Urinary biopyrrins and free immunoglobin light chains are biomarker candidates for screening at-risk mental state in adolescents.

BACKGROUND: Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. AIM: In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. METHODS: Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. RESULTS: Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. CONCLUSION: Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.

Evaluation of autonomic nervous system by salivary alpha-amylase level and heart rate variability in patients with schizophrenia.

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.

Yokukansan (TJ-54) for irritability associated with pervasive developmental disorder in children and adolescents: a 12-week prospective, open-label study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p<0.001). The mean CGAS was 31.92 at baseline, whereas the mean final score at 12 weeks was 54.52 (p<0.001). 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. CONCLUSIONS: 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.

Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: a 12-week prospective, open-label study.

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 <0.0001). TJ-54 was well tolerated. No subject exited the study due to a drug-related adverse event. 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.

May salivary alpha-amylase level be a useful tool for assessment of the severity of schizophrenia and evaluation of therapy? A case report.

Background. Previous studies suggested dysfunction of the autonomic nervous system (ANS) in schizophrenia patients, but the mechanism remains unclear. Recently, the measurement of salivary alpha-amylase (sAA) has been considered a useful tool for evaluating ANS, especially the sympathoadrenal medullary system. Furthermore, there was a report that patients with schizophrenia showed much higher sAA level than normal controls. Methods. We present the case of a 51-year-old female with catatonic schizophrenia. She needed the treatment of electroconvulsive therapy (ECT). We evaluated her sAA level and her psychiatric symptoms during the treatment. Results. Before ECT treatment, she showed high sAA level. Her sAA level decreased during the course of ECT, and this attenuation was accompanied by improvement of schizophrenic symptoms. Conclusion. We consider that measurement of the sAA level may be one of the useful biological markers for assessment of psychotic state and efficacy of treatment in patients with schizophrenia.

High salivary alpha-amylase levels in patients with schizophrenia: A pilot study.

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.

Adverse reactions to zolpidem: case reports and a review of the literature.

OBJECTIVE: 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. DATA SOURCES: 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. STUDY SELECTION AND DATA EXTRACTION: Publications relevant to the objective of this article were obtained (1992-2010), and some adverse neuropsychiatric reactions were summarized. DATA SYNTHESIS: 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. CONCLUSIONS: 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.

Abnormalities in MRI signal intensity in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia.

OBJECTIVE: The purpose of the present study was to examine whether patients with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome; GS) have specific changes in signal intensity on magnetic resonance imaging (MRI). METHODS: Axial 5 mm-thick T1-weighted and T2-weighted MRI was acquired from schizophrenia patients with GS (n = 24) and schizophrenia patients without GS (n = 60). All patients were diagnosed according to DSM-IV criteria and were compared with age- and sex-matched healthy controls without GS (n=60) and controls with GS (n=36). Signal intensity in the hippocampus, amygdala, caudate, putamen, globus pallidus, thalamus, anterior cingulate gyrus, posterior cingulate gyrus, insular cortex, and cerebellum was measured in relation to the signal intensities of the vitreous body. RESULTS: Compared to both schizophrenia patients without GS and the control subjects without or with GS, the schizophrenia patients with GS had significantly decreased signal intensity in almost all the regions measured on T1-weighted MRI. On T2-weighted MRI, the schizophrenia patients with GS had significantly increased signal intensity in almost all the regions measured compared to both schizophrenia patients without GS and the control subjects without or with GS. CONCLUSION: Patients with schizophrenia-associated GS have specific changes in signal intensity on T1- and T2-weighted MRI, suggesting that schizophrenia with GS produces changes specifically in the frontotemporal cortex, limbic system, and basal ganglia.

Yi-gan san as adjunctive therapy for treatment-resistant schizophrenia: an open-label study.

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.

New approaches to antidepressant drug design: cytokine-regulated pathways.

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.

Hyperbilirubinemia-related behavioral and neuropathological changes in rats: a possible schizophrenia animal model.

BACKGROUND: Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and the general healthy population. We examined the hyperbilirubinemia on behavioral and neuropathological changes in rats as a possible animal model of schizophrenia. METHODS: Gunn rats with severe hyperbilirubinemia (j/j), Gunn rats without severe hyperbilirubinemia (+/j), and Wistar rats were examined by open-field, social interaction, and prepulse inhibition tests. TUNEL, AgNOR and Ki-67 were also assayed on paraffin-embedded brain sections of these rats. RESULTS: Compared to Wistar rats, both Gunn j/j and +/j rats showed hyperlocomotion, high sniffing scores, and low defecation scores. They showed significantly more aggressive behaviors and impaired prepulse inhibition. The numbers of Ki-67-labeled cells and AgNOR were lower and the number of TUNEL-positive cells was higher than that of Wistar rats. CONCLUSIONS: These results might support the neurodevelopmental hypothesis of schizophrenia. Both Gunn j/j and +/j rats may be a useful animal model and provide clues to the role of hyperbilirubinemia in schizophrenia.

Successful treatment with levothyroxine for idiopathic hypersomnia patients with subclinical hypothyroidism.

OBJECTIVE: Our objective was to discuss the effect of levothyroxine on excessive daytime sleepiness (EDS) and a prolonged nocturnal sleep at patients with idiopathic hypersomnia who presented with subclinical hypothyroidism. METHODS: We present two patients with hypersomnia who complained of EDS and a prolonged nocturnal sleep time. Sleep architecture and subjective daytime sleepiness were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. Diagnoses were made using the International Classification of Sleep Disorders, 2nd Edition criteria for idiopathic hypersomnia with long sleep time. RESULTS: PSG demonstrated a short sleep latency, a prolonged total sleep time and normal proportions of all non-rapid eye movement (REM) and REM sleep stages. Nocturnal PSG excluded other causes of EDS. No medical, neurological and mental disorders were present. Their laboratory data indicated mildly elevated thyrotropin, despite free thyroxine (T4) and triiodothyronine (T3) estimates within their reference ranges, which is a characteristic of latent hypothyroidism. Levothyroxine (25 microg/day) was administrated orally. After treatment with levothyroxine for 8 weeks, the mean daily sleep times decreased. EDS was also improved, and a significant decrease in the ESS score was observed. Levothyroxine was effective for their hypersomnia and well tolerated. CONCLUSIONS: It should be noted that hypersomnia may be associated with subclinical hypothyroidism, although few abnormalities in physical and neurological examinations are present.

Minocycline as adjunctive therapy for schizophrenia: an open-label study.

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia.

Prediction of response within the first 3 days to treatment with paroxetine for depression.

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.

Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia.

OBJECTIVE: Recently, traditional herbal medicines have been reported to be effective for behavioral and psychological symptoms of dementia (BPSD). This study aims to examine the efficacy of Yi-Gan San (YGS) in the improvement of BPSD and sleep disorders in patients with dementia. METHODS: Five patients (1 male and 4 female) with dementia in accordance with DSM-IV criteria were investigated. Participants were treated with YGS for 4 weeks. The Nursing Home version of Neuropsychiatric Inventory (NPI-NH) for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, polysomnography for evaluation of sleep structure, and the Pittsburgh Sleep Quality Index for subjective sleep quality were carried out at baseline and at the end of treatment. RESULTS: All patients completed the trial. Significant improvements in the total NPI-NH score (34.0+/-6.5 to 12.8+/-6.6) as well as delusions, hallucinations, agitation/aggression, anxiety, and irritability/lability, whereas MMSE scores were unchanged. PSG revealed increases in total sleep time, sleep efficiency, stage 2 sleep, and decreases in the number of arousals and periodic limb movements. Subjective sleep quality was also improved. No adverse effects were observed. CONCLUSION: YGS was effective for BPSD and sleep disturbances, and well tolerated in patients with dementia. Further examinations using a double-blind placebo-controlled design are necessary.

Yi-gan san for the treatment of neuroleptic-induced tardive dyskinesia: an open-label study.

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.