrenia patients with antipsychotics. However, diagnosis of PPA is not very prevalent among psychiatrists, partly due to underrecognition or misunderstanding that it is a worsening of psychiatric symptoms. If psychiatrists do not understand PPA, they cannot treat it appropriately, and the patient's quality of life is impaired. We present a case of PPA in catatonic schizophrenia that was successfully treated by switching to aripiprazole from risperidone. We suggest that the disappearance of PPA in our case was due to both discontinuing risperidone, which completely blocks D2 receptors, and replacing it with aripiprazole, which is characterized as a partial agonist of D2 receptors. Treatment of PPA will improve medication adherence and quality of life. It is important to recognize PPA as a possible side effect of treatment with antipsychotics.

Simple and rapid detection of HLA-A*31:01 for prediction of carbamazepine-induced hypersensitivity using loop-mediated isothermal amplification method.

BACKGROUND: Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01. OBJECTIVE: To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population. METHODS: A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01. RESULTS: The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results. CONCLUSION: High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs.

The effects of combine treatment of memantine and donepezil on Alzheimer's disease patients and its relationship with cerebral blood flow in the prefrontal area.

BACKGROUND: In this study, we evaluated the effect on cognitive function of memantine, behavioral and psychological symptoms of dementia, and the care burden, in patients with moderate-to-severe Alzheimer's disease (AD). Furthermore, with near-infrared spectroscopy (NIRS), we examined the association between effect of memantine and brain blood flow. METHODS: We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24. RESULTS: Significant difference was found between the combination group and the control group in the score variation of Clinical Global Impression-Improvement scale, MMSE, CDT, NPI, and J-ZBI. In the NIRS measurements, trend oxyhemoglobin reduced suppression was observed in some channels centered on the superior frontal gyrus. A significant correlation was observed in the scores of MMSE, CDT, NPI, and J-ZBI. In addition, a significant positive correlation was also observed between the number of words in NIRS and scores of MMSE and CDT. CONCLUSIONS: In this study, by administering memantine in AD patients that inhibit the reduction of cerebral blood flow in the prefrontal area and improve clinical symptoms overall cognitive function, behavioral and psychological symptoms of dementia, thereby reducing the care burden of caregivers was suggested.

Yi-gan san for treatment of charles bonnet syndrome (visual hallucination due to vision loss): an open-label study.

BACKGROUND: Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese) may be safe and useful for treating behavioral and psychological symptoms in dementia, borderline personality disorder, neuroleptic-induced tardive dyskinesia, and treatment-resistant schizophrenia. Visual hallucinations are common and often distressing consequences of vision loss, particularly in age-related macular degeneration. Charles Bonnet syndrome (CBS) is defined by the triad of complex visual hallucinations, ocular pathology causing visual deterioration, and preserved cognitive status. We aimed at evaluating both the efficacy and safety of YGS in patients with CBS. METHODS: Twenty patients diagnosed with CBS were investigated, according to the diagnostic criteria established by Gold and Rabins and Teunisse. Participants were treated in a 4-week open-label study with YGS at an average daily dose of 5.8 ± 2.6 g (2.5-7.5 g). Psychometric instruments used to assess efficacy included the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression. No cases of serious adverse events were attributed to the study's drug therapy. RESULTS: A significant decrease in visual hallucination was observed at 2 and 4 weeks in the Neuropsychiatric Inventory, hallucination subscale of the Positive and Negative Syndrome Scale, and Clinical Global Impression scores. CONCLUSIONS: Yi-gan san may be an effective and safe therapy to control visual hallucination in patients with CBS and should be further tested in double-blind, placebo-controlled trials. Given the design characteristics of this trial, the present findings should be taken cautiously.