Efficacy and moderators of prevention and treatment of delirium with melatonin receptor agonists: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Delirium is a complex and heterogeneous condition that significantly affects patient outcome. This study aimed to conduct a systematic review and meta-analysis to investigate the effects of melatonin and melatonin receptor agonists (MRAs) on delirium prevention and treatment. METHOD: Randomized controlled studies, using MRAs as an intervention and placebo as a control were included. We conducted meta-analyses with random-effects model and trial sequential analysis. RESULTS: A total of 33 studies involving 4850 participants were included. The meta-analysis revealed a significant preventive effect of MRAs on delirium (risk ratio = 0.65, p < 0.01), while no significant therapeutic effect was observed. Additionally, MRAs were associated with a significant reduction in mortality rate (risk ratio = 0.90, p = 0.02) in delirium prevention studies. Furthermore, subgroup analyses revealed that assessment scales and the frequency of delirium detection may be significant moderators of the delirium-preventive efficacy of MRAs. CONCLUSION: This study provides evidence of the potential effects of MRAs in preventing delirium and reducing mortality. Further research is required to elucidate the therapeutic potential of MRAs for delirium and identify specific patient populations that may benefit from this agent.

Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.

Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis.

BACKGROUND: Postmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis. METHODS: This study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged ≥50 years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of ≥6.18 µkat/L (≥370 U/L), a bone-specific alkaline phosphatase (BAP; bone formation marker) level of ≥0.59 µkat/L (≥35.4 U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of ≥4.2 U/L. RESULTS: A total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed. CONCLUSION: The study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy.

Simple and rapid detection of HLA-A*31:01 for prediction of carbamazepine-induced hypersensitivity using loop-mediated isothermal amplification method.

BACKGROUND: Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01. OBJECTIVE: To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population. METHODS: A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01. RESULTS: The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results. CONCLUSION: High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs.

Marked improvement in delirium with ramelteon: five case reports.

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.

NREM sleep stage transitions control ultradian REM sleep rhythm.

STUDY OBJECTIVES: The cyclic sequence of NREM and REM sleep, the so-called ultradian rhythm, is a highly characteristic feature of sleep. However, the mechanisms responsible for the ultradian REM sleep rhythm, particularly in humans, have not to date been fully elucidated. We hypothesize that a stage transition mechanism is involved in the determination of the ultradian REM sleep rhythm. PARTICIPANTS: Ten healthy young male volunteers (AGE: 22 ± 4 years, range 19-31 years) spent 3 nights in a sleep laboratory. The first was the adaptation night, and the second was the baseline night. On the third night, the subjects received risperidone (1 mg tablet), a central serotonergic and dopaminergic antagonist, 30 min before the polysomnography recording. MEASUREMENTS AND RESULTS: We measured and investigated transition probabilities between waking, REM, and NREM sleep stages (N1, N2, and N3) within the REM-onset intervals, defined as the intervals between the onset of one REM period and the beginning of the next, altered by risperidone. We also calculated the transition intensity (i.e., instantaneous transition rate) and examined the temporal pattern of transitions within the altered REM-onset intervals. We found that when the REM-onset interval was prolonged by risperidone, the probability of transitions from N2 to N3 was significantly increased within the same prolonged interval, with a significant delay and/or recurrences of the peak intensity of transitions from N2 to N3. CONCLUSIONS: These results suggest that the mechanism governing NREM sleep stage transitions (from light to deep sleep) plays an important role in determining ultradian REM sleep rhythms.

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.

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.

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.

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.

Novel class of neural stochastic resonance and error-free information transfer.

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.

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.

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.

Yi-gan san for the treatment of borderline personality disorder: an open-label study.

BACKGROUND: Numerous medications have been tested on patients with borderline personality disorder (BPD). Although many of these medications have been demonstrated to be useful, no clear main treatment for BPD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Recent studies indicate that the traditional Chinese herbal medicine yi-gan san (YGS, yokukan-san in Japanese) may be safe and useful in treating behavioral and psychological symptoms in dementia patients. We aimed at evaluating both efficacy and safety of yi-gan san in patients with well-defined BPD. METHODS: Twenty female outpatients diagnosed with BPD according to DSM-IV criteria and the revised Diagnostic Interview for Borderlines completed a 12-week open-label study with yi-gan san at an average daily dosage of 6.4+/-1.9 g (2.5-7.5 g). Psychometric instruments to assess efficacy included the Brief Psychiatric Rating Scale (BPRS), Hamilton Rating Scales for Depression (HAM-D), Global Assessment of Functioning (GAF), Clinical Global Impression Scale (CGI), and Aggression Questionnaire (AQ). RESULTS: Most psychometric scale scores exhibited a highly significant improvement (total BPRS; BPRS somatic concern, anxiety, tension, depressive mood, hostility, suspiciousness, motor retardation, uncooperativeness, and excitement subscale; CGI; GAF; AQ) over time. CONCLUSIONS: In this open-label pilot study, patients treated with YGS showed statistically significant reduction on self-rated and clinician-rated scales. The present findings suggest that yi-gan san might be effective for the treatment of a number of BPD symptoms, including low mood, impulsivity, and aggression.

Increased urinary excretion of biopyrrins, oxidative metabolites of bilirubin, in patients with schizophrenia.

During periods of psychological stress, excess amounts of free radicals are produced, and they play an important role in the pathophysiological process. Bilirubin oxidative metabolites, biopyrrins, are generated from bilirubin as a result of this scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrin is altered during the psychotic state in patients with schizophrenia. Biopyrrin concentrations in urine of 15 patients with schizophrenia and 100 age-matched healthy subjects were measured by enzyme-linked immunosorbent assay with an anti-bilirubin antibody. Urine samples were obtained from the patients on first admission (acute state), 1 month after admission (sub-acute state), and on discharge (remission state). Urinary concentrations of biopyrrins in patients with schizophrenia on admission were significantly higher than those in the controls. Response to treatment was associated with a significant decrease in the concentrations of biopyrrins. Moreover, urinary concentrations of biopyrrins were still significantly higher in patients with schizophrenia in the sub-acute and remission states than in the controls. These results demonstrated an increase in urinary biopyrrins in patients with schizophrenia and a decrease with recovery from the psychotic state. These findings indicate that the urinary biopyrrin level is a possible indicator that can be useful in the continuous monitoring of psychotic states in clinical practice.

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients.

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.

Possible antipsychotic effects of minocycline in patients with schizophrenia.

We present two cases of patients with schizophrenia treated with minocycline. Minocycline (a second-generation tetracycline) is an established and safe broad-spectrum antibiotic that crosses the blood-brain barrier, with additional efficacy for diseases such as acne and rheumatoid arthritis. Animal studies have suggested that minocycline may prevent progression of some neurological disorders. Moreover, it has been reported that minocycline might have antidepressant effects. We report two cases of acute schizophrenia with predominant catatonic symptoms that responded to minocycline.