Practices for Supporting and Confirming Decision-Making Involved in Kidney and Liver Donation by Related Living Donors in Japan: A Nationwide Survey.

This nationwide survey investigated the actual practices for supporting and confirming the decision-making involved in related living-organ donations in Japan, focusing on organ type and program size differences. Answers to a questionnaire survey were collected from 89 of the 126 (71%) kidney and 30 of the 35 (86%) liver transplantation programs in Japan that were involved in living-donor transplantations in 2013. In 70% of the kidney and 90% of the liver transplantation programs, all donors underwent "third-party" interviews to confirm their voluntariness. The most common third parties were psychiatrists (90% and 83%, respectively). Many programs engaged in practices to support decision-making by donor candidates, including guaranteeing the right to withdraw consent to donate (70% and 100%, respectively) and prescribing a set "cooling-off period" (88% and 100%, respectively). Most donors were offered care by mental health specialists (86% and 93%, respectively). Third parties were designated by more of the larger kidney transplant programs compared with the smaller programs. In conclusion, the actual practices supporting and confirming the decision to donate a living organ varied depending on the organ concerned and the number of patients in the program.

Psychological distress in corticosteroid-naive patients with systemic lupus erythematosus: A prospective cross-sectional study.

OBJECTIVE: Psychological distress, such as depression and anxiety, has been intensively studied in patients with systemic lupus erythematosus (SLE). However, those studies have mostly included patients who were treated with corticosteroids, which might themselves induce mood disturbances. We investigated psychological distress in corticosteroid-naive patients with SLE who did not exhibit any overt neuropsychiatric manifestations. METHODS: Forty-three SLE in-patients with no current or past abnormal neuropsychiatric history participated in the study. Patients and 30 healthy control subjects with similar demographic and personality characteristics were administered a comprehensive battery of psychological/neuropsychological tests. The Profile of Mood States (POMS) was used to assess depression and anxiety. Results of clinical, laboratory, and neurological tests were compared with regard to their presence. RESULTS: Prevalence of depression was higher in patients (n = 11, 25.6%) than in controls (n = 2, 6.7%; p = 0.035), although prevalence of anxiety did not differ across groups (patients: 34.9%, n = 15; controls: 16.7%, n = 5; p = 0.147). Using multiple logistic regression analysis, we identified avoidance coping methods (OR, 1.3; 95% CI 1.030-1.644; p = 0.027) as an independent risk factor for depression. CONCLUSION: Our results indicate that depression presents more frequently in corticosteroid-naive patients with early-stage, active SLE than in the normal population, but anxiety does not. Depression may be related to psychological reactions to suffering from the disease.

Paradoxical depression in renal transplant recipients.

Paradoxical depression occurs despite a completely successful transplantation without tissue rejection or other medical complications. In this study, the occurrence of paradoxical depression was retrospectively investigated among 1,139 Japanese successful renal transplant recipients January 1997 through September 2006. Among the 1,139 recipients, 103 visited the Department of Psychiatry after renal transplantation, including 40 with depressive symptoms and 15 with a physical problem considered to have nonparadoxical depression. The other 25 recipients were considered to have paradoxical depression; that is, more than half of the 40 recipients with depressive symptoms had paradoxical depression. There were no significant differences in the clinical characteristics, including average age at the time of renal transplantation, rate of living-donor transplantation, rate of ABO incompatibility, method of dialysis (hemodialysis or peritoneal dialysis), duration of dialysis, and time interval between the renal transplantation and the initial visit to the Department of Psychiatry among the 2 groups. These results suggested that there was another risk factor or interactions between factors. Of the 25 recipients, 6 had relationship problems, 6 had social-rehabilitation problems, and 13 had mentioned no clear psychological problems. These psychological factors might in fact be related to the loss of an imagined past. Additional consecutive prospective studies are needed-a challenging prospect for consultation liaison psychiatrists in the field of transplantation.

Effects of chlorpromazine on phosphatidylinositol turnover following thrombin stimulation of human platelets.

Thrombin stimulation of human platelets is known to result in phosphatidylinositol turnover (PI response), the activation of protein kinase C (C-kinase), and the release of arachidonic acid (AA). The authors studied the effects of chlorpromazine (CPZ) on these responses. At a concentration of 100 microM, CPZ inhibited the phosphorylation of 40,000-dalton protein through C-kinase activation. CPZ failed to inhibit initial transient synthesis of 1,2-diacylglycerol (1,2-DAG) through the PI response, although it slowed the concurrent decreasing process. CPZ inhibited promotion of compensatory synthesis of phosphatidylinositol 4,5-bisphosphate (PIP2), and also inhibited the synthesis of phosphatidic acid (PA). These results suggest that phosphatidylinositol 4-monophosphate kinase and diacylglycerol kinase (DAG-kinase) may be inhibited by CPZ. CPZ also intensified the accumulation of inositol phosphates caused by the PI response, indicating possible inhibition of the phosphatases that metabolize these phosphates. Thus, CPZ partially inhibited the PI response. However, it appears likely that the inhibition of C-kinase activity by CPZ was not due to inhibition of 1,2-DAG production nor to direct inhibition of phospholipase C. CPZ also inhibited AA release. This action might be partially a result of the inhibitory effect of CPZ on PA production.

Different effects of centrally acting drugs on rabbit platelet aggregation: with special reference to selective inhibitory effects of antipsychotics and antidepressants.

Twenty-four drugs, consisting of antipsychotics, tricyclic antidepressants, other centrally acting drugs, and related compounds, were studied for their effects on aggregation of rabbit platelets. Phenothiazine neuroleptics, haloperidol, sultopride, tricyclic antidepressants, sulpiride, atropine, and propranolol showed a selective inhibitory effect on the collagen-induced aggregation, but not on aggregations induced by arachidonic acid (AA) or adenosine diphosphate (ADP). These drugs are thought to inhibit the liberation of AA from phospholipids in platelet membranes, suggesting that they might inhibit phospholipases. Mepyramine, promethazine, phentolamine, and clozapine inhibited the aggregations evoked by collagen and AA, but failed to inhibit the ADP-induced aggregation. These drugs might inhibit the generation of prostaglandin endoperoxides or thromboxanes. Phenobarbital, phenytoin, procaine, lidocaine, flurazepam, trihexyphenydil, and lithium carbonate did not inhibit any kind of aggregation at the concentrations used. The clinical and pharmacological significance of these findings is discussed; it seems that the inhibitory effects of antipsychotics and antidepressants on platelet aggregation are closely related to the specific clinical and psychotropic effects of these drugs, but not to other actions.

Pharmacokinetic study of iminodibenzyl antipsychotic drugs, clocapramine and Y-516 in dog and man.

The pharmacokinetic properties of the iminodibenzyl antipsychotic drugs clocapramine (CCP, 3-chloro-5-[3-(4-carbamoyl-4-piperidino piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) and Y-516 (3-chloro-5-[3-(2-oxo-1, 2, 3, 5, 6, 7, 8, 8a-octahydroimidazo [1,2-a] pyridine-3-spiro-4'-piperidino) propyl]-10, 11-dihydro-5H-dibenzo[b, f]azepine) were investigated in dog and man. Dogs were administered CCP and Y-516 intravenously, intraperitoneally, and orally, and the concentrations of the parent drugs and their metabolites in the plasma and urine were determined. Half-life (t1/2) was approximately the same by all three administration routes, being approximately 5 h for CCP and 3 h for Y-516. Bioavailability following oral administration was 0.16 +/- 0.01 (mean +/- SD, n = 3) for CCP and 0.29 +/- 0.07 for Y-516. The fractions of dose absorbed following oral administration were 0.43 +/- 0.07 and 0.79 +/- 0.24, and the fractions of dose metabolized in the liver due to the first-pass effect were 0.63 +/- 0.05 and 0.63 +/- 0.04 for CCP and Y-516, respectively. Y-516 was detected in the plasma after intraperitoneal and oral administration of CCP. The ratio of the AUC of Y-516 to that of CCP was 0.06 following intraperitoneal administration and 0.40 following oral administration. This indicated that while the metabolism of CCP into Y-516 may occur partly in the liver due to the first-pass effect, it occurs mostly within the gastrointestinal tract itself or its mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Abuse of "BRON": a Japanese OTC cough suppressant solution containing methylephedrine, codeine, caffeine and chlorpheniramine.

1. The paper describes the mental disturbances of 44 abusive cases of "BRON," an over-the-counter (OTC) cough suppressant solution containing methylephedrine, codeine, caffeine, and chlorpheniramine. 2. Major psychiatric symptoms observed included hallucinatory-paranoid state and affective disorder. There also were groups which exhibited a combination of the two states and abuse only. 3. The hallucinatory-paranoid state group had a relatively small BRON usage amount, short usage term and few withdrawal symptoms. The affective disorder group, in contrast, had large usage amount, longer usage term, and showed significant autonomic nerve disorders during withdrawal. These tendencies were seen more clearly in the mixed state group. 4. The hallucinatory-paranoid state group showed little or no physical dependence, while that of the affective disorder group was thought to be firmly established. Thus, in the former group, methylephedrine was considered the major behavior modifying drug, while in the latter, it was thought to be codeine.

Study on the suitability of a rat model for tardive dyskinesia and the preventive effects of various drugs.

1. Male Sprague-Dawley rats (weighing 260-300 g) were administered 1.5 mg/kg of haloperidol (HPD) intraperitoneally once daily for 28 days to produce an animal model for tardive dyskinesia (TD). The daily administration of HPD significantly increased the frequency of involuntary orofacial movements (chewing movements, tongue protrusions and buccal tremors). 2. Its suitability as a model for TD was assessed in terms of the therapeutic effects of 6 drugs [trihexyphenodyl hydrochloride(THP), clonazepam(CZP), sodium valproate(VPA), alpha-tocopherol(Vit E), ritanserin(RS) and propranolol hydrochloride(PPL)]. These drugs were also used concomitantly with HPD to study their preventive effect. 3. As for the therapeutic effects of the drugs, both the single and the 14-day daily administrations of CZP as well as of VPA significantly suppressed the chewing movements. The results were mostly consistent with the effect of each drug on human TD, indicating this would be an excellent model for TD in terms of the drug responsiveness. 4. The concomitant administration of RS from the start of HPD administration significantly suppressed the appearance of chewing movements. The concomitant administration of Vit E for 42 days also suppressed chewing movements and buccal tremors. On the other hand, the concomitant administration of THP tended to aggravate these involuntary movements. 5. The fact that the therapeutic and preventive effects of the drugs on this model differed suggested that the development and recovery of the movements might also differ, at least in part.

Phase I study of a new antianxiety drug, buspirone.

1. A phase I study of buspirone was conducted in 7 healthy male volunteers. 2. Diazepam was selected as the control drug and administered in equipotent doses to buspirone. Dosage was initiated at 2.5mg and doubled until a maximum dosage of 20mg was attained. Subsequently, 10mg was administered once a day for three consecutive days. 3. Clinico-pharmacologically both drugs produced sleepiness/drowsiness, but dizziness, light-headed feeling and feeling of drunkenness were marked only in the diazepam group. 4. No drug-related abnormalities were observed in clinical laboratory test values, endocrinological tests and ECG. 5. On the Uchida-Kraepelin test, no change with the control values was observed under buspirone but subjects administered diazepam exhibited marked deterioration during the latter half of the test. Moreover, in the tapping test, significant impairment was observed in the diazepam group whereas buspirone had no effect. 6. On the EEG some fast waves were observed with diazepam whereas buspirone exhibited slow waves.

Phase 1 study of a new antipsychotic drug, OPC-4392.

1. A phase I study of OPC-4392 (OPC), a quinolinone derivative recently developed in Japan and recognized to have an agonistic effect on dopamine autoreceptors, was performed in 7 male healthy volunteers in comparison with chlorpromazine (CPZ). 2. Clinical pharmacology The main clinical symptoms of OPC were sleepiness, weakness, fatigability, heavy headedness, disturbance of concentration, nausea, etc. The severity of these symptoms increased dose-dependently, and the upper limit dosage of OPC was considered to be 5 mg for the healthy volunteers. 3. Endocrinological research The serum prolactin level decreased dose-dependently in the OPC group, whereas it rose in the CPZ group. A significant negative correlation was recognized between the OPC-plasma level and serum prolactin level as well. 4. Psychological tests In the Kraepelin test, a decrease in the average work quantity was observed in both groups, but it was less in the OPC group. 5. Pharmacokinetic study From the pharmacokinetic parameters measured, two features were recognized: one was the slowness of Tmax (4-6 hours) and the other was the length of its biological half-life (56-88 hours). It was estimated that the plasma level of OPC-4392 would take 2 weeks to reach a steady state.

Long-lasting inhibition of 5-HT uptake of platelets in subjects treated by duloxetine, a potential antidepressant.

Duloxetine is an inhibitor of serotonin and norepinephrine uptake, and is being developed as a new antidepressant. In the present study, using healthy volunteers who took 20 mg of duloxetine for 7 days, the plasma concentrations of duloxetine and the ex vivo serotonin uptake rate in the platelets were simultaneously monitored during and after administration. Furthermore, a comparison was made by measuring parameters for serotonin uptake in vitro and [3H]paroxetine binding before and after administration. Actual values of the uptake inhibition rate ex vivo were stronger than those expected in spite of the dilution of plasma in the experiment, and the inhibitory effect was seen even after the drug was no longer detected in plasma. No significant changes were observed in Vmax, Km, Bmax or Kd. Thereafter, the effect of the washing procedure was examined in platelets treated with different antidepressants in vitro. The minimum effect was seen in platelets treated by duloxetine or paroxetine, while desipramine-treated platelets showed susceptibility to the procedure. These results suggest that duloxetine was hardly dissociated from the serotonin uptake site, which was responsible for the strong and long-lasting effect of plasma.

Partial inhibition of reverse tolerance by a high dose of ritanserin or low dose of haloperidol in methamphetamine-sensitized rat.

To clarify the implication of antagonism of serotonin (5-HT)2 receptors in the treatment of schizophrenia, the effects of ritanserin (RIT) on the development of reverse tolerance in rats repeatedly administered methamphetamine (MAP) were investigated and compared with those of low doses of haloperidol (HPD). RIT administered at a dose of 2 mg/kg and low doses of HPD (0.05, 0.1 mg/kg) shared partial inhibition of the development of reverse tolerance in MAP-sensitized rats; the drugs inhibited sniffing but not head moving and had no effect on locomotion or rearing. A combination of low doses of HPD and RIT resulted in the inhibition of head moving. These results suggested that strong antagonism for 5-HT2 receptors would be useful to some extent to treat MAP-induced psychosis and schizophrenia as well as weak antagonism of dopamine D2 receptors, and that a combination of these two actions would produce better results in these psychoses than that obtained from D2 antagonism alone. In the presence of 0.05 mg/kg of HPD, RIT caused increased locomotion and rearing, whereas it decreased them in the presence of 0.1 mg/kg of HPD. This result suggested that the interactions between 5-HT and dopamine (DA) neurons are complex, and that 5-HT2 antagonism may inhibit or disinhibit DA neurons depending on the level of D2 blockade.

Effects of washing procedure on platelets pretreated with serotonin uptake inhibitors in vitro: low Ki values predict long-lasting inhibition of serotonin uptake in vivo.

The effect of a washing procedure on serotonin (5-HT) uptake in vitro was investigated using human platelets pretreated with nine 5-HT uptake inhibitors and various Ki values to confirm the assumption that a drug with high affinity for the 5-HT uptake site would be hardly removed and have a long-lasting effect in vivo. Among the drugs tested, those with low Ki values, such as clomipramine, duloxetine and paroxetine, inhibited 5-HT uptake even after removal from the medium, while those with high Ki values such as amitriptyline, desipramine, imipramine, mianserin, trazodone, and zimelidine were easily removed by washing. The results indicated that low Ki values might be proportionally related to the long-lasting binding of drugs to the 5-HT uptake site. The results also suggested that the threshold Ki value which could separate 5-HT uptake inhibitors with a probable long-lasting effect in vivo from those without the effect would be between 5 nM and 42 nM.

[Serotonin-noradrenaline reuptake inhibitors(SNRIs)].

Pharmacology, clinical efficacy and tolerability of serotonin noradrenaline reuptake inhibitors(SNRIs) are overviewed. They include milnacipran, venlafaxine, duloxetine, MCI-225 and nefazodone, however, only milnacipran is currently used in Japan. Pharmacology of SNRIs is characterized by inhibition of both serotonin and noradrenaline at the presynaptic membrane and by weak affinity with receptors at the postsynaptic membrane, which expects the same efficacy on major depressive disorder(MDD) as tricyclic antidepressant drugs(TCAs) with less adverse effects in clinical use. Currently available evidences show that SNRIs possess antidepressant effects on MDD at least similar potencies to TCAs with more potencies than selective serotonin reuptake inhibitors. SNRIs are well tolerated in general and safer than TCAs. SNRIs can be considered to be first-line antidepressant drugs.

Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins.

Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case-control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology.

Olanzapine optimal dose: results of an open-label multicenter study in schizophrenic patients. Olanzapine Late-Phase II Study Group.

This open-label clinical study was conducted for patients with schizophrenia in order to investigate the efficacy, safety and optimal dose of olanzapine. One hundred and fifty-six of the 159 enrolled patients were included in the analysis set. For the primary efficacy measure, the Final Global Improvement Rating (FGIR) score, 15.4% of patients had remarkable improvement, 58.3% of patients had moderate improvement or more, 79.5% of patients had slight improvement or more, and 10.3% of patients had increase in disease symptomatology (worsening). Results from the Brief Psychiatric Rating Scale (BPRS) in all individual items were improved from baseline. Olanzapine was effective not only against positive psychotic symptoms but also against negative symptoms. This was consistent with results from the Positive and Negative Syndrome Scale (PANSS). For the majority of patients, a dose range of 7.5-10.0mg/day, as a lower bound on the minimally effective dose, was suggested by the results of the dose to first response based on improvement in Global Improvement Rating (GIR) analyses. The ratio of olanzapine dose to equivalent haloperidol dose was estimated at 1.2 :1. The most commonly reported treatment-emergent signs and symptoms (TESS) occurring at a frequency of 10% or more were insomnia, weight increase, excitement, sleepiness, anxiety, malaise and dull headaches. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms; the most commonly reported were akathisia (6.4%), tremor (5.8%) and muscle rigidity (2.6%).

Efficacy and safety of olanzapine, an atypical antipsychotic, in patients with schizophrenia: results of an open-label multicenter study in Japan.

This first clinical study of olanzapine in Japanese patients with schizophrenia was conducted to investigate the efficacy and safety of olanzapine. Eighty-one patients were included in the analysis set. Mean modal dose for those patients were 9.4 +/- 3.6 mg/day. For the primary efficacy measure (Final Global Improvement Rating score), 14.8% of patients had remarkable improvement, 59.3% of patients had moderate improvement or better, and 86.4% of patients had slight improvement or better. Results from the Brief Psychiatric Rating Scale showed improvement from baseline in all clusters including positive psychotic symptoms (thought disturbance) but also against negative symptoms (anergia). The most commonly reported treatment-emergent signs and symptoms with > or =10% incidence, were insomnia, weight increase, excitement, sleepiness, and anxiety. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms, and events reported were tremor (6.2%), muscle rigidity (3.7%), and akathisia (2.5%). The most commonly reported treatment-emergent laboratory changes, with > or = 20% of incidence, were prolactin elevations (24.3%) followed by increases in triglycerides (20.4%). However, mean prolactin values tended to be normalized during the study. This study result suggests that olanzapine is an "atypical" antipsychotic.

Olanzapine versus haloperidol in the treatment of patients with chronic schizophrenia: results of the Japan multicenter, double-blind olanzapine trial.

This randomized double-blind trial was conducted to test the efficacy and safety of olanzapine in Japanese patients with schizophrenia. Importantly, this study also represents the first large clinical trial of olanzapine conducted in an Asian population. Patients (n = 182) were randomly assigned to treatment with olanzapine or haloperidol over a period of 8 weeks. The primary analyses included: (i) a test of non-inferiority of olanzapine compared with haloperidol in efficacy using the Final Global Improvement Rating (FGIR); and (ii) comparison between the treatment groups in extrapyramidal symptom severity using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Olanzapine was comparable to haloperidol in efficacy in treating positive symptoms and significantly superior in treating negative symptoms. Extrapyramidal symptom severity was significantly improved for olanzapine-treated patients versus haloperidol-treated patients. Olanzapine was shown to be more effective and better tolerated than haloperidol in the treatment of Japanese patients suffering from chronic schizophrenia.