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Aim: Symptoms of dementia are classified into cognitive dysfunction and behavioral and psychological symptoms of dementia, including sleep disturbance. Yokukansan (YKS) is effective for sleep disturbance in patients with dementia, but the mechanisms are still unclear. In this study, we evaluated sleep disturbance in rats with cerebral ischemia. We investigated the effect of YKS on sleep disturbance in cerebral ischemia-treated rats. Methods: Cerebral ischemia was induced by twice occluding both of the common carotid arteries. Wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were classified using electroencephalography and electromyography. mRNA expression of sleep–wakefulness signals were quantified using reverse transcription–polymerase chain reaction. Results: Rats with cerebral ischemia had a higher total wakefulness time and lower total NREM sleep time during the light phase. These changes were ameliorated with 1000 mg/kg YKS for 14 days, but not 3 mg/kg donepezil for 7 days. mRNA expression of the prefrontal cortical prostaglandin (PG) E2 (EP4) receptor and of the PGD2 (DP) receptor was increased by cerebral ischemia. Elevated prefrontal cortical EP4 and DP receptor mRNA expression was reduced by YKS treatment. Conclusion: Rats with cerebral ischemia had NREM sleep disturbance. YKS might reduce this sleep disturbance by preventing neuroinflammation, and this was mediated by the EP4 and DP receptors in the prefrontal cortex.

Telmisartan, an angiotensin type 1 receptor blocker, is used in the management of hypertension to control blood pressure. In addition, telmisartan has a partial agonistic effect on peroxisome proliferator activated receptor γ (PPARγ). Recently, the effects of telmisartan on spatial memory or the inflammatory response were monitored in a mouse model of Alzheimer's disease (AD). However, to date, no studies have investigated the ameliorative effects of telmisartan on impaired spatial memory and the inflammatory response in an AD animal model incorporating additional cerebrovascular disease factors. In this study, we examined the effect of telmisartan on spatial memory impairment and the inflammatory response in a rat model of AD incorporating additional cerebrovascular disease factors. Rats were subjected to cerebral ischemia and an intracerebroventricular injection of oligomeric or aggregated amyloid-β (Aβ). Oral administration of telmisartan (0.3, 1, 3 mg/kg/d) seven days after ischemia and Aβ treatment resulted in better performance in the eight arm radial maze task in a dose-dependent manner. Telmisartan also reduced tumor necrosis factor α mRNA expression in the hippocampal region of rats with impaired spatial memory. These effects of telmisartan were antagonized by GW9662, an antagonist of PPARγ. These results suggest that telmisartan has ameliorative effects on the impairment of spatial memory in a rat model of AD incorporating additional cerebrovascular disease factors via its anti-inflammatory effect.

In the present study, we investigated the effect of the Kampo medicine Yokukansan (YKS) on pentobarbital-induced sleep in group-housed and socially isolated mice. Socially isolated mice showed shorter sleeping time than the group-housed mice. YKS (300 mg/kg, p.o.) prolonged the pentobarbital-induced sleeping time in socially isolated mice without affecting pentobarbital sleep in group-housed mice. The prolongation of sleeping time by YKS was reversed by bicuculline (3 mg/kg, i.p.) and flumazenil (3 mg/kg, i.p.), but not WAY100635. These findings suggest that the GABAA – benzodiazepine receptor complex, but not 5-HT1A receptors, is involved in the reversal effect of YKS on the decrease of pentobarbital sleep by social isolation. Keywords:: sleep, social isolation, Yokukansan

Aims: Despite a range of research on gender identity disorder (GID), at present there is no scientific consensus on whether the etiology of GID is mental or physical. In particular recent advances in the technology of neuroimaging research have led to an increased understanding of the biological basis of various mental disorders. GID also should be evaluated from this perspective. The aim of the present study was therefore to do the first trial to examine the regional cerebral blood flow (rCBF) in GID. Methods: Persons considered biologically male fulfilling the GID criteria are termed male to female (MTF) and, conversely, persons considered biological female are termed female to male (FTM). We compared 11 FTM subjects and nine age- and handedness-matched female control subjects. None of the subjects was regularly taking medication and none had any kind of physical or psychiatric comorbidity. To evaluate rCBF in GID subjects and control subjects, statistical parametric mapping analysis of 99mTc-ethyl-cysteinate dimer single-photon emission computed tomography was used. Results: GID subjects had a significant decrease in rCBF in the left anterior cingulate cortex (ACC) and a significant increase in the right insula compared to control subjects. Conclusions: The ACC and insula are regions that have been noted as being related to human sexual behavior and consciousness. From these findings, useful insights into the biological basis of GID were suggested.

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as on that of their caregivers. However, effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD, such as aggression, agitation, irritability, and hallucinations, in a randomized, single-blind, placebo-controlled study. However, the psychopharmacologic effects of YKS remain unexplored. In the present study, we investigated the effects of YKS on social isolation-induced aggressive behavior and methamphetamine- or MK-801-induced hyperlocomotion in rodents. Social isolation markedly induced aggressive behavior in male Wistar rats. Quetiapine at a dose of 10 mg/kg (per os (p.o.)) significantly inhibited this social isolation-induced aggressive behavior. YKS (100, 300 mg/kg, p.o.) also significantly inhibited the aggressive behavior. Moreover, risperidone (0.1 mg/kg, p.o.) significantly inhibited methamphetamine- or MK-801-induced hyperlocomotion in mice. YKS (300 mg/kg, p.o.) inhibited methamphetamine-induced hyperlocomotion, while YKS at the same dose had no effect on MK-801-induced hyperlocomotion. These findings suggest that YKS may be useful for the treatment of aggression and agitation, and that the psychopharmacologic effects of YKS might be mediated, in part, by inhibiting the activity of the dopaminergic system.

In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. In addition, THC at the same doses did not significantly affect locomotor activity in the open-field test. The selective cannabinoid CB(1) receptor antagonist rimonabant (3 mg/kg, i.p.) significantly reduced the enhancement of immobility by THC (6 mg/kg). Similarly, the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram (10 mg/kg, i.p.) and 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.3 mg/kg, i.p.) significantly reduced this THC-induced effect. Moreover, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide dihydrochloride (WAY100635, 1 mg/kg, i.p.) and the postsynaptic 5-HT(1A) receptor antagonist MM-77 (0.1 mg/kg, i.p.) reversed this reduction effect of 8-OH-DPAT (0.3 mg/kg). In contrast, the selective 5-HT(7) receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this reduction effect of 8-OH-DPAT. WAY100635 (1 mg/kg) also reversed the reduction effect of citalopram (10 mg/kg). These findings suggest that the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility.

Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). However, such interactions have not sufficiently been clear and may have important implications for understanding the pharmacological effects of marijuana. In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Delta(9)-THC on locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory in the eight-arm radial maze task in mice. In addition, we measured expression level of cannabinoid CB(1) receptor at striatum, cortex, hippocampus and hypothalamus. Delta(9)-THC (1, 3, 6 and 10 mg/kg) induced hypoactivity, catalepsy-like immobilisation and hypothermia in a dose-dependent manner. In addition, Delta(9)-THC (1, 3 and 6 mg/kg) dose-dependently impaired spatial memory in eight-arm radial maze. On the other hand, cannabidiol (1, 3, 10, 25 and 50 mg/kg) did not affect locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory on its own. However, higher dose of cannabidiol (10 or 50 mg/kg) exacerbated pharmacological effects of lower dose of Delta(9)-THC, such as hypoactivity, hypothermia and impairment of spatial memory. Moreover, cannabidiol (50 mg/kg) with Delta(9)-THC (1 mg/kg) enhanced the expression level of CB(1) receptor expression in hippocampus and hypothalamus. Cannabidiol potentiated pharmacological effects of Delta(9)-THC via CB(1) receptor-dependent mechanism. These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.

In the present study, we examined the effects of calcium-channel antagonists on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Amlodipine (10 mg/kg, i.p.), cilnidipine (10 mg/kg, i.p.), nilvadipine (3 and10 mg/kg, i.p.), and flunarizine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior in mice. These results suggest that calcium channels may be involved in the marble-burying behavior. Keywords:: marble-burying behavior, calcium-channel antagonist, obsessive-compulsive disorder

The purpose of the present study was to review the prescription patterns of antidepressants in different countries in East Asia. The survey was conducted in China, Japan, Korea, Singapore and Taiwan from October 2003 to March 2004 using the unified research protocol and questionnaire. Twenty teaching hospitals and major psychiatric hospitals participated and a total of 1898 patients receiving antidepressants were analyzed. The survey provided a number of interesting characteristics on the prescription patterns of antidepressant in East Asia. Out of 56 antidepressants listed in the Anatomical Therapeutic Chemical Classification (ATC) index by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology (Oslo), only 26 antidepressants were prescribed in participating countries in East Asia. On average 38.4% of prescriptions of antidepressants were for patients with diagnoses other than depressive disorders. The availability and commonly prescribed antidepressants varied greatly by country. The selective serotonin re-uptake inhibitors (SSRI) and other newer antidepressants were prescribed in approximately 77.0% of all cases. At the time of the survey, only two SSRI medications were available in Japan. However, five types of SSRI were available and were often prescribed in Korea.

To date, only few reports are available regarding the long-term outcome of borderline personality disorder (BPD) in Japan. We conducted a retrospective follow-up study on the long-term outcome and predictive factors of BPD in Japan. Of 72 patients who received treatment at Fukuoka University Hospital between 1973 and 1989 and met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for BPD retrospectively, 19 patients (26.4%) were followed up. We evaluated global outcome at follow-up using the Global Assessment of Functioning Scale scored from a completed self-reported questionnaire. The mean Global Assessment of Functioning score was 60.7, which meant fair to good functioning. The suicide rate was 6.9% (5/72). Using a logistic regression model, overinvolvement in family relationships and the number of medical facilities where patient was previously treated predicted poor outcome. These results are similar to those reported in the United States and Canada, except for the result that Japanese patients with BPD are more likely to live with their original family at follow-up than American patients.

Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used antidepressants. Recently, citalopram has been reported to improve working memory in patients with depression, and psychotic symptoms and behavioral disturbances in patients with dementia. However, the possibility of using citalopram in the treatment of cognitive disorders has not received much attention. The present study investigated the effects of citalopram on scopolamine- and Delta9-tetrahydrocannabinol (THC)-induced impairment of spatial memory using an eight-arm radial maze and electroconvulsive shock (ECS)-induced immobilization (a behavioral model for the disturbance of consciousness). Low dose citalopram reversed both scopolamine- and THC-induced impairment of spatial memory, suppressed ECS-induced immobilization reversed the THC-induced decrease of acetylcholine (ACh) release in the dorsal hippocampus in vivo microdialysis, and enhanced tremors induced by oxotremorine, a muscarinic M1 receptor agonist. Taken together these findings suggest that low dose citalopram is useful for the treatment of memory deficits and consciousness disturbance.

Mutant R406W human tau was originally identified in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and causes a hereditary tauopathy that clinically resembles Alzheimer's disease (AD). In the current study, we examined the performance of R406W transgenic (Tg) mice in the forced swimming test, a test with high predictivity of antidepressant efficacy in human depression, and found an enhancement of the immobility time. In contrast, the motor function and anxiety-related emotional response of R406W Tg mice were normal. Furthermore, a selective serotonin reuptake inhibitor (SSRI), fluvoxamine (100 mg/kg, p.o.), significantly reduced this enhancement of the immobility time, whereas a noradrenaline reuptake inhibitor, desipramine, had no effect. In an in vivo microdialysis study, R406W Tg mice exhibited a significantly decreased extracellular 5-hydroxyindoleacetic acid (5-HIAA) level in the frontal cortex and also exhibited a tendency toward a decreased extracellular 5-hydroxytryptamine (5-HT) level. Moreover, fluvoxamine, which reduced the enhancement of the immobility time, significantly increased the extracellular 5-HT level in R406W Tg mice. These results suggest that R406W Tg mice exhibit changes in depression-related behavior involving serotonergic neurons and provide an animal model for investigating AD with depression.

In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.

Perospirone is a novel atypical antipsychotic drug with dopamine (DA) D2- and serotonin (5-hydroxytryptamine, 5-HT) 5-HT2A-receptor antagonist, and 5-HT1A-receptor agonist properties. In the present study, we examined the effect of perospirone on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), compared with the effects of other antipsychotics such as haloperidol and risperidone. Perospirone at a dose of 10 mg/kg (p.o.) inhibited marble-burying behavior without affecting the locomotor activity in mice. On the other hand, haloperidol (0.1 mg/kg, i.p.) and risperidone (1 mg/kg, p.o.) showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Furthermore, the inhibition of marble-burying behavior by perospirone was antagonized by WAY100135 (10 mg/kg, i.p.), a selective 5-HT1A-receptor antagonist. WAY100135 at the same dose also antagonized the inhibition of marble-burying behavior by 8-OH-DPAT (3 mg/kg, i.p.), a selective 5-HT1A-receptor agonist. These findings suggest that perospirone may exhibit anti-OCD activity in clinical use and that 5-HT1A-receptor agonistic activity may be involved in the inhibition of marble-burying behavior by perospirone. Keywords:: marble-burying behavior, perospirone, antipsychotic drug, 5-HT1A receptor, obsessive-compulsive disorder

Objective This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia. Method The study consisted of a screening phase and three phases: an oral conversion phase (≤ 12 weeks), an oral stabilization phase (≤ 12 weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4 weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400 mg) or oral aripiprazole (6–24 mg/day). The primary endpoint was Kaplan–Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26. Results A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: − 3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of − 3.9% which is well above the pre-defined non-inferiority limit (− 15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole. Conclusions Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole. Clinical Trials Registration JapicCTI-101175

Background Because psychiatric disorders are risk factors for suicide, psychiatric consultation should be an essential element of suicide prevention among individuals with a high risk of suicide. The aim of the present study was to compare the characteristics of individuals who had or had not received psychiatric consultation before they attempted suicide in Japan. Methods Clinical records were used to identify 300 consecutive persons who were admitted to the hospital for attempting suicide between April 2006 and March 2013. We divided the patients into two groups. One group consisted of patients who consulted a psychiatrist before their suicidal behaviours (the consultation group), and the other group consisted of patients who had not consulted a psychiatrist before their suicidal behaviours (the non-consultation group). Group differences were analysed with respect to gender, age, method of suicide attempts, psychiatric diagnosis (ICD-10), and duration of hospitalisation in the emergency unit. Results Females tended to be over-represented in the consultation group (73.0%), and males tended to be over-represented in the non-consultation group (59.8%). Poisoning by prescription drugs was used more frequently as a method of suicide in the consultation group than in the non-consultation group. Neuroticism and related disorders were higher in the non-consultation group (33.7%) than in the consultation group (18.9%). Mood disorders (32.6%) were nearly as common as neuroticism in the non-consultation group, and together they accounted for almost two-thirds of all diagnoses. Mood disorders were comparable between the consultation group (30.9%) and the non-consultation group (32.6%). Adult personality disorders (13.3%) and schizophrenia and related disorders (26.0%) were higher in the consultation group than in the non-consultation group. Conclusions Measures have to be taken to encourage people with these diverse characteristics to consult psychiatrists, and psychiatrists have to regularly evaluate patients for suicide risk. Furthermore, we need further research on the relationship between psychiatric consultation and poisoning by prescribed drugs.

Aim: To examine the effect of donepezil on sleep and daily activity in patients with Alzheimer-type dementia (ATD) using polysomnography and actigraphy. Methods: Ten patients with mild to moderate ATD (mean age: 76 ± 6.2 years) were studied. The Alzheimer’s disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog),polysomnography, and 7-day recording of actigraphy data were performed. Following this baseline assessment, donepezil (5 mg daily) was administered every morning for 6 weeks, after which the ADAS-Jcog, polysomnography, and actigraphy were repeated. Results: After 6 weeks of treatment with donepezil, daily activity was significantly increased (276.2 ± 89.2 vs. 326.1 ± 98.6; p < 0.05). Similarly, rapid eye movement (REM) sleep (11.3 ± 4.1 vs. 17.1 ± 4.4; p

The present study was designed to determine the effect of delta(9)-tetrahydrocannabinol (THC) on susceptibility to stress. We reported that THC significantly prolonged the immobility time during the forced swim-stress. The selective cannabinoid CB(1) receptor antagonist O-2050 significantly reduced the enhancement of immobility by THC. We investigated the effect of THC on levels of stress hormone corticosterone under non-stress and forced swim-stress conditions. THC did not affect plasma corticosterone levels under non-stress conditions. However, THC, together with forced swim-stress, significantly increased plasma corticosterone levels. This effect was inhibited by O-2050. This evidence suggests that THC, under stressful conditions, enhances the susceptibility of the hypothalamus-pituitary-adrenal-axis to stress via the CB(1) receptor, thereby increasing the risk of depression.

Two hundred and seventy healthy university students were surveyed in December 1995 using Bond's Defense Style Questionnaire (DSQ) to measure the subjects' defense mechanisms. At the same time, a survey using Byrne's R-S Scale (Repression–Sensitization Scale) of the MMPI (Minnesota multiphasic personality inventory) and five psychiatric symptom indexes (anxiety, sense of inadequacy, sensitivity, depression and impulsive anger) selected from the CMI (Cornell Medical Index-Health Questionnaire) was conducted. Three factors were extracted from the DSQ through factor analysis: immature defenses, neurotic defenses, and mature defenses. The results of analysis of variance revealed the following: (i) for anxiety and anxiety related symptoms, both immature defenses and neurotic defenses indicated principal effect; (ii) for impulsive anger and depression, immature defenses presented principal effect; and (iii) for sensitivity and impulsive anger, interaction between a mature defense style and neurotic defense style was noted. The relationship between defense styles and psychiatric symptoms in healthy people is studied in this paper.

We conducted a survey with the Lynfield obsessive-compulsive symptom questionnaire (revised version) on 48 obsessive-compulsive neurotic patients as the survey subjects. In the factor analysis five factors of obsessions, were identified: (i) the desire for perfection; (ii) compulsive checking; (iii) washing; (iv) feelings of uncleanliness; and (v) anthropophobia. High correlations were noted between these factors. We also investigated the premorbid personalities of obsessive-compulsive neurotic patients with a multidimensional personality scale and obtained an extroversion dimension and neuroticism dimension. The influence of these premorbid personality dimensions on obsessive-compulsive symptoms became clear; (i) neuroticism is related to the levels of obsession after onset, but not related to compulsive behaviors; and (ii) No differences in premorbid personality dimensions were noted between compulsive checking and compulsive washing behaviors. We also studied whether it was possible to predict the efficacy of pharmacotherapy upon obsessive-compulsive symptoms. It was elucidated that the obsessions of those whose premorbid personalities are emotionally stable and extroversive are susceptible to antidepressants. Based on these results, we discussed the usefulness of premorbid personalities in predicting diversity of obsessive-compulsive symptoms, as well as in prediction the efficacy of medication.

Compulsion becomes long-term when treatment is commenced with very severe resistance. Patients showing emotional changes are rare compared to those with conversion and phobic disorders. However, most people improve when careful treatment is carried out. Although there are those in whom drug treatment is effective, drug treatment and psychotherapy are concomitantly used in most cases. In this lecture, the characteristics of compulsion were psychodynamically investigated regarding: 1. Central conflict, 2. Defense mechanisms, 3. Condition of love life (including sex life), 4. Growth history, by comparing with phobias. When the life of the inner-self protrudes, obsessive-compulsive patients try to contradict and deny this. The symptoms sometimes directly represent the mental conflict of the person, and sometimes the symptom formation process may be understood to some extent. It is said that such cases are suitable for psychotherapy. Psychodynamic psychotherapy involves regaining the continuity of emotional life divided due to defenses such as negation, reaction formation, and isolation. Meanwhile, the real nature of phobias is avoidance and escape. Therefore, the trick in proceeding with interviews is to lead the phobia patient to areas which they avoid during interviews and areas which they avoid in daily life, and to have the patient enter these fields at times by encouraging them.

The aim of this study was to clarify the difference between the morphological and perfusion changes occurring with the progression of Alzheimer’s disease (AD). The study focused on 37 patients who were clinically diagnosed with AD and were examined by both MRI and perfusion SPECT twice during a 1- to 2-year clinical observation period. Twenty-four of the 37 patients showed a progression of cognitive deterioration during the 1.2(±0.4)-year period of clinical observation (rapidly progressing group: initial mean MMSE score = 23.3; second mean MMSE score = 20.2), while 13 patients showed no apparent progression of cognitive deterioration (slowly progressing group: initial mean MMSE score = 21.2; second mean MMSE score = 22.2). The morphological changes were evaluated using a voxel-based morphometric technique with segmented MRI images. Cerebral perfusion was measured by Tc-99m ECD SPECT. Data analysis was performed by SPM on a MATLAB work space (2007.a). There was no significant difference in either the perfusion or gray matter density between the rapidly progressing and slowly progressing groups at the initial examination. The rapidly progressing group showed an interval decrease of perfusion in the bilateral parieto-occipital cortex and a decrease of gray matter density in the bilateral temporal and cingulate cortex. The slowly progressing group did not show a significant interval change in either the cerebral perfusion or gray matter density. These results suggest that rapid symptomatic progression in AD patients accompanies rapid progression of both morphological and perfusion changes, although the regions of the changes differ between them.

The aim of this study was to investigate the effect of Yokukansan (YKS) on the impairment of spatial memory and cholinergic involvement in a rat model of early-phase Alzheimer’s disease (AD). In this model, rats underwent four-vessel transient cerebral ischemia and then were treated with beta amyloid oligomers injected intracerebroventricularly once daily for 7 days. These animals showed memory impairment in an eight-arm radial maze task without histological evidence of apoptosis but with a decrease in expression of hippocampal dynamin 1, an important factor in synaptic vesicle endocytosis. Oral administration of YKS for 2 weeks significantly increased the number of correct choices and decreased the number of error choices in the eight-arm radial maze task (P

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with dementia. Current pharmacological approaches to treatment are inadequate, despite the availability of serotonergic agents to ameliorate anxiety, one of the symptoms of BPSD. The herbal medicine yokukansan has been demonstrated to improve BPSD in a randomized, single-blinded, placebo-controlled study. However, the mechanisms of the anxiolytic effect of yokukansan have not been clarified. There are also no reports on the anxiolytic effect of yokukansan in cerebrovascular ischemia models. In this study, we examined whether rats subjected to repeated cerebral ischemia exhibited anxiety-like behavior in a plus-maze task, a light/dark box test and an open-field task. We then investigated the effect of yokukansan on anxiety-like behavior in ischemic rats. Repeated ischemia was induced by the four-vessel occlusion method in which a 10-min ischemic episode was repeated once after 60 min. Yokukansan was orally administered once a day for 14 days from 7 days before ischemia induction. The last administration was performed 1 h before the behavioral experiments. The ischemic rats showed anxiety-like behavior in all three tasks, suggesting that this rat may be a good model for anxiety in cerebrovascular dementia. Yokukansan exhibited anxiolytic effects on the anxiety-like behavior in rats subjected to repeated cerebral ischemia, and exerted antagonistic effects on the wet-dog shakes induced by 1-(2,5-dimethoxy-4-indophenyl)-2-amino propane, a serotonin receptor (5-HT(2A)) agonist. This study revealed that yokukansan shows anxiolytic effects not only in normal animals but also in cerebrovascular model rats.

Telmisartan, an angiotensin type 1 receptor blocker (ARB), is used for hypertension to control blood pressure and has been shown to have a partial agonistic effect on peroxisome proliferator-activated receptor gamma (PPARgamma). Recently, the ligand of PPARgamma has been implicated in cerebroprotection due to its anti-inflammatory effect. In this study, we investigated whether telmisartan has a cerebroprotective effect on memory impairment and neuronal cell death induced by repeated cerebral ischemia. Repeated cerebral ischemia (RI: 10 min x 2) significantly induced impairment of spatial memory and hippocampal apoptosis in rats. Fourteen-day pre- and post-ischemic administration of telmisartan (0.3, 1, 3mg/kg/day, p.o.) increased the number of correct choices and reduced the number of errors made in the eight-arm radial maze task in a dose-dependent manner in RI treated rats. TUNEL-positive cells in the hippocampus CA1 areas were also reduced following 14-day administration of telmisartan (3mg/kg/day, p.o.). Seven-day post-ischemic administration of telmisartan improved spatial memory and reduced TUNEL-positive cells while 7-day pre-ischemic administration of telmisartan did not. These effects of telmisartan were inhibited by the PPARgamma antagonist, GW9662. On further experiment, 7-day post-ischemic administration of telmisartan reduced the expression of caspase-3 in the hippocampus, and this effect was also inhibited by GW9662. These results suggest that telmisartan improves memory impairment and reduces neuronal apoptosis via a PPARgamma-dependent caspase-3 inhibiting mechanism. Telmisartan, which has the unique character of having both ARB and PPARgamma agonistic effect, will be useful for preventing memory impairment after cerebrovascular disease.

Paroxetine discontinuation symptoms can at times be severe enough to reduce the quality of life. However, it is currently not possible to predict the occurrence of discontinuation syndrome before the initiation or discontinuation of paroxetine treatment. In this study, we investigated the effects of genetic polymorphisms in the serotonin 1A, 2A, 2C, 3A, and 3B receptor, the serotonin transporter, and the cytochrome P450 2D6 (CYP2D6) genes on the occurrence of paroxetine discontinuation syndrome. A consecutive series of 56 Japanese patients who had a diagnosis of major depressive or anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, were treated with paroxetine. Paroxetine discontinuation syndrome was found in 35.7% of the patients by direct interview. Patients who stopped taking paroxetine abruptly experienced paroxetine discontinuation syndrome significantly more often than patients who had a tapering off of the dosage of medication. Patients who had the -1019C allele experienced paroxetine discontinuation syndrome more frequently than patients who had the -1019G homozygote (nominal P = 0.0423) of the serotonin 1A receptor gene. However, this result did not remain significant after the Bonferroni correction for multiple comparisons. The findings suggest that the abrupt stoppage of medication is a major risk factor for the occurrence of paroxetine discontinuation syndrome and that C(-1019)G polymorphism of the serotonin 1A receptor gene may be related to the occurrence of the syndrome.

The methionine variant of Val66Met brain-derived neurotrophic factor (BDNF met ) and catecholamine-O-methyltransferase (COMT L ) is associated with a deficit in attention and aggravation of delusions in schizophrenia.We hypothesized that the BDNF-COMT gene interaction would affect the symptoms and cognition in schizophrenia. Ninety-six schizophrenic patients and 79 control participants were recruited. The patients who were BDNf met/met x COMT L carriers had the highest scores of delusion of Positive Symptoms and the Scale for Assessment of Negative Symptoms, word reading of the color word test, and trail-making test B time, compared with the other three genotype interactions. The current results suggest that patients with the BDNf met/met x COMT L allele had more delusional symptoms and poorer cognitive flexibility, compared with the other three genotype interactions.

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.

Clinical evidence demonstrates altered glutamatergic neurotransmission in patients suffering from obsessive–compulsive disorder (OCD). We examined the effects of glutamate-related drugs on marble-burying behavior, which is an animal model of OCD. The uncompetitive N-methyl- d -aspartate (NMDA) antagonists memantine (10 mg/kg, i.p.) and amantadine (30 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity in mice. Similarly, the uncompetitive NMDA receptor antagonist 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801, 0.3 mg/kg, i.p.) inhibited marble-burying behavior. However, MK-801 at the same dose markedly increased locomotor activity. By contrast, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and the glutamate release inhibitor riluzole showed no effect on marble-burying behavior and significant suppression of locomotor activity. MK-801 (0.3 mg/kg, i.p.) and memantine (10 mg/kg, i.p.) significantly disrupted prepulse inhibition as an operational measure of sensorimotor gating. By contrast, amantadine (30 mg/kg, i.p.) did not affect prepulse inhibition. These findings suggest that amantadine could be a useful drug for the treatment of OCD.

In the present study, we examined the involvement of the sigma1 receptor in the inhibitory effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, compared with that of paroxetine, on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Sigma1 receptor agonists (+)-SKF 10047 and PRE-084 significantly inhibited marble-burying behavior. Sigma receptor antagonist BD 1047 and selective sigma1 receptor antagonist BD 1063 significantly attenuated the inhibition of marble-burying behavior by fluvoxamine. In contrast, selective sigma2 receptor antagonist SM-21 failed to affect the inhibition of marble-burying behavior by fluvoxamine. On the other hand, BD 1047 and BD 1063 had no effect on the inhibition of marble-burying behavior by paroxetine. These observations show that activation of the sigma1 receptor is a necessary component in the inhibitory effect of fluvoxamine on marble-burying behavior, and that the mechanism of its action is clearly different from that of paroxetine.

The purpose of this study was to identify mechanisms that mediate the impairment of spatial memory induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A/5-HT7 receptor agonist, in the eight-arm radial maze in rats. WAY-100635 and NAN-190, 5-HT1A receptor antagonists, reversed the impairment of spatial memory induced by systemic injection of 8-OH-DPAT (1 mg/kg, i.p.). On the other hand, the α1-adrenoceptor antagonist prazosin and a selective 5-HT7 receptor antagonist SB269970 had no effect on 8-OH-DPAT-induced impairment of spatial memory. Bilateral microinjection of 8-OH-DPAT (4 μg/side) impaired spatial memory when injected into the dorsal hippocampus (DH). Contrastingly, spatial memory was unaffected by microinjections of 8-OH-DPAT into the other six areas examined: ventral hippocampus (VH), central amygdaloid nucleus (ACE), lateral hypothalamus (LH), nucleus accumbens (NAc), and dorsal (DR) and median (MR) raphe nucleus. Furthermore, NAN-190 significantly reversed the impairment of spatial memory induced by intra-DH injection of 8-OH-DPAT. These findings suggest that 5-HT1A receptors in the DH play an important role in the mechanisms underlying the 8-OH-DPAT-induced impairment of spatial memory in rats.

Most children who go through adolescence manage to overcome the "storm of adolescence," but some children are not so fortunate and have difficulty in coping. They may feel that their inability to cope is unique or that they will forever be handicapped or diseased as a result. In reality, the trials of adolescence, combined with a sub optimal personal life often result in setbacks. Adolescence, by definition is a time of development. And this development is extensive; physical, mental, sexual and self-awareness. Personality change is inevitable. Over a relatively short period, young children evolve into adults. Every one experiences these drastic changes, but to each child, it seems that he/she is going through the experience alone, for the first time. We must convey to these children that this situation is normal, and is inevitably stressful. If we can succeed in even a small way to do this, I believe we can find a way to help adolescent children.

The present study was undertaken to investigate the antagonistic effects of the methanolic extract of Polygala telephioides (PT) on morphine responses in mice. Single administration of PT tended to antagonize the morphine-induced analgesia in a hot-plate test. Moreover, PT (300 mg/kg, p.o.) improved the morphine-induced memory impairment in an elevated plus maze test. However, PT alone had no effect on behaviors in the open-field, hot-plate and elevated plus maze tests. We investigated the effects of PT on naloxone-induced jumping (as withdrawal sign) in morphine-dependent mice. To induce dependence, mice were twice daily treated with morphine (10-45 mg/kg, s.c.) for 5 days. Co-administrations of PT (10, 100 and 300 mg/kg, p.o.) during repeated morphine treatments significantly suppressed the naloxone (10 mg/kg, i.p.)-induced jumping. However, the naloxone-induced jumping was not affected by a single large administration of PT on the 5th day. The inhibitory effect of PT on the naloxone-induced jumping was due to the development of dependence rather than expression of withdrawal sign. Moreover, single administration of PT (300 mg/kg, p.o.) decreased the morphine levels in plasma. These results indicate that PT may be useful in facilitating narcotic detoxification.