Hiroaki Kawasaki | Fukuoka University (original) (raw)
Papers by Hiroaki Kawasaki
Molecular Psychiatry, Jan 24, 2017
Psychogeriatrics, Feb 9, 2022
Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients wi... more Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients with MDDPF have been reported to be at increased risk of suicide, and urgent treatment of MDDPF is therefore important. In addition, psychotic features are more likely to appear in older patients with major depressive disorder. In general, MDDPF is recommended to be treated with antidepressants and antipsychotics. However, little is known regarding which antipsychotic and antidepressant to use for combination treatments for MDDPF. There are no reports of the efficacy of asenapine in MDDPF. This case report describes our experience of the effects of combination pharmacotherapy with asenapine and escitalopram drug therapy on MDDPF, along with a review of the related literature. The patient was a 70-year-old Japanese man with no history of psychiatric and physical illness except for type 2 diabetes. He was diagnosed with retinal detachment and had surgery. His anxiety worsened after the surgery, and he attempted to hang himself while in the ophthalmology ward. As a result, he was admitted to the psychiatric ward for medical protection. Other than his eye surgery, there were no organic abnormalities based on examinations and his Mini Mental State Examination score was 30. He said he was a sinful and worthless man because he had caused a plane crash. His clinical symptoms led to a diagnosis of MDDPF in accordance with DSM-5 criteria, and his depressive symptoms were depressive mood, agitation, suicidal ideation, self-accusation, and delusions of guilt; his score on the Hamilton Rating Scale for Depression (HAM-D) was 28 at time of admission to the psychiatric ward. He started treatment with escitalopram 10 mg/day, but his symptoms did not improve after a week of administration and the suicidal ideation was continuing at a high level. We considered escitalopram to be inadequate for improving his symptoms and therefor augmentation with olanzapine would be appropriate. However, olanzapine is contradindicated for patients with diabetes in Japan. For this reason, we added asenapine 5 mg/day once a day to escitalopram for augmentation therapy. A few days after administration, he responded to asenapine, and we observed improvements in self-accusation, delusions of guilt, and irritation. After asenapine had been increased to 10 mg/day twice a day he became over-sedated, so we changed the dose back to asenapine 5 mg/day once a day with escitalopram 10 mg/day and no other side effects were observed. His psychiatric symptoms reached remission after 2 months; his HAM-D score was 4 at discharge and his symptoms continued to improve a year later without side effect. In this case, combination therapy of asenapine and escitalopram was effective for treating MDDPF. Asenapine may be suitable for a combination of antidepressant and antipsychotic treatment options in MDDPF. In this case, the patient’s depressive symptoms improved immediately after the addition of asenapine, without increasing the escitalopram dose. Regarding the drug treatment in this case, we considered the improvement in several symptoms to be related to the broad anti-depressive effect, anti-aggressive effect, and immediate efficacy of asenapine. First, asenapine has an affinity for several serotonin receptors (5-HT2A, 5HT1B, 5-HT2C, 5-HT6 and 5-HT7), associated with anti-depressant effect. 2 In addition, 5-HT6 antagonists have been shown to increase acetylcholine in the hippocampus and prefrontal cortex of rats, and to have an anxiolytic effect similar to diazepam in rats. Other findings suggested that 5-HT7 antagonists improve sleep disturbance as well as having anxiolytic effects.
Frontiers in Psychiatry
In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not r... more In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups—low rate group (LG), medium rate group (MG), and high rate group (HG)—according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, ...
Psychogeriatrics, 2022
Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients wi... more Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients with MDDPF have been reported to be at increased risk of suicide, and urgent treatment of MDDPF is therefore important. In addition, psychotic features are more likely to appear in older patients with major depressive disorder. In general, MDDPF is recommended to be treated with antidepressants and antipsychotics. However, little is known regarding which antipsychotic and antidepressant to use for combination treatments for MDDPF. There are no reports of the efficacy of asenapine in MDDPF. This case report describes our experience of the effects of combination pharmacotherapy with asenapine and escitalopram drug therapy on MDDPF, along with a review of the related literature. The patient was a 70-year-old Japanese man with no history of psychiatric and physical illness except for type 2 diabetes. He was diagnosed with retinal detachment and had surgery. His anxiety worsened after the surgery, and he attempted to hang himself while in the ophthalmology ward. As a result, he was admitted to the psychiatric ward for medical protection. Other than his eye surgery, there were no organic abnormalities based on examinations and his Mini Mental State Examination score was 30. He said he was a sinful and worthless man because he had caused a plane crash. His clinical symptoms led to a diagnosis of MDDPF in accordance with DSM-5 criteria, and his depressive symptoms were depressive mood, agitation, suicidal ideation, self-accusation, and delusions of guilt; his score on the Hamilton Rating Scale for Depression (HAM-D) was 28 at time of admission to the psychiatric ward. He started treatment with escitalopram 10 mg/day, but his symptoms did not improve after a week of administration and the suicidal ideation was continuing at a high level. We considered escitalopram to be inadequate for improving his symptoms and therefor augmentation with olanzapine would be appropriate. However, olanzapine is contradindicated for patients with diabetes in Japan. For this reason, we added asenapine 5 mg/day once a day to escitalopram for augmentation therapy. A few days after administration, he responded to asenapine, and we observed improvements in self-accusation, delusions of guilt, and irritation. After asenapine had been increased to 10 mg/day twice a day he became over-sedated, so we changed the dose back to asenapine 5 mg/day once a day with escitalopram 10 mg/day and no other side effects were observed. His psychiatric symptoms reached remission after 2 months; his HAM-D score was 4 at discharge and his symptoms continued to improve a year later without side effect. In this case, combination therapy of asenapine and escitalopram was effective for treating MDDPF. Asenapine may be suitable for a combination of antidepressant and antipsychotic treatment options in MDDPF. In this case, the patient’s depressive symptoms improved immediately after the addition of asenapine, without increasing the escitalopram dose. Regarding the drug treatment in this case, we considered the improvement in several symptoms to be related to the broad anti-depressive effect, anti-aggressive effect, and immediate efficacy of asenapine. First, asenapine has an affinity for several serotonin receptors (5-HT2A, 5HT1B, 5-HT2C, 5-HT6 and 5-HT7), associated with anti-depressant effect. 2 In addition, 5-HT6 antagonists have been shown to increase acetylcholine in the hippocampus and prefrontal cortex of rats, and to have an anxiolytic effect similar to diazepam in rats. Other findings suggested that 5-HT7 antagonists improve sleep disturbance as well as having anxiolytic effects.
Research Square (Research Square), Aug 30, 2022
Objective Comorbid psychiatric disorders negatively affect the survival rate of patients with som... more Objective Comorbid psychiatric disorders negatively affect the survival rate of patients with some physical disorders. In liver transplant recipients, various psychiatric disorders have been identi ed as worsening prognosis. However, little is known about how the presence of any comorbid (overall) disorders affect the survival rate of transplant recipients. In this study, we examined the effect of overall comorbid psychiatric disorders on survival rate in liver transplant recipients. Methods A total of 1006 recipients who underwent liver transplantation between September 1997 and July 2017 across eight transplant facilities with a psychiatric consultation-liaison team were identi ed consecutively. Recipients were categorized into those with comorbid psychiatric disorders and those without comorbid psychiatric disorders. In the comorbid psychiatric disorder group, psychiatric disorder diagnosis and time of diagnosis were investigated retrospectively. Results Of the 1006 recipients, 294 (29.2%) had comorbid psychiatric disorders. Comorbid psychiatric disorders in the 1006 recipients were insomnia (N = 107, 10.6%), delirium (N = 103, 10.2%), major depressive disorder (N = 41, 4.1%), adjustment disorder (N = 19, 1.9%), anxiety disorder (N = 17, 1.7%), intellectual disability (N = 11, 1.1%), autism spectrum disorder (N = 7, 0.7%), somatic symptom disorder (N = 4, 0.4%) schizophrenia (N = 4, 0.4%), substance use disorder (N = 24, 2.4%) and personality disorder (N = 2, 0.2%). The most common time of psychiatric disorder diagnosis was within the rst 3 months after liver transplantation (51.6%). The nal mortality in patients with comorbid psychiatric disorder diagnosis during the ve periods (pretransplant, transplant to 3 months, months to 1 year, 1 to 3 years, and over 3 years posttransplant) was 16.2%, 18.8%, 39.1%, 28.6%, and 16.2% respectively, and there were no signi cant differences between the ve periods (χ2=8.05, df = 4, p = 0.09). Overall comorbid psychiatric disorders were signi cantly associated with shorter survival time (log-rank test: p = 0.01, hazard ratio: 1.60 [95% con dence interval: 1.15-2.24], survival rate at the endpoint [%]: 62.0 vs. 83.3). However, after adjusting for confounding variables using Cox proportional hazards regression, there was no signi cant effect of overall comorbid psychiatric disorders on prognosis. Conclusion Comorbid psychiatric disorders did not affect the survival rate of liver transplant recipients in this study.
Japanese Journal of Radiology, 2020
Purpose The Cingulate Island Sign score (CIScore) by rCBF SPECT is used in the differentiation be... more Purpose The Cingulate Island Sign score (CIScore) by rCBF SPECT is used in the differentiation between Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) but has some false-positive AD cases. To resolve the problem, we developed new differential diagnosing method incorporating occipital lobe and para-hippocampal rCBF. Materials and methods In 27 DLB and 31 AD cases undertaken Tc-99 m-ECD SPECT, we evaluated the mean Z score in the bilateral superior, middle, inferior occipital gyri, cuneus, amygdala, hippocampus, and para-hippocampus. One criterion of DLB was defined as the case with CIScore lower than 0.27. The other criteria were the cases of following either or both two conditions were satisfied. (1) The number of occipital gyri with mean Z score higher than 1 is three or more. (2) The number of hippocampal regions with mean Z score higher than 1 is one or less. We compared the differential diagnostic ability among these four criterions. Results The diagnostic accuracy by CIscore was 69% and that of the occipital gyri analysis 84%, para-hippocampal regions analysis 76% and combined occipital gyri and para-hippocampal regions analysis 93%. Conclusion The new method by combined rCBF analysis of occipital gyri and para-hippocampal regions showed best diagnostic ability in differentiating DLB from AD.
We have identified creatine as an endogenous inhibitor of [3H]flunitrazepam (FNZ) binding from pu... more We have identified creatine as an endogenous inhibitor of [3H]flunitrazepam (FNZ) binding from purified fractions that have inhibitory activity for [3H]FNZ binding. The techniques used for the identification were Electron Impact (EI) and Negative Ion Fast Atom Bombardment(NG-FAB) mass spectrometry, 270 MHz 1H-and 13C-Fourier Transformation-Nuclear Magnetic Resonance Spectroscopy (FT-NMR), Ultra Violet(UV) spectroscopy, and HPLC. Elemental analysis revealed that the purified substance had approximately the same combustion ratio as creatine. Creatine inhibited the [3H]FNZ binding competitively and dose-dependently with Ki of 19.54 mM, but had no effect on the binding of the peripheral BZ receptor ligand [3H]Ro 5-4864. In the presence of 100 mM gamma-aminobutyric acid(GABA), the inhibitory activity of creatine to the [3H]FNZ binding was not enhanced. This is the first report of the inhibitory effect of creatine on benzodiazepine (BZ) binding to the central BZ receptor. These results su...
Annals of general psychiatry, 2017
Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that t... more Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that the serotonergic systems are involved in the pathogenesis, while structural imaging studies have found some neuroanatomical abnormalities in OCD patients. In the etiopathogenesis of OCD, few studies have performed concurrent assessment of genetic and neuroanatomical variables. We carried out a two-way ANOVA between a variable number of tandem repeat polymorphisms (5-HTTLPR) in the serotonin transporter gene and gray matter (GM) volumes in 40 OCD patients and 40 healthy controls (HCs). We found that relative to the HCs, the OCD patients showed significant decreased GM volume in the right hippocampus, and increased GM volume in the left precentral gyrus. 5-HTTLPR polymorphism in OCD patients had a statistical tendency of stronger effects on the right frontal pole than those in HCs. Our results showed that the neuroanatomical changes of specific GM regions could be endophenotypes of 5-HTTLPR...
International journal of bipolar disorders, Jan 10, 2018
The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently ... more The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed b...
The Journal of Comparative Neurology, 2001
CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide e... more CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide exchange factors (GEFs) that can be stimulated by calcium and diacylglycerol and that can activate small GTPases, including Ras and Rap1, molecules increasingly recognized as having signaling functions in neurons. Here, we show that CalDAG-GEFI and CalDAG-GEFII mRNAs, detected by in situ hybridization analysis, have sharply contrasting forebrain-predominant distributions in the mature brain: CalDAG-GEFI is expressed mainly in the striatum and olfactory structures and deep cortical layers, whereas CalDAG-GEFII is expressed widely in the forebrain. Within the striatum, however, the two CalDAG-GEF mRNAs have nearly identical distributions: they are coexpressed in striatal projection neurons that give rise to the direct and indirect pathways of the basal ganglia. Subcellular fractionation analysis of the substantia nigra with monoclonal antibodies against CalDAG-GEFI suggests that CalDAG-GEFI protein is present not only in the cell bodies of striatal projection neurons but also in their axons and axon terminals. These results suggest that the CalDAG-GEFs may be key intracellular regulators whereby calcium and diacylglycerol signals can regulate cellular functions through small GTPases in the basal ganglia circuits.
Cancer Research, 2005
Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a ... more Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor x...
Palliative Care Research, 2011
Background. Research on the dimensional structure and reliability of the Hospital Anxiety and Dep... more Background. Research on the dimensional structure and reliability of the Hospital Anxiety and Depression Scale (HADS) and its relationship with age is scarce. Moreover, its efficacy in determining the presence of depression in different patient groups has been questioned. Methods. Psychometric properties of the HADS were assessed in six different groups of Dutch subjects (N l 6165) : (1) a random sample of younger adults (age 18-65 years) (N l 199) ; (2) a random sample of elderly subjects of 57 to 65 years of age (N l 1901) ; (3) a random sample of elderly subjects of 66 years or older (N l 3293) ; (4) a sample of consecutive general practice patients (N l 112) ; (5) a sample of consecutive general medical outpatients with unexplained somatic symptoms (N l 169) ; and (6) a sample of consecutive psychiatric outpatients (N l 491). Results. Evidence for a two-factor solution corresponding to the original two subscales of the HADS was found, although anxiety and depression subscales were strongly correlated. Homogeneity and test-retest reliability of the total scale and the subscales were good. The dimensional structure and reliability of the HADS was stable across medical settings and age groups. The correlations between HADS scores and age were small. The total HADS scale showed a better balance between sensitivity and positive predictive value (PPV) in identifying cases of psychiatric disorder as defined by the Present State Examination than the depression subscale in identifying cases of unipolar depression as defined by ICD-8. Conclusions. The moderate PPV suggests that the HADS is best used as a screening questionnaire and not as a ' case-identifier ' for psychiatric disorder or depression.
Depression Journal デプレッションジャーナル 学術雑誌, Jul 1, 2013
The World Journal of Biological Psychiatry, 2014
To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed epis... more To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (-11.3 vs. -5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (-0.4 vs. -0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated.
![Research paper thumbnail of Purification of endogenous inhibitors of [3H]flunitrazepam binding from bovine brain](https://attachments.academia-assets.com/52225656/thumbnails/1.jpg)
](Neurochemical Research, 1991
Endogenous substances which inhibited the binding of [3H]flunitrazepam ([3H]FNZ) to bovine synapt... more Endogenous substances which inhibited the binding of [3H]flunitrazepam ([3H]FNZ) to bovine synaptosomal membranes have been purified from the hot acetic acid extracts of the bovine brain~ Three peaks of inhibitory activity were obtained by Sephadex G-10 gel chromatography. Two of the peaks (Peak 2, and Peak 3) which had lower molecular weights than that of peak 1 were identified as inosine and hypoxanthine by TLC methods. Another peak (Peak 1) wa.s further purified to homogeneity using both cation and anion ion-exchange chromatography and the following twostep reversed-phase HPLC. The purified substance inhibited the [3H]FNZ binding dose-dependently and competitively but did not have an effect on the binding of the peripheral-type BZ ligand [3H]Ro 5-4864. It was also shown that the substance was heat-stable and resistant to proteolytic degradation (trypsin, ct-chymotrypsin, pronase). However, a significant loss of inhibitory activity to [3H]FNZ binding was observed after acid hydrolysis. Molecular weight estimates based on gel filtration methods were less than 500 dalton, and the maximal ultraviolet absorption peak was at 314 nm. These results suggest that this substance is a new endogenous ligand for the central BZ receptor and may play an important role in regulating the GABAergic tone in the central nervous system.
Molecular Psychiatry, Jan 24, 2017
Psychogeriatrics, Feb 9, 2022
Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients wi... more Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients with MDDPF have been reported to be at increased risk of suicide, and urgent treatment of MDDPF is therefore important. In addition, psychotic features are more likely to appear in older patients with major depressive disorder. In general, MDDPF is recommended to be treated with antidepressants and antipsychotics. However, little is known regarding which antipsychotic and antidepressant to use for combination treatments for MDDPF. There are no reports of the efficacy of asenapine in MDDPF. This case report describes our experience of the effects of combination pharmacotherapy with asenapine and escitalopram drug therapy on MDDPF, along with a review of the related literature. The patient was a 70-year-old Japanese man with no history of psychiatric and physical illness except for type 2 diabetes. He was diagnosed with retinal detachment and had surgery. His anxiety worsened after the surgery, and he attempted to hang himself while in the ophthalmology ward. As a result, he was admitted to the psychiatric ward for medical protection. Other than his eye surgery, there were no organic abnormalities based on examinations and his Mini Mental State Examination score was 30. He said he was a sinful and worthless man because he had caused a plane crash. His clinical symptoms led to a diagnosis of MDDPF in accordance with DSM-5 criteria, and his depressive symptoms were depressive mood, agitation, suicidal ideation, self-accusation, and delusions of guilt; his score on the Hamilton Rating Scale for Depression (HAM-D) was 28 at time of admission to the psychiatric ward. He started treatment with escitalopram 10 mg/day, but his symptoms did not improve after a week of administration and the suicidal ideation was continuing at a high level. We considered escitalopram to be inadequate for improving his symptoms and therefor augmentation with olanzapine would be appropriate. However, olanzapine is contradindicated for patients with diabetes in Japan. For this reason, we added asenapine 5 mg/day once a day to escitalopram for augmentation therapy. A few days after administration, he responded to asenapine, and we observed improvements in self-accusation, delusions of guilt, and irritation. After asenapine had been increased to 10 mg/day twice a day he became over-sedated, so we changed the dose back to asenapine 5 mg/day once a day with escitalopram 10 mg/day and no other side effects were observed. His psychiatric symptoms reached remission after 2 months; his HAM-D score was 4 at discharge and his symptoms continued to improve a year later without side effect. In this case, combination therapy of asenapine and escitalopram was effective for treating MDDPF. Asenapine may be suitable for a combination of antidepressant and antipsychotic treatment options in MDDPF. In this case, the patient’s depressive symptoms improved immediately after the addition of asenapine, without increasing the escitalopram dose. Regarding the drug treatment in this case, we considered the improvement in several symptoms to be related to the broad anti-depressive effect, anti-aggressive effect, and immediate efficacy of asenapine. First, asenapine has an affinity for several serotonin receptors (5-HT2A, 5HT1B, 5-HT2C, 5-HT6 and 5-HT7), associated with anti-depressant effect. 2 In addition, 5-HT6 antagonists have been shown to increase acetylcholine in the hippocampus and prefrontal cortex of rats, and to have an anxiolytic effect similar to diazepam in rats. Other findings suggested that 5-HT7 antagonists improve sleep disturbance as well as having anxiolytic effects.
Frontiers in Psychiatry
In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not r... more In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups—low rate group (LG), medium rate group (MG), and high rate group (HG)—according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, ...
Psychogeriatrics, 2022
Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients wi... more Major depressive disorder with psychotic features (MDDPF) is a subtype of depression; patients with MDDPF have been reported to be at increased risk of suicide, and urgent treatment of MDDPF is therefore important. In addition, psychotic features are more likely to appear in older patients with major depressive disorder. In general, MDDPF is recommended to be treated with antidepressants and antipsychotics. However, little is known regarding which antipsychotic and antidepressant to use for combination treatments for MDDPF. There are no reports of the efficacy of asenapine in MDDPF. This case report describes our experience of the effects of combination pharmacotherapy with asenapine and escitalopram drug therapy on MDDPF, along with a review of the related literature. The patient was a 70-year-old Japanese man with no history of psychiatric and physical illness except for type 2 diabetes. He was diagnosed with retinal detachment and had surgery. His anxiety worsened after the surgery, and he attempted to hang himself while in the ophthalmology ward. As a result, he was admitted to the psychiatric ward for medical protection. Other than his eye surgery, there were no organic abnormalities based on examinations and his Mini Mental State Examination score was 30. He said he was a sinful and worthless man because he had caused a plane crash. His clinical symptoms led to a diagnosis of MDDPF in accordance with DSM-5 criteria, and his depressive symptoms were depressive mood, agitation, suicidal ideation, self-accusation, and delusions of guilt; his score on the Hamilton Rating Scale for Depression (HAM-D) was 28 at time of admission to the psychiatric ward. He started treatment with escitalopram 10 mg/day, but his symptoms did not improve after a week of administration and the suicidal ideation was continuing at a high level. We considered escitalopram to be inadequate for improving his symptoms and therefor augmentation with olanzapine would be appropriate. However, olanzapine is contradindicated for patients with diabetes in Japan. For this reason, we added asenapine 5 mg/day once a day to escitalopram for augmentation therapy. A few days after administration, he responded to asenapine, and we observed improvements in self-accusation, delusions of guilt, and irritation. After asenapine had been increased to 10 mg/day twice a day he became over-sedated, so we changed the dose back to asenapine 5 mg/day once a day with escitalopram 10 mg/day and no other side effects were observed. His psychiatric symptoms reached remission after 2 months; his HAM-D score was 4 at discharge and his symptoms continued to improve a year later without side effect. In this case, combination therapy of asenapine and escitalopram was effective for treating MDDPF. Asenapine may be suitable for a combination of antidepressant and antipsychotic treatment options in MDDPF. In this case, the patient’s depressive symptoms improved immediately after the addition of asenapine, without increasing the escitalopram dose. Regarding the drug treatment in this case, we considered the improvement in several symptoms to be related to the broad anti-depressive effect, anti-aggressive effect, and immediate efficacy of asenapine. First, asenapine has an affinity for several serotonin receptors (5-HT2A, 5HT1B, 5-HT2C, 5-HT6 and 5-HT7), associated with anti-depressant effect. 2 In addition, 5-HT6 antagonists have been shown to increase acetylcholine in the hippocampus and prefrontal cortex of rats, and to have an anxiolytic effect similar to diazepam in rats. Other findings suggested that 5-HT7 antagonists improve sleep disturbance as well as having anxiolytic effects.
Research Square (Research Square), Aug 30, 2022
Objective Comorbid psychiatric disorders negatively affect the survival rate of patients with som... more Objective Comorbid psychiatric disorders negatively affect the survival rate of patients with some physical disorders. In liver transplant recipients, various psychiatric disorders have been identi ed as worsening prognosis. However, little is known about how the presence of any comorbid (overall) disorders affect the survival rate of transplant recipients. In this study, we examined the effect of overall comorbid psychiatric disorders on survival rate in liver transplant recipients. Methods A total of 1006 recipients who underwent liver transplantation between September 1997 and July 2017 across eight transplant facilities with a psychiatric consultation-liaison team were identi ed consecutively. Recipients were categorized into those with comorbid psychiatric disorders and those without comorbid psychiatric disorders. In the comorbid psychiatric disorder group, psychiatric disorder diagnosis and time of diagnosis were investigated retrospectively. Results Of the 1006 recipients, 294 (29.2%) had comorbid psychiatric disorders. Comorbid psychiatric disorders in the 1006 recipients were insomnia (N = 107, 10.6%), delirium (N = 103, 10.2%), major depressive disorder (N = 41, 4.1%), adjustment disorder (N = 19, 1.9%), anxiety disorder (N = 17, 1.7%), intellectual disability (N = 11, 1.1%), autism spectrum disorder (N = 7, 0.7%), somatic symptom disorder (N = 4, 0.4%) schizophrenia (N = 4, 0.4%), substance use disorder (N = 24, 2.4%) and personality disorder (N = 2, 0.2%). The most common time of psychiatric disorder diagnosis was within the rst 3 months after liver transplantation (51.6%). The nal mortality in patients with comorbid psychiatric disorder diagnosis during the ve periods (pretransplant, transplant to 3 months, months to 1 year, 1 to 3 years, and over 3 years posttransplant) was 16.2%, 18.8%, 39.1%, 28.6%, and 16.2% respectively, and there were no signi cant differences between the ve periods (χ2=8.05, df = 4, p = 0.09). Overall comorbid psychiatric disorders were signi cantly associated with shorter survival time (log-rank test: p = 0.01, hazard ratio: 1.60 [95% con dence interval: 1.15-2.24], survival rate at the endpoint [%]: 62.0 vs. 83.3). However, after adjusting for confounding variables using Cox proportional hazards regression, there was no signi cant effect of overall comorbid psychiatric disorders on prognosis. Conclusion Comorbid psychiatric disorders did not affect the survival rate of liver transplant recipients in this study.
Japanese Journal of Radiology, 2020
Purpose The Cingulate Island Sign score (CIScore) by rCBF SPECT is used in the differentiation be... more Purpose The Cingulate Island Sign score (CIScore) by rCBF SPECT is used in the differentiation between Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) but has some false-positive AD cases. To resolve the problem, we developed new differential diagnosing method incorporating occipital lobe and para-hippocampal rCBF. Materials and methods In 27 DLB and 31 AD cases undertaken Tc-99 m-ECD SPECT, we evaluated the mean Z score in the bilateral superior, middle, inferior occipital gyri, cuneus, amygdala, hippocampus, and para-hippocampus. One criterion of DLB was defined as the case with CIScore lower than 0.27. The other criteria were the cases of following either or both two conditions were satisfied. (1) The number of occipital gyri with mean Z score higher than 1 is three or more. (2) The number of hippocampal regions with mean Z score higher than 1 is one or less. We compared the differential diagnostic ability among these four criterions. Results The diagnostic accuracy by CIscore was 69% and that of the occipital gyri analysis 84%, para-hippocampal regions analysis 76% and combined occipital gyri and para-hippocampal regions analysis 93%. Conclusion The new method by combined rCBF analysis of occipital gyri and para-hippocampal regions showed best diagnostic ability in differentiating DLB from AD.
We have identified creatine as an endogenous inhibitor of [3H]flunitrazepam (FNZ) binding from pu... more We have identified creatine as an endogenous inhibitor of [3H]flunitrazepam (FNZ) binding from purified fractions that have inhibitory activity for [3H]FNZ binding. The techniques used for the identification were Electron Impact (EI) and Negative Ion Fast Atom Bombardment(NG-FAB) mass spectrometry, 270 MHz 1H-and 13C-Fourier Transformation-Nuclear Magnetic Resonance Spectroscopy (FT-NMR), Ultra Violet(UV) spectroscopy, and HPLC. Elemental analysis revealed that the purified substance had approximately the same combustion ratio as creatine. Creatine inhibited the [3H]FNZ binding competitively and dose-dependently with Ki of 19.54 mM, but had no effect on the binding of the peripheral BZ receptor ligand [3H]Ro 5-4864. In the presence of 100 mM gamma-aminobutyric acid(GABA), the inhibitory activity of creatine to the [3H]FNZ binding was not enhanced. This is the first report of the inhibitory effect of creatine on benzodiazepine (BZ) binding to the central BZ receptor. These results su...
Annals of general psychiatry, 2017
Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that t... more Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that the serotonergic systems are involved in the pathogenesis, while structural imaging studies have found some neuroanatomical abnormalities in OCD patients. In the etiopathogenesis of OCD, few studies have performed concurrent assessment of genetic and neuroanatomical variables. We carried out a two-way ANOVA between a variable number of tandem repeat polymorphisms (5-HTTLPR) in the serotonin transporter gene and gray matter (GM) volumes in 40 OCD patients and 40 healthy controls (HCs). We found that relative to the HCs, the OCD patients showed significant decreased GM volume in the right hippocampus, and increased GM volume in the left precentral gyrus. 5-HTTLPR polymorphism in OCD patients had a statistical tendency of stronger effects on the right frontal pole than those in HCs. Our results showed that the neuroanatomical changes of specific GM regions could be endophenotypes of 5-HTTLPR...
International journal of bipolar disorders, Jan 10, 2018
The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently ... more The long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) was recently approved for maintenance treatment of bipolar I disorder (BP-I). The purpose of this study was to evaluate the safety, tolerability, and efficacy of AOM 400 as long-term maintenance treatment for BP-I. This open-label multicenter study evaluated the effectiveness of AOM 400 as maintenance treatment for BP-I by assessing safety and tolerability (primary objective) and efficacy (secondary objective). The study enrolled AOM 400-naive ("de novo") patients as well as AOM 400-experienced ("rollover") patients with BP-I from a lead-in randomized, placebo-controlled clinical trial that demonstrated the efficacy of AOM 400 in the maintenance treatment of BP-I (Calabrese et al. in J Clin Psychiatry 78:324-331, 2017). Safety variables included frequency and severity of treatment-emergent adverse events (TEAEs) and TEAEs resulting in study discontinuation. Efficacy was assessed b...
The Journal of Comparative Neurology, 2001
CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide e... more CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide exchange factors (GEFs) that can be stimulated by calcium and diacylglycerol and that can activate small GTPases, including Ras and Rap1, molecules increasingly recognized as having signaling functions in neurons. Here, we show that CalDAG-GEFI and CalDAG-GEFII mRNAs, detected by in situ hybridization analysis, have sharply contrasting forebrain-predominant distributions in the mature brain: CalDAG-GEFI is expressed mainly in the striatum and olfactory structures and deep cortical layers, whereas CalDAG-GEFII is expressed widely in the forebrain. Within the striatum, however, the two CalDAG-GEF mRNAs have nearly identical distributions: they are coexpressed in striatal projection neurons that give rise to the direct and indirect pathways of the basal ganglia. Subcellular fractionation analysis of the substantia nigra with monoclonal antibodies against CalDAG-GEFI suggests that CalDAG-GEFI protein is present not only in the cell bodies of striatal projection neurons but also in their axons and axon terminals. These results suggest that the CalDAG-GEFs may be key intracellular regulators whereby calcium and diacylglycerol signals can regulate cellular functions through small GTPases in the basal ganglia circuits.
Cancer Research, 2005
Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a ... more Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase β (LPAAT-β), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-β converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-β was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-β using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-β also enhanced the survival of mice bearing ovarian tumor x...
Palliative Care Research, 2011
Background. Research on the dimensional structure and reliability of the Hospital Anxiety and Dep... more Background. Research on the dimensional structure and reliability of the Hospital Anxiety and Depression Scale (HADS) and its relationship with age is scarce. Moreover, its efficacy in determining the presence of depression in different patient groups has been questioned. Methods. Psychometric properties of the HADS were assessed in six different groups of Dutch subjects (N l 6165) : (1) a random sample of younger adults (age 18-65 years) (N l 199) ; (2) a random sample of elderly subjects of 57 to 65 years of age (N l 1901) ; (3) a random sample of elderly subjects of 66 years or older (N l 3293) ; (4) a sample of consecutive general practice patients (N l 112) ; (5) a sample of consecutive general medical outpatients with unexplained somatic symptoms (N l 169) ; and (6) a sample of consecutive psychiatric outpatients (N l 491). Results. Evidence for a two-factor solution corresponding to the original two subscales of the HADS was found, although anxiety and depression subscales were strongly correlated. Homogeneity and test-retest reliability of the total scale and the subscales were good. The dimensional structure and reliability of the HADS was stable across medical settings and age groups. The correlations between HADS scores and age were small. The total HADS scale showed a better balance between sensitivity and positive predictive value (PPV) in identifying cases of psychiatric disorder as defined by the Present State Examination than the depression subscale in identifying cases of unipolar depression as defined by ICD-8. Conclusions. The moderate PPV suggests that the HADS is best used as a screening questionnaire and not as a ' case-identifier ' for psychiatric disorder or depression.
Depression Journal デプレッションジャーナル 学術雑誌, Jul 1, 2013
The World Journal of Biological Psychiatry, 2014
To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed epis... more To investigate the efficacy and safety of aripiprazole in Asian patients with manic or mixed episodes associated with bipolar I disorder. Subjects were randomised to aripiprazole (24 mg/day; reduced to 12 mg/day if needed for tolerability; n = 128) or placebo (n = 130) for 3 weeks in this multicentre, double-blind study. The primary efficacy measure was mean change from baseline in Young Mania Rating Scale (YMRS) Total score. A total of 136 patients (aripiprazole 56.3%; placebo 49.2%) completed the study. The majority of patients (92.6%) received aripiprazole 24 mg/day. Aripiprazole produced statistically significant mean improvements in YMRS Total scores compared with placebo from Day 4 through to Week 3 (-11.3 vs. -5.3; P < 0.001). The most common adverse events (> 15% of patients; aripiprazole vs. placebo) were akathisia (22.0 vs. 5.6%) and insomnia (16.3 vs. 9.6%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight from baseline (-0.4 vs. -0.7 kg; P = 0.231). Aripiprazole was not associated with an elevated serum prolactin level. Aripiprazole had significantly greater efficacy than placebo for the treatment of acute manic or mixed episodes associated with bipolar I disorder in Asian patients. Treatment was generally safe and well tolerated.
Neurochemical Research, 1991
Endogenous substances which inhibited the binding of [3H]flunitrazepam ([3H]FNZ) to bovine synapt... more Endogenous substances which inhibited the binding of [3H]flunitrazepam ([3H]FNZ) to bovine synaptosomal membranes have been purified from the hot acetic acid extracts of the bovine brain~ Three peaks of inhibitory activity were obtained by Sephadex G-10 gel chromatography. Two of the peaks (Peak 2, and Peak 3) which had lower molecular weights than that of peak 1 were identified as inosine and hypoxanthine by TLC methods. Another peak (Peak 1) wa.s further purified to homogeneity using both cation and anion ion-exchange chromatography and the following twostep reversed-phase HPLC. The purified substance inhibited the [3H]FNZ binding dose-dependently and competitively but did not have an effect on the binding of the peripheral-type BZ ligand [3H]Ro 5-4864. It was also shown that the substance was heat-stable and resistant to proteolytic degradation (trypsin, ct-chymotrypsin, pronase). However, a significant loss of inhibitory activity to [3H]FNZ binding was observed after acid hydrolysis. Molecular weight estimates based on gel filtration methods were less than 500 dalton, and the maximal ultraviolet absorption peak was at 314 nm. These results suggest that this substance is a new endogenous ligand for the central BZ receptor and may play an important role in regulating the GABAergic tone in the central nervous system.