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Objectives. We aimed at evaluating both the efficacy and safety of TJ-54 (Yokukansan) in patients with treatment-resistant schizophrenia. This randomized, multicenter, double-blind, placebo-controlled study was conducted.Methods. One hundred and twenty antipsychotic-treated inpatients were included. Patients were randomized to adjuvant treatment with TJ-54 or placebo. During a 4-week follow-up, psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).Results. TJ-54 showed a tendency of being superior to placebo in reduction total, positive, and general PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant in both per-protocol set (PPS) and intention-to-treat (ITT). However, in PPS analysis, compared to the placebo group, the TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores for lack of spontaneity and flow of conversation (TJ-54:−0.23±0.08; placebo:−0.03±0.08,P<0.018), tension (TJ-54:−0.42±0.09; placebo:−0.18±0.09,P<0.045), and poor impulse control (TJ-54:−0.39±0.10; placebo:−0.07±0.10,P<0.037).Conclusions. The results of the present study indicate that TJ-54 showed a tendency of being superior to placebo in reduction PANSS scores in treatment-resistant schizophrenia, but the difference was not statistically significant. However, compared to the placebo group, TJ-54 group showed statistically significant improvements in the individual PANSS subscale scores.

Background: Prior research confirms that insomnia is highly prevalent in patients with psychiatric disorders. Benzodiazepine hypnotics, causing serious disadvantages, have been widely used in psychiatry for a long time. Sansoninto (SNT), Japanese herbal medicine, is used for patients with weakness and fatigue, annoyance, insomnia, amnesia, and neurotic symptoms. Objective: The efficacy and safety of SNT was examined in adult psychiatric disorder patients with insomnia symptoms. Methods: Eighty-one adults with sleep disturbance meeting DSM-IV-TR diagnostic criteria for psychiatric disorders (schizophrenia: 17; monopolar depression: 20; bipolar depression: 10; adjustment disorder: 12; anxiety disorder: 5; others: 17) were treated openly for four weeks with SNT (2.5-7.5 g) at bedtime. Patients maintained sleep throughout the study. Efficacy was analyzed using a repeated measures methodology. The primary outcome was the Pittsburgh Sleep Quality Index (PSQI). The secondary outcomes were the Insomnia Severity Index (ISI), Athens Insomnia Scale (AIS), Clinical Global Impression-Improvement (CGI-I), and change of dosage of benzodiazepine hypnotics (diazepam equivalent). Results: After 4 weeks of SNT therapy, significant symptom reduction was observed on all parameters (PSQI: 10.22 ± 3.23 vs. 3.11 ± 3.52; ISI: 20.63 ± 4.86 vs. 3.38 ± 5.10; AIS: 17.41 ± 4.69 vs. 2.85 ± 4.23; dosage of benzodiazepine hypnotics [diazepam equivalent, mg]:10.5 ± 4.71 vs. 2.98 ± 3.37). No withdrawal involved treatmentrelated adverse events. Conclusion: Data from this 4-week open-label study suggests SNT was an effective and generally well tolerated treatment for insomnia symptoms in this sample of adult patients with psychiatric disorders.

ResumenAntecedentesLos pacientes con esquizofrenia muestran una frecuencia significativamente más alta de hiperbilirrubinemia que los pacientes que sufren de otros trastornos psiquiátricos y la población general sana. El objetivo del actual estudio fue determinar si los pacientes con hiperbilirrubinemia no conjugada idiopática (síndrome de Gilbert, SG) asociada a la esquizofrenia tienen cambios especificos en las intensidades de señal en imagénes de resonancia magnética (RM) de inversión-recuperación con atenuación de fluido (FLAIR).MétodosSe comparó imágenes de RM FLAIR axiales de 5 mm de grosor de pacientes de esquizofrenia con SG (n = 18) y pacientes de esquizofrenia sin SG (n = 18), diagnosticados todos ellos según los criterios del DSM-IV, con controles no psiquiátricos emparejados por la edad y el sexo (n = 18). Se graduaron las intensidades de señal en el hipocampo, la amígdala, el caudado, el putamen, el tálamo, el giro cingulado y la ínsula en relación con la intensidad de la señal cortical en el lóbulo frontal.ResultadosComparado con los pacientes de esquizofrenia sin SG y los controles normales, los pacientes de esquizofrenia con SG mostraron aumentos significativos de la intensidad de señal en casi todas las regiones estudiadas.ConclusiónLos pacientes con SG asociado a esquizofrenia tienen cambios específicos de las intensidades de señal en las imágenes de RM FLAIR, indicando que la esquizofrenia con SG produce cambios en la corteza frontotemporal, el sistema límbico y los ganglios basales.

The purpose of the present paper was to evaluate the prevalence of restless legs syndrome (RLS) in a non-institutionalized Japanese elderly population. The subjects consisted of 8900 elderly people >65 years of age belonging to the Seniors Association in Izumo City in November 2000. The present study was conducted in two parts. The phase 1 investigation was a screening by mailed questionnaire and the phase 2 investigation was diagnosis by face-to-face interview. Subjects with possible cases of RLS in phase 1 proceeded to phase 2 and definite cases of RLS were then detected. In phase 1, a total of 3287 subjects completely answering all questionnaire items, were defined as the subjects of the present study. A total of 150 were classified as having 'probable RLS', resulting in a prevalence of 4.6%. These subjects with probable RLS in phase 1 were detected as the subjects of phase 2. By face-to-face interview and various clinical examinations, a total of 35 subjects (nine male, 26 female) were diagnosed as having definite RLS, resulting in a prevalence of 1.06%. Furthermore, seven subjects (two male, five female) with symptomatic RLS were detected and finally 28 subjects (seven male, 21 female) were diagnosed as having idiopathic RLS. It was significantly higher in women for both the total and idiopathic RLS groups (0.60% male vs 1.46% female; 0.46% male vs. 1.18% female, respectively). The prevalence of RLS may be lower in the Japanese elderly than that in Caucasian subjects. These results could enhance understanding of the differences in predisposition between the races.

Several authors have suggested that psychological stress induces the production of reactive oxygen species (ROS). Several studies have supported the idea that bilirubin exerts antioxidative effects in vivo, and it was reported psychological stress provokes bilirubin oxidation in vivo [Yamaguchi T., Shioji I., Sugimoto A., Yamaoka M., 2002. Psychological stress increases bilirubin metabolites in human urine. Biochem. and Biophys. Res. Commun. 293, 517-520]. We investigated whether the concentration of bilirubin oxidative metabolites (biopyrrins) is increased in urine from patients with psychiatric disorders. The concentration of biopyrrins in urine of 25 patients with psychiatric disorders (schizophrenia, 15; depression, 10) was compared with 96 healthy volunteers. The concentrations of biopyrrins, as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. The concentration of biopyrrins in patients with psychiatric disorders (schizophrenia and depression) was significantly higher than that of healthy volunteers. In schizophrenia, biopyrrins levels correlated with scores of the Brief Psychiatric Rating Scale (BPRS), and in depression, biopyrrins levels correlated with scores of the Hamilton Depression Rating Scale (HAM-D). These finding suggest that psychotic states are associated with an increase in the oxidative metabolites of bilirubin in human urine.

Objective: Some patients develop an eating disorder at a late age. It is worth investigating why this syndrome develops at such widely different ages. Methods: Two Japanese cases of late onset anorexia nervosa are reported. Results: In these late onset cases, anorexia developed out of sadness over a loss such as bereavement, divorce, and fear or anxiety for the future. In addition, these two patients didn't demonstrate a fear of aging or of losing their attractiveness and sexuality, nor did they develop a dissociative disturbance based on an early traumatic history of sexual abuse in PTSD. Conclusion: Although the clinical features are similar, there appear to be differences between late onset and adolescent cases in psychological mechanisms.

Previous studies have supported the claim that psychological stress induces the production of reactive oxygen species. Several authors have suggested that patients with psychiatric disorders show high levels of oxidative stress markers. We examined different oxidative stress markers in patients with chronic schizophrenia.This study included 29 patients with chronic schizophrenia and 30 healthy volunteers. The concentration of urinary biopyrrins and 8-hydroxydeoxyguanosine (8-OHdG), as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. Psychiatric symptoms were assessed by the administration of the Brief Psychiatric Rating Scale (BPRS).The concentration of biopyrrins in patients with chronic schizophrenia was significantly higher when compared with healthy volunteers. The correlation between biopyrrin level and the duration of illness was highly significant. There were no significant differences in the levels of urinary 8-OHdG between the two groups. In schizophrenic patients, the level of urinary biopyrrins showed correlations with BPRS scores, while the level of urinary 8-OHdG did not show correlations with BPRS.Urinary biopyrrins are increased in patients with chronic schizophrenia while urinary 8-OHdG is not increased. These findings suggest that patients with chronic schizophrenia are under the condition of certain oxidative stresses.

Progressive disability in schizophrenia has been considered to be associated with onset-age. The objective of this study was to evaluate age onset-related degeneration in rCBF in patients with schizophrenia. We evaluated characteristic changes in brain perfusion by age, gender, medication and clinical symptoms in medicated patients with early-onset (EOS: developed at younger than 40 years old: n = 44) and late-onset (LOS: developed at older than 40 years old: n = 19) schizophrenia and control subjects matched for age and gender (n = 37) using statistical parametric mapping (SPM8) applied to 99mTc-ECD SPECT. We performed SPECT with 99mTc-ECD on the brains of subjects. A voxel-by-voxel group analysis was performed using SPM 8 and ANOVA. rCBF in EOS was found to be reduced in the precentral and inferior frontal gyri; on the other hand, rCBF was reduced in the bilateral postcentral gyrus in LOS. This study revealed a significant difference in brain perfusion between EOS and LOS. The present study might suggest that the characteristic changes in rCBF are related to onset-age in schizophrenia.

Activated astrocytes, which can also be referred to as reactive astrocytes or astrogliosis, have been identified in affected regions of common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Activated astrocytes may be beneficial, promoting neuronal survival due to their production of growth factors and neurotrophins. Activated astrocytes can also be detrimental to neighboring neurons in neuroinflammatory processes. Astrocytes exposed to certain inflammatory stimulants in vitro have been shown to release potentially neurotoxic molecules, including inflammatory cytokines, glutamate, nitric oxide and reactive oxygen species. It has recently been shown that adult human astrocytes stimulated with interferon-γ, a common inflammatory cytokine evidently present in neuropathological brains, exert potent neurotoxicity in vitro. This interferon- γ-induced astrocytic neurotoxicity is mediated by the activation of the Janus kinase-signal transducer and activator of transcription (STAT) 3 pathway in the astrocytes, and involves intracellular phosphorylation of STAT3 at tyrosine-705 residue. Therefore, control of STAT3 activation in human astrocytes may be a promising new therapeutic strategy for a broad spectrum of neurodegenerative and neuroinflammatory disorders where activated astrocytes may contribute to the pathology.

We report the case of a 58-year-old female without a history of psychosis or epilepsy presenting with abrupt late-onset persistent visual hallucinations that had prominent epileptiform discharges with a diffuse sharp and slow wave complex on electroencephalography. Except for the visual hallucinations, other psychotic symptoms and epileptic seizures, such as disturbance of consciousness and convulsion, were not observed. The epileptiform discharge disappeared within 20 days after initiation of treatment with sodium valproate. Clinical improvement commenced after the electroencephalography improvement was complete. The cause remains obscure, but it was suggested that there were some organic factors in the aetiology of this late-onset visual hallucination.

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

Background: Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome) is a benign hyperbilirubinemia found in the general population. There has been only 1 previous report of Gilbert's syndrome occurring in schizophrenic patients. The present study was conducted to determine the frequency of Gilbert's syndrome in schizophrenic patients relative to patients with other psychiatric disorders. Method: Plasma bilirubin concentrations of every patient admitted to the psychiatric hospital during a 3-year period were collected, and patients were examined to exclude all other causes of hyperbilirubinemia. In addition, the psychiatric symptoms of schizophrenic patients (ICD-10 criteria) with hyperbilirubinemia were evaluated by the Positive and Negative Syndrome Scale (PANSS). Results: Schizophrenic patients showed a significantly higher incidence of hyperbilirubinemia (p

A 70-year-old male began to show akinesia, rigidity of extremities, finger tremor, disturbed vertical external ocular movement, and nuchal dystonia, which progressed slowly. Brain CT scan and magnetic resonance images showed slight atrophy of the frontal lobe and slight enlargement of the lateral ventricles. Hasegawa's dementia rating scale-revised version gave a moderate score of 11/30 points. He died of pneumonia at the age of 76. The clinical diagnosis was progressive supranuclear palsy (PSP). However, there were no neuropathological characteristics of PSP. Neuropathologically, Parkinson's disease was diagnosed. In addition, many argyrophilic grains (ArGs) in the gray matter were stained, especially in the insula, amygdala, hippocampus, parahippocampal gyrus, lateral occipitotemporal gyrus, and substantia nigra, by the Gallyas-Braak method. We consider that ArGs could modify the symptoms of Parkinson's disease and that Parkinson's disease with ArGs may show a PSP-like clinical course.

The regulated expression of Wnt-1, one member of the wingless/Wnt pathway, in the brain is critical for many neurodevelopmental processes. Recently, it has been reported that the wingless/Wnt pathway participates in a complex behavioral phenomenon and suggested that this pathway's molecules are candidate genes for neuropsychiatric disorders. Thus, we investigated the expression of Wnt-1 in the hippocampal region, which is believed to be closely involved in the pathophysiology of schizophrenia, of postmortem brains from 10 schizophrenic and 10 control individuals. Immunohistochemical analysis with polyclonal antibodies recognizing Wnt-1 revealed immunoreactivity primarily in the pyramidal cell layer, particularly in CA3 and CA4 regions. We observed a significant elevation in the number of Wnt-1-immunoreactive neurons in the great majority of schizophrenic brains relative to that in controls. The expression of Wnt-1 may be related to cell adhesion, synaptic rearrangement, and plasticity. Therefore, the increase in Wnt-1 immunoreactivity in schizophrenic hippocampi suggests an altered plasticity of this structure in a large proportion of schizophrenic brains. These findings suggest an abnormality of the wingless/Wnt pathway present in the schizophrenic brain and may support the 'neurodevelopmental hypothesis' of schizophrenia.

Polyclonal antibodies were generated against ADP-ribosylarginine hydrolase (AAH), using recombinant fusion protein of rat AAH and glutathione-S-transferase as a immunogen, and affinity-purified. Western blotting showed that the antibodies recognized in mouse brain homogenate a single protein with a molecular mass of 38 kDa, the expected size for mouse AAH. An analysis using the antibodies revealed that heavy labelings were apparent in various brain regions. In the cerebral cortex, pyramidal cells in layers III and V were the most heavily labeled. In the hippocampal formation, labeling was present on the pyramidal neurons and granule cells. The most heavily immunostained cell type was the pyramidal neuron of CA3. In the cerebellum, Purkinje cells were the most heavily labeled. Less intense staining was present over the granule cells. In the basal ganglia, neurons in the caudate nucleus and large multipolar cells in the amygdaloid complex were immunoreactive. Heavy labeling was seen in many midbrain and brainstem nuclei. Neurons in the habenula and ependymal cells were stained heavily. On Western blot analysis of rat cerebrospinal fluid (CSF), the anti-AAH antibodies recognized a protein with a molecular mass of 38 kDa. This is apparently the first evidence of a widespread but distinctive distribution of AAH in neurons of mouse brain and the presence of extracellular AAH in rat CSF.

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

Aims: Although there have been no conclusive pathophysiological findings in support of the degeneration theory in the etiology of schizophrenia to date, results of our neuroimaging studies suggest functional changes in the brains of schizophrenics. We evaluated age-related changes of brain perfusion in medicated patients with schizophrenia. Method: In this study, we evaluated age-related changes in brain perfusion in medicated schizophrenia patients (n = 44) and control subjects (n = 37) undergoing 99mTc-ethyl cysteinate dimer single-photon emission computed tomography. Result: Although the regional cerebral blood flow (rCBF) was found to be reduced in bilateral frontal lobes by analysis with age in the patients with schizophrenia, significant differences compared to controls in age effects on perfusion were found in the patients with schizophrenia in bilateral temporal lobes. Moreover, in multiple regression analysis including age, total time of treatment and overall neuroleptic dose, rCBF was found to be reduced in bilateral frontal and parietal lobes. As a result, cerebral perfusion in temporal lobes with schizophrenia might be related to age rather than medication. Conclusion: In this study, the patients with schizophrenia appeared to have significant bilateral temporal hypoperfusion related to age compared with controls. And bilateral temporal rCBF is decreased in patients with schizophrenia and even more in older schizophrenia patients. These changes might be consistent with degenerative changes observed in patients with schizophrenia and be a promising method for the efficient development of a treatment strategy by measuring temporal perfusion in patients with schizophrenia.

Autistic disorder is a neuropsychiatric syndrome characterized by deficits in social interaction; qualitative impairments in communication; and restricted, repetitive, and stereotyped patterns of behavior, interests, or activities. It is classified as a type of pervasive developmental disorder (PDD). All PDDs have a qualitative impairment in social relatedness. However, many individuals with PDDs have interfering symptoms, including irritability (aggression, self-injurious behavior, and severe tantrums). Behavioral therapy is often helpful in decreasing these behaviors; however, sometimes adjunctive medications are needed, because of the intensity and severity of irritability. Numerous medications have been tested on patients with PDDs. Although many of these medications have been demonstrated to be useful, no clear main treatment for PDD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Yokukansan (TJ-54), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situations for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous system. Recent studies indicate that TJ-54 may be safe and useful in treating behavioral and psychological symptoms in dementia patients. We aimed at evaluating both the efficacy and the safety of TJ-54 in patients with PDDs.This was a 12 week prospective, open-label investigation of TJ-54 in 20 children and adolescents ages 6-17 years diagnosed with PDDs. Primary outcome measures included the Clinical Global Impressions-Improvement of Illness Scale (CGI-I), Children's Global Assessment Score (CGAS), and the Aberrant Behavior Checklist (ABC) irritability subscale.Twenty subjects, ages 6-17 years, received TJ-54 in the dosage range of 2.5-7.5 g/day. The CGI-I was significantly improved from 8 weeks (p0.001). The mean CGAS was 31.92 at baseline, whereas the mean final score at 12 weeks was 54.52 (p0.001). The ABC irritability/agitation subscale (subscale 1) was significantly improved from 8 weeks, and the hyperactivity/noncompliance subscale (subscale 4) was significantly improved in 12 weeks. TJ-54 was well tolerated. No subject left the study because of a drug-related adverse event.These preliminary data suggest that TJ-54 may be effective and well tolerated for the treatment of severe irritability/agitation and hyperactivity/noncompliance in children and adolescents ages 6-17 years with PDD. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

Delirium is a common and serious acute neuropsychiatric syndrome characterized by inattention and global cognitive dysfunction. Delirium is associated with higher morbidity, higher mortality and longer hospitalization, but its aetiology remains unclear. We successfully treated five cases of delirium within 1 day with ramelteon, a novel selective melatonin receptor agonist. This suggests that correction of the circadian rhythm disturbance, one of the main symptoms of delirium, plays a crucial role in its treatment and sheds new light on a therapeutic strategy for treatment of delirium.

Several researches indicate that autonomic nervous system (ANS) dysfunction in patients with schizophrenia. Recently, salivary alpha-amylase (sAA) has been employed as a useful marker for ANS function. We investigated the extent of ANS dysfunction by measuring sAA and heart rate variability (HRV) of 25 patients with schizophrenia compared with controls. Schizophrenia group demonstrated a significant increase in sAA and markedly lower parasympathetic nervous system (PNS) activity in the HRV. However, there were no significant differences between two groups in sympathetic nervous system (SNS) activity. We concluded that PNS might be suppressed and the SNS shows relatively high activity in schizophrenia.

Jaw-opening dystonia (oromandibular dystonia with jaw-opening; Brueghel's syndrome) is a rare condition, and only a limited number of cases have been reported in the literature. However, many patients may remain undiscovered or misdiagnosed, like a patient described previously. A case (40-year-old man) of jaw-opening dystonia (oromandibular dystonia with jaw-opening; Brueghel's syndrome) is reported. In this case, brain anomalies, cavum septi pellucidi and Verga's ventricle, were observed on magnetic resonance imaging of the brain. This case and a review of the literature indicate the presence of organic factors in the etiology of Brueghel's syndrome. The etiological relationship of brain anomalies in Bruegel's syndrome is discussed.

We describe a patient who developed Korsakoff syndrome following a spontaneous chronic subdural hematoma. The present case demonstrates persistence of both amnesia and confabulation long after recovery from the acute phase of spontaneous chronic subdural hematoma. There are few reports describing persistent amnesia with confabulation following brain damage. We considered that chronic subdural hematoma in the bilateral frontal and temporal lobes caused amnesia and confabulations, and these conditions persisted as a result of organic atrophic changes of both the frontal and temporal lobes due to long-term compression by chronic subdural hematoma.

Background Numerous medications have been tested on patients with pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger’s disorder. Although many of these medications have been demonstrated to be useful, no clear primary treatment for PDD-NOS and Asperger’s disorder has emerged. Despite the efficacy of some of the medicines, the acceptability and side effects have proven to be barriers to their use. Recent studies indicate that the traditional Japanese herbal medicine yokukansan (TJ-54) may be safe and useful in treating behavioral and psychological symptoms in dementia and some neuropsychiatric disorders. We aimed at evaluating both the efficacy and safety of TJ-54 in patients with well-defined PDD-NOS and Asperger’s disorder. Methods This was a 12-week prospective, open-label investigation of TJ-54 in 40 children, adolescents, and adults diagnosed with PDD-NOS or Asperger’s disorder. Primary outcome measures included the Clinical Global Impressions-Severity of Illness Scale (CGI-S) and the Aberrant Behavior Checklist-Iritability subscale score (ABC-I). Results Forty subjects, ages 8–40 years (mean 22.7 ± 7.3 years) received a mean final TJ-54 dosage of 6.4 ± 1.3 g/day (range 2.5-7.5 g/day). Full-scale intelligence quotient (IQ) scores ranged from 70 to 110 (mean 88.9 ± 13.2). Thirty-six (90%) of 40 subjects showed fewer interfering symptoms of irritability, including aggression, self-injury, and tantrums, with a final CGI-S of 1 or 2 (normal, not at all ill or borderline mentally ill) and a 80% or greater improvement on the ABC-I. The mean CGI-S score at baseline was 6.8 ± 0.8 whereas scores at end point was 1.9 ± 0.1 (< 0.0001). ABC-I scores ranged from 11 to 29 (mean 17.4 ± 3.66) at baseline, whereas scores at week 12 ranged from 0 to 5 (mean 0.93 ± 0.97) (p Conclusions These preliminary data suggest that TJ-54 may be effective and well tolerated for treatment of severe irritability, lethargy/withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech in patients with PDD-NOS or Asperger’s disorder. However, given the characteristics of this trial, the present findings should be taken cautiously, and larger-scale placebo-controlled studies are needed to elucidate the efficacy and tolerability of TJ-54 in this understudied population.

Background Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats. Methods Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus. Results We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function. Conclusions We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.

Progressive supranuclear palsy (PSP) is a parkinsonian-like disorder characterized by postural instability, rigidity, bradykinesia, supranuclear ocular palsy, dysarthria, dysphagia and dementia. There is no satisfactory treatment. A 68-year-old woman with initial progressive supranuclear palsy is described, who was generally apathetic, withdrawn, lacked spontaneity in speech and behavior, and suffered episodes of depression. Treatment with levodopa/carbidopa was ineffective in controlling her parkinsonism and depression, but these symptoms responded to fluvoxamine. This response may be related to fluvoxamine's putative effect on the serotonin system.

Background There have been reports of a positive relationship between schizophrenia and hyperbilirubinemia. Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and when compared to the general population. Previously we observed that patients suffering from schizophrenia frequently present an elevated unconjugated bilirubin plasma concentration, when admitted to the hospital. In addition it was recently reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. We also reported that Gunn rats, which tend to show a high frequency of hyperbilirubinemia, may be used as an animal model of schizophrenia. In the present study, we assessed the effects of antipsychotics on Gunn rat behavioral abnormalities. Methods We examined the behavior of Gunn rats after treatment with risperidone (0.1 mg/kg), haloperidol (0.2 mg/kg), or aripiprazole (0.4 mg/kg) using an open-field test, social interaction test and a prepulse inhibition (PPI) test. Results The administration of antipsychotics alleviated behavioral abnormalities, mimicking some positive and negative symptoms and cognitive defects of schizophrenia. The pharmacological reaction of Gunn rats to antipsychotics echoes the pharmacological response of humans to such antipsychotics. Conclusions Our study suggested that the Gunn rat may be useful as a preclinical model of schizophrenia with which to evaluate the pharmacological properties of antipsychotics. The results obtained to date have been encouraging and warrant further research.

Background Approximately 25% of patients admitted to a hospital as a result of depression are actually suffering from psychotic depression. Psychotic symptoms can be present in patients with either unipolar depression or bipolar depression and can be difficult to treat. It was reported the second-generation tetracycline may exert potential antidepressant effects through its robust neuroprotective activities, which include neurogenesis, antioxidation, and anti-glutamate excitotoxicity, and may direct regulation of pro-inflammatory agents. Methods This was a 6-week, open-label study to evaluate the efficacy and safety of minocycline in combination with antidepressants in adult inpatients (n = 25) diagnosed with major depression with psychotic features (psychotic depression) according to DSM-IV-TR. The primary endpoint was the change from baseline in the Hamilton Depression Rating Scale (HAM-D-21) score from baseline to week 6. Secondary endpoints were changes in the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale scores from baseline to week 6. Spontaneously reported adverse events were recorded. Results The patients' average age was 46.9 ± 10.2 years. Minocyline (150 mg/day) in combination with antidepressants (fulvoxamine, paroxetine, and sertraline) provided significant improvement in depression. Mean (± SD) HAM-D-21 was reduced to 6.7 ± 1.9 at week 6 from a baseline value of 40.4 ± 2.5. Significant improvement of psychotic symptoms (mean ± SD) was indicated by the decrease in BPRS scores from baseline (63.3 ± 8.7) to week 6 (4.6 ± 2.4). No serious adverse events occurred. Conclusions These preliminary data suggest that minocycline in combination with antidepressants is effective and well tolerated in the treatment of unipolar psychotic depression. Further studies using larger, double-blind, parallel-group design are warranted to confirm these findings.

Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome, or GS) is a relatively common congenital hyperbilirubinemia occurring in 3-7% of the world's population. It has been recognized as a benign familial condition in which hyperbilirubinemia occurs in the absence of structural liver disease or hemolysis, and the plasma concentration of conjugated bilirubin is normal. Recently, it has been reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. The 'neurodevelopmental hypothesis' of schizophrenia proposes that an as-yet-unidentified event occurs in utero or during early postnatal life. We have observed that patients suffering from schizophrenia frequently present with an increased unconjugated bilirubin plasma concentration when admitted to the hospital. As a result, we noticed a relationship between unconjugated bilirubin and the etiology of, and vulnerability to, schizophrenia. Our reported findings suggest that there are significant biological and clinical character differences between schizophrenic patients with and without GS. From the viewpoint of the heterogeneity of schizophrenia, there may be a poor outcome for the subtype of schizophrenia with GS.

We report the case of a 62-year-old man who was administered sodium valproate (VPA) and who subsequently developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). He had been taking VPA for treatment of idiopathic generalized tonic-clonic convulsions since he was 56 years old. After substituting VPA with zonisamide, the serum sodium level returned to normal. We consider this episode of SIADH to be the result of a combination of factors including a weakness of the central nervous system and the long-term administration of VPA.

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

Zolpidem, a nonbenzodiazepine hypnotic, is very effective and widely prescribed in clinical practice for the treatment of insomnia and is thought to have few adverse effects. However, zolpidem-induced adverse effects have begun to be reported in the literature, but few systemic descriptions of the adverse effects (especially for psychotic reactions) of zolpidem have been undertaken. In light of the accumulating reports of adverse reactions to zolpidem, we present 2 case reports of zolpidem-induced adverse effects and review the literature on this subject.Articles were selected by the authors on the basis of our experience and by a PubMed search using the terms zolpidem or side effects or adverse effects or adverse reactions.Publications relevant to the objective of this article were obtained (1992-2010), and some adverse neuropsychiatric reactions were summarized.Zolpidem has been associated with the development of adverse neuropsychiatric reactions, such as hallucinations/sensory distortion, amnesia, sleepwalking/somnambulism, and nocturnal eating. The following 4 variables should be considered when prescribing zolpidem: (1) gender: women have been found to have a significantly higher serum zolpidem concentration than men; (2) zolpidem dose: the adverse reactions that develop are dose dependent; (3) protein binding affinity: a high proportion of zolpidem is protein bound; therefore, low serum albumin results in a higher level of free zolpidem leading to adverse psychiatric reactions; and (4) cytochrome P450 (CYP) isoenzyme inhibition: concomitant administration of zolpidem and other drugs may cause interactions that lead to increased concentrations of zolpidem.Zolpidem is clinically very effective in treating insomnia. However, while rare, zolpidem-induced unusual complex behavior may develop. Primary care physicians should be alert to the possible unusual complex adverse effects of zolpidem.

Previous studies have demonstrated the autonomic dysregulation in patients with schizophrenia using electrophysiological methods, such as electrodermal measures and heart rate analysis. Several theories have been proposed to explain the underlying mechanisms of schizophrenia and its autonomic function. Recently, the measurement of salivary alpha-amylase has been considered to be a useful tool for evaluating the sympathetic-adrenal-medullary (SAM) system. Psychosocial stress increases the release of salivary alpha-amylase. Although some studies have evaluated salivary alpha-amylase under psychosocial stress, no studies have demonstrated the change in the salivary alpha-amylase (sAA) activity level in schizophrenic patients. We examined the relationship between sAA level and psychiatric state in patients with schizophrenia (n = 54) using a portable and rapid hand-held monitor to investigate sAA. The sAA activity in the patients was significantly higher than that in the control subjects (n = 55) (p < 0.01). The correlation between amylase level and psychiatric symptoms was highly significant (r = 0.37, p < 0.01). These findings indicate that higher increases in sAA may indicate severe psychiatric symptoms. These results indicate a predominant role of the sympathetic nervous system in the secretion of sAA, together with parasympathetic withdrawal, under psychosocial stress.

ObjectiveIn this study, we evaluated brain perfusion in patients with first-episode medicated schizophrenia using the new analytical method, statistical parametric mapping (SPM) applied to single photon emission computed tomography (SPECT).MethodWe performed SPECT with 99-Tc-ethyl cysteinate dimer (99mTc-ECD) of the brain and magnetic resonance imaging (MRI) in patients with schizophrenia (n = 30) and control subjects matched for age and gender (n = 37). A voxel-by-voxel group analysis was performed using SPM2 (Z > 3.0, P < 0.001, uncorrected for multiple comparisons).ResultIn comparison with control subjects, the volumes of the bilateral frontal areas were found to be decreased on MRI. Blood flow was found to be reduced in the bilateral temporal areas in the patients with schizophrenia on SPECT.ConclusionIn this study, patients with first-episode schizophrenia appeared to have significant bilateral temporal hypoperfusion, although temporal volumes were not significantly decreased in comparison with control subjects. Abnormality of temporal lobe blood flow in schizophrenia may show that functional changes occur earlier than structural changes, and may assist in the diagnosis of schizophrenia.

In this review article, in order to explore the mechanisms underlying the hallucinations/delusions of schizophrenia, we discuss the contribution of the following four questions: (i) can an understanding of dreams contribute to our understanding of the genesis of halluciations and/or delusions; (ii) are the mechanisms underlying psychotropic drug-induced psychoses the same as those underlying the hallucinations and/or delusions in schizophrenia; (iii) does disturbed consciousness contribute to the manifestation of psychotic features; and (iv) are the psychoses caused by organic brain disorders any different to the hallucinations and/or delusions seen in schizophrenia? We conclude that there is a strong association between drug-induced hallucinations or hallucinations associated with organic brain disorders and simple hallucinosis or fluctuations in arousal level. Because intermediate configurations and/or cross-staining phenomena exist for hallucinations and delusions, especially in schizophrenic disorders, it is difficult to isolate the hallucinations and to recognize them as being abnormal experiences.

Background Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS; yokukan-san in Japanese) may be safe and useful in treating behavioral and psychological symptoms in patients with dementia and borderline personality disorder. We aimed at evaluating both the efficacy and safety of YGS in patients with treatment-resistant schizophrenia. Methods Thirty-four patients diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (YGS-free) group (n = 25) and treated in a 4-week open-label study with YGS at an average daily dosage of 6.7 +/- 2.5 g (range, 2.5-7.5 g). Psychometric instruments used to assess efficacy included the Positive and Negative Syndrome Scale for Schizophrenia and the Drug-Induced Extrapyramidal Symptom Scale. Results A significant decrease was observed at 2 weeks and at 4 weeks in each Positive and Negative Syndrome Scale for Schizophrenia subscale score in the YGS group, but this was not observed in the control group. However, the Drug-Induced Extrapyramidal Symptom Scale total score did not change in both groups. Conclusions In this open-label pilot study, patients treated with YGS showed a statistically significant reduction on clinician-rated scales. The present findings suggest that an adjunction of YGS might be effective for treatment-resistant schizophrenia.

Monoamine oxidase inhibitor and tricyclic antidepressants have been serendipitously used for the treatment of depression for more than half a century and subsequently found to promote monoaminergic signals in the brain. Antidepressant drugs are still clinically used and industrially designed on the basis of the monoaminergic theory. Recent developments regarding selective monoaminergic uptake inhibitors can further improve the safe and rational treatment for patients with depression. However, monoamine-based antidepressants may cause unfavorable and incomplete remission of a considerable number of patients with depression; therefore, development of new antidepressant drugs based on other mechanisms is required. Meanwhile, there has been an impressive accumulation of knowledge about cytokines that might contribute to the understanding of the pathophysiology of depression. Therefore, this review focuses on the association between depressive disorder and cytokines and discusses the strategies for developing new cytokine-based antidepressant drugs.

We investigate a novel class of neural stochastic resonance (SR) exhibiting error-free information transfer. Unlike conventional neural SR, where the decrease of a system's response with too much noise is associated with an increase in the baseline firing rate, here the bell-shaped SR behavior of the input-output cross correlation emerges versus increasing input noise in spite of no significant increase of the baseline firing rate. The neuron thus acts as an error-free detector for weak signals. An integrate-and-fire model with short-term synaptic depression convincingly validates our experimental findings for SR in the human tactile blink reflex.

Objective: In the treatment of depression, clinical and psychopharmacologic aspects have been investigated to predict the response to anti-depressants. Some trials have reported clinical improvement as early as the first week; however, few have investigated the early effects of selective serotonin reuptake inhibitors. The aim of this study was to investigate therapeutic efficacy of paroxetine within the first 3 days of therapy onset. Method: Subjects included 29 outpatients diagnosed at first interview with major depressive disorder according to DSM-IV criteria (June 2003 to January 2007). Paroxetine 5–20 mg/day was administered for at least 2 weeks. Treatment efficacy was defined as a > 50% decrease in Hamilton Rating Scale for Depression (HAM-D) total scores from baseline to the end of the second week. To determine efficacy within the first 3 days, patients completed the HAM-D as a self-rated questionnaire on the first and third days and at the end of the first, second, and fourth weeks. Result: Subjects were divided into 2 groups: successful (17 responders) and failed (12 non-responders). There was a significant difference between the reduction rates of self-rated HAM-D total scores on the third day (p < .01). Conclusion: In patients responding to paroxetine in the early stages of treatment, the prediction of response within the first 3 days using the self-rated HAM-D is suggested.

Background Recent studies indicate that the traditional Japanese herbal medicine yi-gan san (YGS, yokukan-san in Japanese), a serotonin modulator, may be safe and useful in treating behavioral and psychological symptoms in dementia and borderline personality disorder patients. The authors examined the efficacy, tolerability, and safety of YGS in patients with tardive dyskinesia. Methods Twenty-two patients with schizophrenia who had neuroleptic-induced tardive dyskinesia were given 7.5 g/day of YGS for 12 weeks in an open-label study. Results Administration of YGS resulted in a statistically significant improvement in tardive dyskinesia and psychotic symptoms. Conclusions YGS may be an effective and safe therapy to control tardive dyskinesia and psychosis in patients with schizophrenia, that should be further tested in double-blind, placebo-controlled trials.