Neutrophil-Lymphocyte Ratio in Patients With Acute Schizophrenia.

Introduction Schizophrenia symptom severity is linked to neuroinflammation. Certain blood cell indexes such as neutrophil-lymphocyte ratio (NLR) and neutrophil-albumin ratio (NAR) have been used as biomarkers in various diseases, including schizophrenia. In acute clinical practice, it is challenging to decide whether to provide intravenous antipsychotic treatment in some cases due to the lack of objective biomarkers of psychiatric symptoms. The NLR of individuals with schizophrenia is thought to be associated with disease severity, and changes in NLR may reflect a patient's response to antipsychotic treatment. We investigated the application of NLR as a biomarker for identifying acute severity and determining acute treatment response in patients with schizophrenia. Methods We retrospectively examined 251 inpatients diagnosed with schizophrenia and classified them according to treatment (intravenous haloperidol vs. oral antipsychotic medication during the acute phase) and investigated their NLR and NAR while receiving inpatient care. Results A total of 48 inpatients were given intravenous haloperidol to manage their acute symptoms; 208 were given oral antipsychotics. The intravenous haloperidol group experienced more severe symptoms, such as agitation and disorganized thinking, during the acute phase. Further, those who received intravenous haloperidol had significantly higher Clinical Global Impression-Severity (CGI-S) scores than the oral antipsychotic group. NLR and NAR were also significantly higher in the haloperidol intravenous group. Conclusion Elevated NLR and NAR could be easily measured in patients with psychomotor agitation who should be treated at any facility. Further, they are useful biomarkers for determining disease severity and the effects of treatment on psychomotor excitement in patients who require intravenous haloperidol.

Effects of Parity and Postpartum Depression on Mother-Infant Bonding in the First Month Postpartum: A Retrospective Study.

Objective This study aimed to examine the relationship between parity, postpartum depression (PPD), and mother-infant bonding (MIB) failure in the first month postpartum. Methods The study included 1,509 Japanese patients (748 primiparous and 761 multiparous). MIB was assessed using the Mother-to-Infant Bonding Scale Japanese version (MIBS-J), which was translated in 2012, and its subscales, including lack of affection (LA) and anger and rejection (AR). Postpartum depression (PPD) was assessed using the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) and its subscales, including anxiety (ANX), anhedonia (ANH), and depression (DEP). Multiple regression analyses using interaction terms were performed to examine the association of parity with the MIBS-J and EPDS. Results Parity was significantly associated with AR. ANX and ANH were strongly associated with LA, and ANX and DEP were strongly associated with AR. The interaction term "parity×EPDS total" was significantly associated with MIBS-J total, LA, and AR scores. Conclusions Primiparas and mothers with high ANX had more negative emotions toward their children during the first month postpartum, and mothers with high ANX or ANH had less interest in their children.

Efficacy and safety of lemborexant as an alternative drug for patients with insomnia taking gamma-aminobutyric acid-benzodiazepine receptor agonists or suvorexant.

BACKGROUND: Although gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor agonists are used to treat insomnia, their long-term or high-dosage use causes adverse events. Nevertheless, evidence regarding the discontinuation and replacement of GABA-BZ receptor agonists with alternative agents is lacking. Suvorexant (SUX), an existing orexin receptor antagonist, is effective in preventing nocturnal awakening in 70%-75% of patients with insomnia. METHODS: The novel dual orexin receptor antagonist lemborexant (LEM) has fewer adverse effects than GABA-BZ receptor agonists. Therefore, in this retrospective study, we categorised patients taking GABA-BZ receptor agonists and SUX into LEM-treated (switched) and non-treated (non-switched) groups and compared their outcomes over a 12-week period. RESULTS: The GABA-BZ group (N = 59) comprised 34 'switched' and 25 'non-switched' and the SUX group (N = 14) comprised 6 'switched' and 8 'non-switched' patients. A mixed model showed a significant diazepam equivalence reduction in patients taking GABA-BZ receptor agonists and improved Athens Insomnia Scale score in those taking SUX. The safety and tolerability of GABA-BZ receptor agonists and SUX were high, and no serious adverse effects were observed after switching to LEM. CONCLUSIONS: Lemborexant may be a useful alternative for long-term GABA-BZ receptor agonist users. For SUX, the number of cases (N = 6) was insufficient to draw definite conclusions.

Effectiveness of change from suvorexant to lemborexant drug in the treatment of sleep disorders.

BACKGROUND: This study aimed to examine the effects of a change in medication from suvorexant to lemborexant among patients with insomnia. METHODS: Patients with chronic insomnia who had persistent insomnia for 3 months or longer and who had been taking suvorexant for 3 months or longer were selected. The participants were divided into two groups: the 'modified' group and the 'non-modified' group. Four sub-types of insomnia (i.e., difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep) were investigated. Logistic regression was used to investigate improvements in both the groups after 12 weeks. RESULTS: Among the 77 participants, 43 and 34 patients were in the modified drug group and the non-modified drug group, respectively. Comparing sleep disorders between the two groups, we found significant improvement after 12 weeks in the modified drug group in terms of difficulty initiating sleep, compared with the non-modified drug group (odds ratio = 0.036, P = 0.008, 95% CI = 0.003-0.415). However, no significant differences were found between the two groups in terms of difficulty maintaining sleep, early-morning awakening, and non-restorative sleep. CONCLUSIONS: Sleep disorders can be treated by alleviating difficulties in initiating sleep by changing from suvorexant to lemborexant. In addition, it was confirmed that the drug change caused no serious side effects and that it was highly safe and tolerated.

Risk factors for readmission in schizophrenia treated with combined psychoeducation and standard therapy.

BACKGROUND: We conducted a historical cohort study of patients with schizophrenia to identify more robust risk factors at discharge that contribute to readmission within a year. METHODS AND FINDINGS: The subjects underwent brief psychoeducation during hospitalization. Multivariate analysis was conducted using factors selected in the univariate analysis. Using logistic regression analysis, the number of hospital admissions (P = .01) and Schedule for Assessment of Insight Japanese version score (P = .04) were identified as risk factors for readmission, with odds ratios of 0.70 and 1.18, respectively. CONCLUSIONS: These results suggest that improvement in insight and early intervention may lead to a more stable community life.

Use of Suvorexant and Antipsychotics in the Treatment of Delirium After Infectious Diseases: A Retrospective Study.

BACKGROUND: Delirium is often treated on a subjective basis and per the discretion of the attending physician because of a lack of pharmacological evidence in the literature. To address this knowledge gap, we aimed to examine the efficacy of a hypnotic drug, suvorexant, as a therapeutic agent for the treatment of delirium. METHODS: Fifty-seven patients were targeted. Of the 57 patients, 39 were in the subolexant group, 17 in the antipsychotic group, and 1 was taking antidepressants. The Delirium Rating Scale-Revised 98 was used to evaluate the symptoms of delirium before and 3 and 7 days after drug administration. In addition, the medical history, occurrence of adverse effects, white blood cell count, and C-reactive protein level of participants were examined. RESULTS: Both drugs exhibited therapeutic effects on delirium, but suvorexant had a more pronounced effect. Furthermore, the suvorexant group exhibited decreased levels of C-reactive protein, suggesting an anti-inflammatory effect. Suvorexant seems to improve the symptoms of inflammation-related delirium without any serious adverse effects, suggesting that it can be explored as a safe treatment option for clinical use in future studies. CONCLUSIONS: Our findings will be relevant for physicians interested in learning about new pharmacological treatment options and researchers interested in validating our results.

Asphyxia risk factors in adult psychiatric wards.

PURPOSE: To identify factors for choking in psychiatric wards that can be easily screened. DESIGN AND METHODS: Data were collected from patients admitted to the acute phase psychiatric wards who were assessed for swallowing function by dentists. We defined 47 and 102 patients of choking in the high- and low-risk groups, respectively. FINDINGS: Through multivariate analysis, we identified basal metabolic index and two Drug-induced Extra-pyramidal Symptoms Scale items, bradykinesia and tremor, as independent choking factors. PRACTICE IMPLICATIONS: Choking risk is related to patient tolerability rather than to the absolute severity of psychiatric symptoms or psychotropic dose.

Serum Anticholinergic Activity as an Index of Anticholinergic Activity Load in Alzheimer's Disease.

We reported a procedure of serum anticholinergic activity (SAA) measurement and the reliability and reproducibility of the receptor binding assay, and we also described the usefulness of SAA measurement reflecting the anticholinergic activity (AA) in the central nervous system (CNS). According to the results of a 10 times repeated measurement of standard atropine binding, the relative error was between -5.5 and +3.7%, and we considered that measurement of SAA in our studies is accurate and validated. Downregulation of acetylcholine activates inflammation in both CNS and peripheral tissue, which causes AA in both sites. Therefore, changes of AA in the CNS link with SAA in the peripheral system even if a substance having AA does not penetrate through the blood-brain barrier. Then we redescribe issues that require attention in the measurement of SAA. It is generally defined that any SAA greater than the detection limit of a quantitative atropine equivalent level (≥1.95 nM in our study) is positive. According to previous studies, SAA is considered to be positive when its atropine equivalent is ≥1.95 nM and undetectable when this is <1.95 nM. Nevertheless, as a low SAA can act as AA in the CNS, we should assume that SAA might also be positive if its marker concentration is between 0 and 1.95 nM. In addition, SAA should be measured around 11 a.m. or somewhat later because of the diurnal rhythm of cortisol in humans.

Hypothesis of Endogenous Anticholinergic Activity in Alzheimer's Disease.

In this article, we review and repropose our hypothesis of the endogenous appearance of anticholinergic activity (AA) in Alzheimer's disease (AD). First, we introduce our previous articles and speculate that, because acetylcholine (ACh) regulates both cognitive function and inflammation, downregulation of this neurotransmitter causes upregulation of the inflammatory system. AA then appears endogenously with the production of cytokines and the downregulation of ACh in AD. To support our hypothesis, we present a female AD patient whose AA was considered to occur endogenously through her AD pathology. Her serum anticholinergic activity (SAA) was positive at her first visit to our memory clinic, was negative at the 1-year and 2-year follow-up visits, and had become positive again by 3 years. We speculate that the initial positive SAA was related to her AD pathology plus mental stress, and that her SAA at 3 years was related to her AD pathology only. Consequently, we believe that 2 patterns of SAA positivity (and therefore AA) exist. One occurs when the downregulation of ACh reaches a critical level, and the other occurs with the addition of some other factor such as medication, induced illness or mental stress that causes AA to affect AD pathology. Finally, we consider the pharmacotherapy of AD based on the proposed hypothesis and conclude that cholinesterase inhibitors can be used to prevent rapid disease progression, whereas N-methyl-D-aspartate receptor antagonists should be reserved for the treatment of AD that is already in a stage of rapid progression. We also propose a staging schema for patients with AD.

Pharmacotherapy for Neurocognitive Disorders Based on the Hypothesis of Endogenous Appearance of Anticholinergic Activity.

We previously proposed the hypothesis of endogenous anticholinergic activity (AA) in Alzheimer's disease (AD). According to this hypothesis, the downregulation of acetylcholine seen in AD is associated with upregulation/hyperactivity of N-methyl-D-aspartate receptor (NMDAR). The hyperactivation of NMDAR then induces inflammation, which, in turn, causes AA to appear endogenously. Based on this hypothesis, we commented that cholinesterase inhibitors (ChEIs) are 'preventative' therapy for AD and NMDAR antagonists are the true 'treatment' for AD. We also noted that ChEIs, such as donepezil, could treat delirium. Moreover, we proposed measuring serum anticholinergic activity in patients, particularly AD patients, in out-of-hospital pharmacies to monitor the anticholinergic burden for targeted treatment.

A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium.

We have previously proposed a hypothesis in which we argue that anticholinergic activity (AA) appears endogenously in Alzheimer's disease (AD). Acetylcholine (ACh) controls both cognitive function and inflammation. Consequently, when the downregulation of ACh reaches critical levels, the inflammatory system is upregulated and proinflammatory cytokines with AA appear. However, factors other than downregulation of ACh can produce AA; even if ACh downregulation does not reach critical levels, AA can still appear if one of these other AA-producing factors is added. These factors can include neurocognitive disorders other than AD, such as delirium and Lewy body disease (LBD). In delirium, ACh downregulation fails to reach critical levels, but AA appears due to the use of medicines, physical illnesses or mental stress (termed 'AA inserts'). In LBD, we speculate that AA appears endogenously, even in the absence of severe cognitive dysfunction, for 2 reasons. One reason is that patterns of ACh deterioration are different in LBD from those in AD, with synergistic actions between amyloid and α-synuclein thought to cause additional or severe symptoms that accelerate the disease course. The second reason is that AA occurs through disinhibition by reduced cortisol levels that result from severe autonomic parasympathetic dysfunction in LBD.

Anticholinergic Activity and Schizophrenia.

In this article, we review the downregulation of acetylcholinergic activity in schizophrenia and discuss the similarity and difference between Alzheimer's disease (AD) and schizophrenia in terms of acetylcholine (ACh) and anticholinergic activity (AA); then, we propose the use of cognition-enhancing therapy for schizophrenia. As ACh regulates an inflammatory system, when the cholinergic system is downregulated to a critical level, the inflammatory system is activated. We consider the possibility that AA appears endogenously in AD and accelerates AD pathology. This hypothesis can also be applied to schizophrenia. In fact, even before the onset of the disorder, in the prodromal phase of schizophrenia, cognitive dysfunction exists, and antibodies against astrocyte muscarinic-1 and muscarinic-2 receptors are present in the serum of patients with the paranoid type of schizophrenia. Then we noted that the prodromal phase in schizophrenia might correspond to the mild stage in AD and the acute phase to moderate stage concerning AA. We also think that we should enhance cognition in schizophrenia even in the prodromal phase because as mentioned above, downregulation of ACh is prominent in schizophrenia even in the prodromal phase.

Demonstrating the Role of Anticholinergic Activity in a Mood Disorder.

We report a case of a 54-year-old woman presenting with amnesia, apathy, work-related difficulties and mental stress. At presentation, her Mini-Mental State Examination score was 27 and her serum anticholinergic activity (SAA) was positive without medication or recent physical illnesses. In addition, magnetic resonance imaging revealed mild atrophy of the frontal and temporal lobes, with a relatively intact hippocampus. Consequently, we diagnosed mild cognitive impairment due to Alzheimer's disease and prescribed a cholinesterase inhibitor (donepezil, 10 mg/day); her SAA fully disappeared and clinical symptoms partially resolved. Addition of duloxetine coupled with environmental adjustments caused her cognitive function to return to a normal level, so we diagnosed pseudodementia due to depression. In this case, we believe that the simultaneous cholinergic burden and mental stress led to positive SAA, which made it reasonable to prescribe a cholinesterase inhibitor to ameliorate the associated acetylcholine hypoactivity. We believe that it is essential to recognize the importance of prescribing a cholinesterase inhibitor for specific patients, even those with pseudodementia, to control their clinical symptoms. Moreover, SAA might be a useful biomarker for identifying this subgroup of patients. We propose that anticholinergic activity appears endogenously in mood disorders (depression and bipolar disorder) and set out our rationalization for this hypothesis.

Beyond the Hypothesis of Serum Anticholinergic Activity in Alzheimer's Disease: Acetylcholine Neuronal Activity Modulates Brain-Derived Neurotrophic Factor Production and Inflammation in the Brain.

The brain of Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of ß-amyloid protein, which leads to oxygen stress and inflammation. The active oxygen directly damages the neuron by increasing intracellular Ca(2+). The inflammation is due to activation of the microglia, thereby producing cytokines which inhibit the production of brain-derived neurotrophic factor (BDNF). As the BDNF acts by neuronal protection, synaptogenesis and neurogenesis, the reduction of BDNF in the brain of AD patients worsens the symptoms of AD. On the other hand, treatment of AD patients with a cholinesterase inhibitor enhances ACh activity and inhibits inflammation. Then the expression of BDNF is restored and neuroprotection reestablished. However, there are several reports which showed controversial results concerning the relationship between BDNF and AD. We speculate that BDNF is related to some neurocognitive process and reflects neuronal activity in other neurodegenerative and neuropsychiatric disorders and that in the mild cognitive impairment stage, BDNF and choline acetyltransferase (ChAT) activities are hyperactivated because of a compensatory mechanism of AD pathology. In contrast, in the mild stage of AD, BDNF and ChAT activity are downregulated.

Plasma Cholinesterase Activity in Alzheimer's Disease.

Cholinesterase inhibitors (ChEIs) are not allowed to be prescribed in combination, which means that we need to select 1 of 3 ChEIs for use in a patient with Alzheimer's disease (AD). However, there is no quantitative analysis on the differences between these agents. In this article, we propose that plasma cholinesterase activity (pChE) could be used as the standard for differentiating between rivastigmine (Riv) and donepezil (Don) in the management of AD. To date, we have treated 6 patients with Riv 18 mg and 5 patients with Don 5 mg. The pChE is related to low-grade inflammation associated with AD, diabetes mellitus and lipid metabolic dysfunction. Moreover, low pChE is related to liver dysfunction. The pChE must be kept under control. We speculated that Riv is the most appropriate therapy for patients with relatively high pChE, whereas Don is best reserved for those AD patients with relatively low pChE.

Assessment of Cognitive Dysfunction Caused by Anticholinergic Burden in Japanese Alzheimer's Disease Patients, Using the Most Commonly Used Scales in Japan.

Anticholinergic activity (AA) is generally thought to cause cognitive dysfunction, especially in Alzheimer's disease (AD), one of the neurocognitive disorders related to memory disturbances. Therefore, it is important to evaluate cognitive functions to determine whether they are associated with anticholinergic burden. In Japan, the most frequently used cognitive scale for evaluating cognitive functions is the revised version of Hasegawa's Dementia Rating Scale (HDS-R). However, the relationship between anticholinergic burden and cognitive functions has not been previously examined using the HDS-R. Therefore, here we used the HDS-R to evaluate the relationship between serum anticholinergic activity (SAA) and cognitive functions in 76 patients with AD, 26 of whom had positive SAA [SAA (+)] with a mean of 4.14 ± 2.70 nM. Total scores for orientations to time and place, registration, and recall were significantly lower in the SAA (+) group than in the SAA (-) group (P < 0.05), suggesting potential relationships between SAA and disorientations to time and place in current surroundings as well as memory disturbances. Thus, the disorientations to time and place might explain the clinical features of confusion in current surroundings caused by anticholinergic burden in AD.

P300 component of event-related potentials in persons with asperger disorder.

In the present study, we investigated auditory event-related potentials in adults with Asperger disorder and normal controls using an auditory oddball task and a novelty oddball task. Task performance and the latencies of P300 evoked by both target and novel stimuli in the two tasks did not differ between the two groups. Analysis of variance revealed that there was a significant interaction effect between group and electrode site on the mean amplitude of the P300 evoked by novel stimuli, which indicated that there was an altered distribution of the P300 in persons with Asperger disorder. In contrast, there was no significant interaction effect on the mean P300 amplitude elicited by target stimuli. Considering that P300 comprises two main subcomponents, frontal-central-dominant P3a and parietal-dominant P3b, our results suggested that persons with Asperger disorder have enhanced amplitude of P3a, which indicated activated prefrontal function in this task.

[A study of the rehabilitation support system for illegal substance use disorder patients from the viewpoint of the designated hospital. 4 case studies focusing on judicial treatment and drug urine monitoring].

This study was designed to reveal the current status of the rehabilitation support system for patients with Illegal Substance Use Disorder (ISUD). From among 465 patients who had been admitted to a psychiatric hospital in Tokyo within the past 10 years by order of the prefectural governor, 65 patients with ISUD were selected for inclusion in this study. Based on whether or not the person was arrested at the time of discharge, whether or not urine drug monitoring was ordered, and the results of the monitoring, each subject was classified into one of the following four types: 1) Arrested; 2) Not arrested and no urine drug monitoring; 3) Not arrested and positive urine drug monitoring results; and 4) Not arrested and negative urine drug monitoring results. In Group 1, every subject underwent urine drug monitoring prior to an involuntary examination; however, even though 10 percent of the subjects in this study were found to have positive results on urine drug monitoring, none of them were arrested. Moreover, 40 percent of the study subjects were not subjected to urine drug monitoring, and about 30 percent of non-arrested subjects were shown not to have used any illegal substances. Based on these results, it appears to be ideal for patients in Group 1 to apply to a diversion program, followed by medical treatment for addiction. To avoid the elimination of patients from medical services due to the vagueness of the classifications, whether or not judicial administration is required at the time of police intervention should be clearly and appropriately clarified for patients in Groups 2 and 3. Patients in Group 4 may experience a relapse of psychiatric symptoms, even if they do not use illegal substances; therefore, it is necessary for designated hospitals to perform medical treatment interventions responsibly for both endogenous psychosis and substance abuse, and to collaborate with appropriate social support facilities within the community regarding the medical discharge of such patients.

[Investigation of community support measures for patients with comorbid substance use disorder and psychotic disorder: nationwide survey of drug addiction rehabilitation centers].

In psychiatric care practice, patients are often seen who have difficulty with their social lives due to protracted psychiatric symptoms despite years without drug abuse. The difficulty of dealing with such cases and the lack of preparedness of the legal system leave circumstantial care as the only option. Western.countries have recently begun using the name 'concurrent disorder' as a diagnosis for patients deemed unable to recover solely through such treatment for drug addiction, signifying the presence of both a substance use disorder (SUD) and a mental health disorder. Various assessment and intervention methods are being investigated, and many studies have been reported. Based on the hypothesis that Drug Addiction Rehabilitation Center (DARC) are partly involved in supporting those with psychotic concurrent disorders (PSCD) in Japan, we conducted a survey to clarify the actual support for PSCD patients at DARC and the challenges they face. Surveys were administered to DARC-related institutions all over Japan (44 governing organizations and 66 institutions). Complete responses from 86 full-time employees and 445 DARC users were analyzed. DARC users were divided into two groups: psychiatric concurrent disorders (PSCD group, n = 178) and those without such symptoms (SUD group, n = 267), with the PSCD group accounting for 40% of the DARC users surveyed. Compared to the SUD group, the PSCD group was significantly less satisfied with their lifestyle and interpersonal relations at the DARC and a significantly higher proportion of the PSCD group requested assistance in communicating with others. When employees were presented with a hypothetical PSCD case and asked what was needed to deal with it, some responses were, "an institution that can treat both drug addiction and other mental health disorders," "a psychiatric care institution that provides 24-hour care," and "sufficient manpower and training." In the future, a treatment system must be established based on public medical institutions with a dedicated PSCD program that can provide medical care under legal observation.

Misalignments of rest-activity rhythms in inpatients with schizophrenia.

AIMS: Rest-activity rhythms of human beings generally synchronize to a 24-h time cue. Very few detailed research studies have examined rest-activity rhythms in patients with schizophrenia. The present study aimed to explore (i) rest-activity rhythms in patients with schizophrenia, and (ii) factors relevant to their rhythm characteristics. METHODS: We selected only inpatients for this research, because the time cue for inpatients was considered more standardized than that of outpatients. Sixteen inpatients with schizophrenia wore an ActiTrac accelerometer-based activity monitor (IM Systems Inc., Baltimore, USA) for eight consecutive days to measure their activity. We used a chi(2) periodogram to compute rest-activity rhythms from the activity data, whereby the chi(2) value amplitude was regarded as an index of regularity. We conducted non-parametric tests to identify factors relevant to rhythm cycles and patterns. RESULTS: Half of the participants exhibited prolonged rest-activity cycles, and 25% also had irregular rest-activity patterns defined by insufficient chi(2) value amplitude, even though they were clearly under a 24-h time cue. Participants with misaligned rest-activity rhythms had attended daytime non-medical treatment programs less frequently, and had received more anti-anxiety/hypnotic medications than those with proper rhythms. CONCLUSION: Changes in rest-activity rhythms by optimizing pharmacological and non-pharmacological treatment could improve social adjustment or quality of life in patients with schizophrenia.