Early predictors of poor treatment response in patients with schizophrenia treated with atypical antipsychotics.

BACKGROUND: The aims of this study were to explore the relationship between early reduction in psychotic symptoms and the ultimate response in patients with schizophrenia treated by atypical antipsychotics, and to determine the best time to switch or maitain the regimen. We also explore the possible predictors for the clinical response. METHODS: One hundred eleven inpatients with acutely exacerbated schizophrenia were randomized to give optimal therapy of olanzapine, risperidone, and paliperidone in one-week run-in period and 12 weeks' intervention. All participants were assessed using Positive and Negative Syndrome Scale (PANSS). Early Response, defined as reduction of 25% in PANSS score, was examined at weeks 1, 2, 3, 4 and 8, and these ratings were used to predict ultimate response (25% PANSS reduction) at week 12. We hypothesized that early treatment response at Week 1 or 2 could predict Week 12's treatment outcome. RESULTS: The early treatment response at Week 2 had a greater negative prediction value (NPV, 93.6%) than did the response at Week 1 (NPV, 69.7%), Week 3 (NPV, 91.5%), Week 4 (NPV, 90.7%) and Week 8 (NPV, 87.2%). The positive predictive value became more acceptable (65%) until Week 4. There was no any other potential predictors, including types of antipsychotics medication and treatment dosage, were associated with ultimate response in this study. CONCLUSION: The treatment non-response at Week 2 optimally predicted the ultimate (Week 12) non-response, in terms of negative predictive value (NPV). These finding suggests that the revision of treatment strategy should be considered t if patients with schizophrenia was not responsive to them after 2 weeks' treatment, and for those who are responders at Week 2, another two weeks are needed to further evaluate whether they will be continuously responsive. TRIAL REGISTRATION: NCT03730857 at ClinicalTrial.gov . Date of registration: 30/Oct/2018.

Reliability and Validity of the Short Version of Udvalg for Kliniske Undersogelser in Antipsychotic Treatment.

The aim of this study was to develop a reliable and valid short version of the Udvalg for Kliniske Undersogelser (UKU) to efficiently evaluate the side effects of antipsychotics in patients with schizophrenia. This multi-site study included 10 hospitals, which included 331 inpatients and outpatients diagnosed with schizophrenia. UKU, Clinical Global Impression-Severity (CGI-S), Personal and Social Performance (PSP) and dosage of paliperidone were collected. The predictive validity of the UKU-short version, as well as that of the CGI-S, PSP and paliperidone dosages, was analyzed using structural equation modeling (SEM), latent growth models (LGM), and confirmatory factor analysis to test its content and construct validity. The UKU-short included nine-items of sedation, reduced sleep, rigidity, tremor, akathisia, headache, reduced salivation, constipation and orthostatic dizziness, and has good construct and content validity over time. Confirmatory factor analysis showed good construct validity, with the psychic, neurological and autonomic side effect dimensions having correlations between 0.60 and 0.71. The predictive validity of the short-version UKU for psychiatric symptoms (CGI-S), quality of life (PSP) and dosage showed that the effects of drug dosage were negligible, and only neurological side effects were associated with psychiatric symptoms and quality of life. The UKU-short showed good content, construct and predictive validity. It is a more time-efficient instrument than the original UKU. This study only included patients treated with paliperidone, larger scale studies is needed to validate the UKU-short in detection of side effects in routine clinical practice to prevent non-adherence in patients with schizophrenia.

Generalized estimating equation model and long-term exposure effect of antipsychotics on SH-SY5Y cells against oxidative stressors.

A comparison of the neuroprotective effect of different antipsychotics (APDs) over time on naïve SH-SY5Y against oxidative stressor insults using the generalized estimating equation (GEE). The hydrogen peroxide (H2O2), N-methyl-4-phenylpyridinium ion (MPP+), and ß-amyloid peptide were used to treat cells with or without APDs (paliperidone, risperidone, olanzapine and haloperidol); cell survival and oxidative stress markers were measured and analyzed. Only haloperidol had higher baseline cytotoxicity than paliperidone. GEE showed the proper exposure time for evaluating the neuroprotection of APDs was 24 h, rather than 48 or 72 h. Paliperidone was superior to other APDs in protecting naïve SH-SY5Y, had the best effect against H2O2-, MPP+-induced cell death, and caused a significantly higher GST, lower HNE and protein carbonyl productions of naïve SH-SY5Y after stressor insults, which may implicate a molecular mechanism underlying its neuroprotective action. Repeated GEE measurements can correct for the correlation among the clusters to obtain a more accurate result for evaluating drug outcome. The interaction between drugs and stressors should be taken into account when determining the neuroprotective effect of APDs against different stressors. Paliperidone might be useful in alleviating oxidative stress induced by Aß25-35 and MPP+, and provide neuroprotection against hydrogen peroxide in naïve SH-SY5Y.

An open-label, randomized, controlled trial of zotepine and risperidone for acutely ill, hospitalized, schizophrenic patients with symptoms of agitation.

Acutely ill, schizophrenic patients frequently require management of agitation. This study was conducted to compare the efficacy of oral zotepine and risperidone in hospitalized, acutely ill schizophrenic patients with symptoms of agitation.This was a 6-week, multicenter, randomized, open-label, parallel-group, flexible dosing study. Thirty-nine patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who met the criteria of a Positive and Negative Syndrome Scale (PANSS) total score of greater than or equal to 60 points, PANSS-excitement component (EC) score of greater than or equal to 14 points, and at least 1 PANSS-EC score of greater than or equal to 4 were randomly assigned to either the zotepine or risperidone group. The primary outcome was a comparison of the change in the PANSS-EC total score from baseline to the end of the study between groups.There was no significant between-group difference in dropout rates (zotepine, 15.8% [3/19]; risperidone, 20.0% [4/20]). The mean (SD) daily dose of zotepine from baseline to study end point ranged from 127.6 (62.3) to 236.8 (74.2) mg/d; the corresponding values for risperidone ranged from 3.3 (1.6) to 4.8 (1.7) mg/d. There were no statistically significant differences in patient characteristics, PANSS total score, and PANSS-EC total score between the zotepine and risperidone groups at baseline. Both groups showed significant reductions in the PANSS-EC total scores (zotepine, -10.1 [4.7], P < 0.001; risperidone, -8.0 [5.3], P < 0.001) and PANSS total scores (zotepine, -34.7 [15.8], P < 0.001; risperidone, -28.6 [14.3], P < 0.001). However, there were no significant differences in PANSS-EC total score (P = 0.265) and PANSS total score (P = 0.125) changes from baseline to study end point between the 2 treatment groups. Serum uric acid and prolactin decreased more in the zotepine group than the risperidone group (P < 0.001 and P = 0.018, respectively).Zotepine seemed to be as effective as risperidone in treating hospitalized, acutely ill, schizophrenic patients with agitation, and had the advantages of lowering hyperuricemia and hyperprolactinemia. Double-blind, fixed dose studies with a larger sample size of acutely ill, schizophrenic patients with agitation are needed to confirm the study results.

Rapid initiation of quetiapine well tolerated as compared with the conventional initiation regimen in patients with schizophrenia or schizoaffective disorders.

A 2-week, randomized, parallel-group open trial was designed to evaluate the safety and tolerability of a rapid initiation regimen with a higher dose of quetiapine (up to 800 mg/d by Day 4) than that used in the conventional initiation regimen of quetiapine (up to 400mg/d by Day 5) in patients with schizophrenia or schizoaffective disorders. Forty patients were recruited and randomly (3:1) assigned to either the group with rapid initiation of quetiapine or the group with conventional initiation. At the end of the investigation, the difference between the groups in the incidence of adverse events was not significant; a significant drop in the Barnes Akathisia Rating Scale and Simpson-Angus Scale scores was observed only in the group with the rapid initiation regimen. The groups did not differ in terms of improvement on the Clinical Global Impression-Severity of Illness and Positive and Negative Syndrome Scale at the end of the study. The results of our 2-week study suggest that rapid initiation with a higher dose of quetiapine (up to 800 mg/d by Day 4) is well tolerated in patients with schizophrenia or schizoaffective disorders and does not compromise efficacy relative to the conventional initiation.

Application of the Cockcroft-Gault method to estimate lithium dosage requirement.

The aim of the present study was to assess the precision and bias of a priori methods in the estimation of lithium dosage requirement among bipolar patients. The charts of 82 Diagnostic and Statistical Manual of Mental Disorder-fourth edition bipolar patients with previous history of lithium intoxication were reviewed. After excluding patients who had discontinued lithium treatment, 69 patients were entered to the study. Another 60 bipolar patients without history of lithium intoxication were also included in the study. The demographic data regarding factors thought to affect serum lithium concentrations, including gender, weight, and renal function, was retrospectively collected. Predicted daily lithium doses were calculated by using the new equation derived by the present authors and a priori methods proposed by Pepin et al., Zetin et al., Terao et al. and Keck et al. Mean error was calculated to assess the precision and bias of each a priori method. The Zetin method, the Terao method, and the Keck method had a significant tendency to overpredict dosage requirement. The Pepin method significantly underpredicted dosage. Only the 95% confidence interval of mean error of the present authors' equation was across zero. The present authors' equation represents a precise approach to estimate the lithium dose requirement and is easy to calculate. Regardless of the accuracy of each a priori method in predicting a patient's drug dosage, there is no substitute for proper serum drug concentration monitoring and good clinical judgment. Predictions made by any method should always be assessed clinically before applying its use in a patient.

The early effect of olanzapine and risperidone on insulin secretion in atypical-naïve schizophrenic patients.

Recently, increasing attention has been drawn to the potential diabetogenic effect of atypical antipsychotics. The goal of this prospective study is to evaluate the early effect of olanzapine and risperidone treatment on pancreatic beta-cell function in atypical-naive schizophrenic patients. Twenty-six subjects were assigned randomly to therapy with olanzapine or risperidone for 14 days. The metabolic parameters were quantitatively assessed by using the intravenous glucose tolerance test. The levels of fasting glucose, fasting insulin, lipid profiles, and leptin were also assessed. There were no significant within-group changes in weight or body mass index for both groups after 2 weeks of treatment. The levels of fasting glucose, fasting insulin, cholesterol, or leptin did not change in both groups. The triglyceride level significantly increased in olanzapine group. Glucose disappearance rate and insulin sensitivity did not change in both groups. Insulin secretion significantly decreased in olanzapine group. After 2 weeks of olanzapine treatment, schizophrenic patients decreased insulin secretory response to a hyperglycemic challenge. The results of this study support the hypothesis that olanzapine might directly impair pancreatic beta-cell function.

Anti-heat shock protein 90 is increased in acute mania.

OBJECTIVE: The aim of this work was to examine autoantibodies in patients with bipolar disorder. METHOD: We enrolled 94 patients with acute bipolar mania, with 37 of them medicated and 57 unmedicated at the time of blood sampling. The samples also consisted of 44 patients in the remission state and another 48 normal controls. We first used human glioblastoma (U373 MG) cell lysate to screen the potential autoantibodies present in sera of bipolar mania patients, and anti-heat shock protein (anti-HSP) 60, 70 and 90 autoantibodies were identified. We then examined the serum levels of these autoantibodies by enzyme-linked immunosorbent assay. RESULTS: The findings of this study showed that serum anti-HSP90 level was significantly higher in bipolar patients in acute mania than those in remission (p = 0.002). CONCLUSIONS: The data of this study suggest that increased anti-HSP90 might be a state marker for acute mania in patients with bipolar disorder.

Heavy smoking, reduced olanzapine levels, and treatment effects: a case report.

A 30-year-old schizophrenic male patient, a heavy smoker, was successfully treated with olanzapine 15 mg/d during hospitalization. His cigarette consumption increased rapidly from 12 to 80 cigarettes per day following his discharge. Ten days later, his delusion of persecution, levels of hostility, and aggressive behavior worsened, while the plasma levels of olanzapine concurrently decreased. Based on our observations of this case, we suggest that the reduced levels of plasma olanzapine and exacerbated clinical symptoms are closely related to the increased consumption of cigarettes. A possible explanation would be that heavy smoking induced cytochrome P4501A2, the major enzyme involved in olanzapine metabolism. Therefore, patients who smoke should be closely monitored for their cigarette consumption when the dosage of olanzapine is adjusted.

Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances.

BACKGROUND: Adjunctive fluvoxamine inhibits clozapine metabolism and decreases plasma norclozapine (a toxic metabolite of clozapine) to clozapine ratios. This study aimed to demonstrate the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities. METHOD: Sixty-eight treatment-resistant inpatients with a DSM-IV diagnosis of schizophrenia were randomly assigned to 2 treatment groups for 12 weeks. The monotherapy group (N = 34) received clozapine (< or = 600 mg/day). The coadministration group (N = 34) received fluvoxamine (50 mg/day) plus low-dose clozapine (< or = 250 mg/day). The study was conducted from August 1999 to October 2002. RESULTS: The 2 groups were similar in demographic data; baseline body weight and body mass index (BMI); baseline serum glucose, triglyceride, and cholesterol levels; and steady-state plasma clozapine concentration. The monotherapy patients (but not the coadministration patients) had significantly higher (p < .05) body weight, BMI, and serum glucose and triglyceride levels after treatment than at baseline. At week 12, the monotherapy patients also had significantly higher glucose (p = .035), triglyceride (p = .041), and norclozapine (p = .009) (and numerically higher cholesterol) levels than the cotreatment patients. The changes in weight and serum glucose and triglyceride levels were significantly correlated (p = .026, p = .005, and p = .028, respectively) with the plasma concentration of norclozapine but not with plasma levels of clozapine. CONCLUSION: These results suggest that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients. Plasma levels of norclozapine, but not clozapine, are associated with increases in weight and serum glucose and triglyceride levels. Of note, coadministration of fluvoxamine could increase plasma clozapine levels markedly and carry the risk of adverse events. If this combined treatment is applied, conservative introduction with reduced clozapine dosage and careful therapeutic drug monitoring of clozapine concentration is recommended.

Immunologic variables in acute mania of bipolar disorder.

Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-gamma and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores > or =26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores < or =12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-gamma was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in pre-medicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.

Implication of serum concentration monitoring in patients with lithium intoxication.

The aim of the present study was to determine the relationships between serum lithium level, duration of lithium intoxication, severity of symptoms, and the outcome of the disease. Subjects with a serum lithium level of >/=1.2 mEq/L were included in the study. Seventy-eight patients with lithium intoxication were identified between 1 July 1999 and 31 December 2002. The demographic characteristics, clinical manifestations, and concomitant medications were recorded. Most patients with acute lithium intoxication had mild symptoms, independent of the serum lithium levels. In patients with chronic lithium intoxication, the frequency of severe symptoms was higher than in those with acute intoxication. None of the 78 intoxicated patients in the present survey died or suffered from persistent neurological sequelae. Patients with concomitant medications, older age, and existing neurological illness may have an increased susceptibility to lithium toxicity. Regular monitoring of serum lithium level is essential for lithium-treated patients. Clinicians should pay attention to patients with pre-existing neurological illness, older age, or receiving medications that may interact with lithium.