Showa University East Hospital

The brain of Alzheimer's disease (AD) patients is characterized by neurodegeneration, especially an acetylcholine (ACh) neuronal deficit with accumulation of β-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.

Adult attention-deficit/hyperactivity disorder (ADHD) frequently leads to psychological/social dysfunction if unaddressed. Identifying a reliable biomarker would assist the diagnosis of adult ADHD and ensure that adults with ADHD receive treatment. Pupil diameter can reflect inherent neural activity and deficits of attention or arousal characteristic of ADHD. Furthermore, distinct profiles of the complexity and symmetricity of neural activity are associated with some psychiatric disorders. We hypothesized that analysing the relationship between the size, complexity of temporal patterns, and asymmetricity of pupil diameters will help characterize the nervous systems of adults with ADHD and that an identification method combining these features would ease the diagnosis of adult ADHD. To validate this hypothesis, we evaluated the resting state hippus in adult participants with or without ADHD by examining the pupil diameter and its temporal complexity using sample entropy and the asymmetricity of the left and right pupils using transfer entropy. We found that large pupil diameters and low temporal complexity and symmetry were associated with ADHD. Moreover, the combination of these factors by the classifier enhanced the accuracy of ADHD identification. These findings may contribute to the development of tools to diagnose adult ADHD.

Although behavioral studies have repeatedly demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) have deficits in alertness, little is known about its underlying neural basis. It is hypothesized that pupil diameter reflects the firing of norepinephrine (NE) neurons in the locus coeruleus (LC), and that the LC-NE neuromodulatory system for regulating alertness may be dysfunctional in ADHD. To clinically and non-invasively examine this hypothesis, we monitored the kinetics of pupil diameter in response to stimuli and compared them between adults with ADHD (n = 17) and typically developing (TD) adults (n = 23) during an auditory continuous performance task. Individuals in the ADHD group exhibited a significantly larger tonic pupil diameter, and a suppressed stimulus-evoked phasic pupil dilation, compared to those in the TD group. These findings provide support for the idea that the aberrant regulatory control of pupil diameter in adults with ADHD may be consistent with a compromised state of alertness resulting from a hyperactivated LC-NE system.

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.

Purpose: Generalized anxiety disorder (GAD) is among the most prevalent and highly disabling mental health conditions that negatively impacts patient’s quality of life (QOL) and disrupts activities of daily living. However, the recognition of GAD is difficult due to substantial overlap with other mental disorders. The purpose of this study was to estimate the prevalence of GAD, assess QOL of probable GAD patients in Japan, and gain insights on the status of visiting medical institutions as well as their recognition/awareness of the disorder. Patients and Methods: We conducted a web-based cross-sectional survey of 20,009 participants using a questionnaire with approximately 30 single/multiple choice or open-ended questions in Japanese. Results: Overall prevalence of GAD based on Generalized Anxiety Disorder 7-item (GAD-7) cutoff score of ≥ 10 and questionnaires developed with reference to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria was 7.6% (n=1530) and 6.0% (n=1197), respectively. The degree of coincidence between GAD diagnosis by DSM-5 criteria and GAD-7 scores was moderate (Cohen’s Kappa=0.47, p < 0.01). Younger people reported a substantially higher prevalence of GAD compared to older. QOL scores assessed using EuroQol 5 dimensions 5-level and EuroQol Visual Analog Scale were substantially lower in probable GAD patients than those with GAD-7< 10. Anxiety/depression and pain/discomfort were the most prevalent issues and depression was the most reported comorbidity for the probable GAD patients. Probable GAD patients “currently visiting medical institutions” for anxiety or other mental issues were 27.6% (422/1530); a majority had seen specialists. Most of the probable GAD patients had never heard of the disease. Conclusion: We found higher prevalence of GAD and lower QOL of probable GAD patients in Japan. There is a need for creating awareness about GAD among the general population and developing clinical guidelines on GAD in Japan so that physicians can educate their patients. Keywords: GAD-7, generalized anxiety disorder, Japan, prevalence, quality of life

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.

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.

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.

Locus coeruleus (LC) overactivity, especially in the right hemisphere, is a recognized pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and may be related to inattention. LC activity synchronizes with the kinetics of the pupil diameter and reflects neural activity related to cognitive functions such as attention and arousal. Recent studies highlight the importance of the complexity of the temporal patterns of pupil diameter. Moreover, asymmetrical pupil diameter, which correlates with the severity of inattention, impulsivity, and hyperactivity in ADHD, might be attributed to a left-right imbalance in LC activity. We recently constructed a computational model of pupil diameter based on the newly discovered contralateral projection from the LC to the Edinger-Westphal nucleus (EWN), which demonstrated mechanisms for the complex temporal patterns of pupil kinetics; however, it remains unclear how LC overactivity and its asymmetry affect pupil diameter. We hypothesized that a neural model of pupil diameter control featuring left-right differences in LC activity and projections onto two opponent sides may clarify the role of pupil behavior in ADHD studies. Therefore, we developed a pupil diameter control model reflecting LC overactivity in the right hemisphere by incorporating a contralateral projection from the LC to EWN and evaluated the complexity of the temporal patterns of pupil diameter generated by the model. Upon comparisons with experimentally measured pupil diameters in adult patients with ADHD, the parameter region of interest of the neural model was estimated, which was a region in the two-dimensional plot of complexity versus left-side LC baseline activity and that of the right. A region resulting in relatively high right-side complexity, which corresponded to the pathophysiological indexes, was identified. We anticipate that the discovery of lateralization of complexity in pupil diameter fluctuations will facilitate the development of biomarkers for accurate diagnosis of ADHD.

In addition to photic reflex function, the temporal behavior of the pupil diameter reflects levels of arousal and attention and thus internal cognitive neural activity. Recent studies have reported that these behaviors are characterized by baseline activity, temporal complexity, and symmetricity (i.e., degree of symmetry) between the right and left pupil diameters. We hypothesized that experimental analysis to reveal relationships among these characteristics and model-based analysis focusing on the newly discovered contralateral projection from the locus coeruleus (LC) to the Edinger-Westphal nucleus (EWN) within the neural system for controlling pupil diameter could contribute to another dimension of understanding of complex pupil dynamics. In this study, we aimed to validate our hypothesis by analyzing the pupillary hippus in the healthy resting state in terms of sample entropy (SampEn), to capture complexity, and transfer entropy (TranEn), to capture symmetricity. We also constructed a neural model embedded with the new findings on neural pathways. The following results were observed: first, according to surrogate data analysis, the complexity and symmetricity of pupil diameter changes reflect a non-linear deterministic process. Second, both the complexity and the symmetricity are unimodal, peaking at intermediate pupil diameters. Third, according to simulation results, the neural network that controls pupil diameter has an inverted U-shaped profile of complexity and symmetricity vs. baseline LC activity; this tendency is enhanced by the contralateral synaptic projections from the LCs to the EWNs. Thus, we characterized the typical relationships between the baseline activity and the complexity and symmetricity of the pupillometric data in terms of SampEn and TranEn. Our evaluation method and findings may facilitate the development of estimation and diagnostic tools for exploring states of the healthy brain and psychiatric disorders based on measurements of pupil diameter.

AIM: The purpose of this study was to examine the symptoms of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in the adult clinical population using the Autism-Spectrum Quotient (AQ) and the Adult ADHD Rating Scales self-report screening version (CAARS-S:SV). METHODS: We included 50 adults with ASD and 52 with ADHD diagnosed using the DSM-5 criteria. Clinical symptoms were evaluated using the AQ and CAARS-S:SV. RESULTS: The AQ score was elevated in the ADHD group and the CAARS scores were increased in the ASD group. Specifically, the total AQ score in adults with ADHD was lower than that in the ASD group, but was higher than that in controls. Similarly, the CAARS scores in adults with ASD were lower than in those with ADHD, but were higher than those in controls. No significant correlations were found between AQ, CAARS Inattention/Memory Problems, and CAARS Hyperactivity/Restlessness scores in both the ASD and ADHD groups. CONCLUSION: While adults with ASD and ADHD exhibited similar clinical symptoms, the absence of AQ-CAARS correlations suggests the need for examining factors other than the apparent similarity of clinical symptoms of the two disorders.

Constipation is a prevalent gastrointestinal disorder that affects people globally, decreasing their quality of life and life expectancy. Individuals with schizophrenia often suffer from constipation, which could be a result of the illness itself or the side effects of psychotropic medications. However, little research has been conducted on factors contributing to constipation in individuals with schizophrenia. To address this issue, we conducted a survey using self-administered questionnaires and medical records to identify factors associated with constipation in psychiatric outpatients. This study included 399 patients with schizophrenia, resulting in a high prevalence of constipation (43.4%). The analysis suggested that female gender, the doses of antiparkinsonian medications, and benzodiazepine sleeping pills may be associated with constipation.

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.

Given the relationship between anticholinergic activity (AA) and Alzheimer's disease (AD), we rereview our hypothesis of the endogenous appearance of AA in AD. Briefly, because acetylcholine (ACh) regulates not only cognitive function but also the inflammatory system, when ACh downregulation reaches a critical level, inflammation increases, triggering the appearance of cytokines with AA. Moreover, based on a case report of a patient with mild AD and slightly deteriorated ACh, we also speculate that AA can appear endogenously in Lewy body disease due to the dual action of the downregulation of ACh and hyperactivity of the hypothalamic-pituitary-adrenal axis. Based on these hypotheses, we consider AA to be a behavioral pathology of Lewy body disease. We also propose the concept of "anticholinergic spectrum disorders," which encompass a variety of conditions, including AD, Lewy body disease, and delirium. Finally, we suggest the prescription of cholinesterase inhibitors to patients in this spectrum of disorders to abolish AA by upregulating ACh.

AIMS: While several studies have reported various cognitive impairments in children with attention-deficit/hyperactivity disorder, the neuropsychological profiles of adults with this disorder are understudied. Here, the intelligence and memory functions of adults with attention-deficit/hyperactivity disorder without intellectual disability were evaluated. METHODS: The Wechsler Adult Intelligence Scale-Third Edition and Wechsler Memory Scale-Revised were administered to 30 adults with attention-deficit/hyperactivity disorder whose full-scale intelligence quotients were >85. Diagnoses were based on the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Conners' Adult ADHD Rating Scales-Self-Report-screening version and the Autism Spectrum Quotient were also evaluated. RESULTS: In the Wechsler Adult Intelligence Scale-Third Edition, the verbal intelligence quotient was significantly higher than the performance intelligence quotient and the verbal comprehension score was the highest among the secondary indices. In the Wechsler Memory Scale-Revised, the visual memory score was the highest measure. Although the verbal intelligence quotient had no correlation with any Wechsler Memory Scale-Revised measures, the performance intelligence quotient was significantly correlated with the visual memory and attention scores of the Wechsler Memory Scale-Revised. Conners' Adult ADHD Rating Scales hyperactive-impulsive score was significantly correlated with the verbal intelligence quotient, whereas the inattention score was not correlated with any measures of the Wechsler Adult Intelligence Scale-Third Edition or Wechsler Memory Scale-Revised. CONCLUSIONS: The results suggest that while adults with normal-intelligence attention-deficit/hyperactivity disorder have comparatively high verbal comprehension and social knowledge, their ability of information processing and visual-motor coordination are relatively weak.

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.

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.

Purpose: Generalized anxiety disorder (GAD) is a suboptimally managed chronic recurring psychiatric condition with a lifetime prevalence of 2.6% in Japan. We assessed the current status of GAD management in Japan. Patients and Methods: This was an observational, cross-sectional study conducted through an anonymous web-based survey in Japan from December 12-16, 2022. Psychiatrists and psychosomatic medicine physicians who agreed to participate and saw ≥10 outpatients in the previous month were eligible. Survey questionnaire comprised 37 single/multiple choice, numerical entry, or open-ended questions in Japanese. Results: Among 509 participants (493 psychiatrists and 16 psychosomatic medicine physicians), 96.9% were aware of GAD. On average, 12.4 outpatients and 1.0 inpatient were diagnosed with GAD per physician per month. Of 433 physicians having patients diagnosed with GAD, 46.9% used operational diagnostic tools; among these, DSM-5 diagnostic criteria were used by 81.5% physicians. The majority (54.7%) of participants did not use a self-administered rating scale; depression scales were used more than anxiety scales. Among these 433 physicians, 96.8% used selective serotonin reuptake inhibitors for GAD management, and 79.2% used it as the first choice; of 431 physicians who prescribed drug therapy, 54.3% gave antidepressant monotherapy as first choice. The most frequent symptom in patients diagnosed with GAD was excessive anxiety/worry (96.5%); depression was the most commonly reported comorbidity (84.3%) as per physicians aware of GAD (N=508). Conclusion: This study illustrates that although GAD awareness is high among Japanese psychiatric specialists, GAD is not frequently diagnosed using operational diagnostic approaches. Due to a lack of Japanese guidelines for GAD diagnosis and treatment, diverse international guidelines are followed, with similar treatment paradigms as that of depression. This may not be an optimal approach given cultural/geographical differences. These findings highlight the need for uniform diagnosis and treatment recommendations for GAD management in Japan. Clinical Trial Registration: UMIN-CTR: UMIN000049572.

Purpose: Sleep plays an essential role in maintaining both physical and mental well-being. Many patients in psychiatric outpatient settings complain of insomnia. However, the causal relationship between insomnia and depressive symptoms in all mental illnesses remains unclear. Moreover, research on insomnia and the continuation of outpatient treatment is lacking. We hypothesize a high correlation between depression and insomnia among patients with diverse mental illnesses. Additionally, we posit that insomnia significantly influences the continuity of outpatient visits. To this end, we evaluated insomnia and depression symptoms in psychiatric patients both at their initial visit and one year later. We also examined factors related to insomnia at the outset and factors associated with the ongoing utilization of outpatient treatment. Patients and Methods: The participants of the study consisted of patients who made their first visit to the outpatient department of psychiatry and neurology at Showa University East Hospital between June 1, 2021, and March 31, 2023, and who continued attending the outpatient clinic for one year. Clinical characteristics were assessed using the Self-rating Depression Scale (SDS) and the Athens Insomnia Scale (AIS). Results: The study's findings were collected from a cohort of 1106 patients and revealed that more than 70% experienced insomnia at the time of their initial visit. In total 137 patients continued to receive outpatient treatment for one year, and their AIS scores improved from 9 points to 5 points. A multivariate analysis revealed that the SDS items of depressed mood and insomnia were confounding factors influencing AIS improvement. Conclusion: Given that 70% of patients complained of insomnia at the time of their first visit and that sleep improved in many of the 12.4% of patients who continued to receive outpatient treatment for at least one year, the results suggest that sleep status is an important determinant of whether a patient continues to attend outpatient clinics.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induces hyponatremia accompanied by uric acid reduction. We report a case of a patient with small-cell lung cancer who developed SIADH with hypouricemia after duloxetine treatment and discuss the potential underlying mechanisms. SIADH and hypouricemia improved after duloxetine was switched to mirogabalin.