Abstract Objective This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of ...schizophrenia. Methods Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of fixed-dose, double-blind treatment with lurasidone 80 mg (n = 125), lurasidone 160 mg (n = 121), quetiapine XR 600 mg (QXR-600 mg; n = 119; active control included to test for assay sensitivity), or placebo (n = 121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure). Results Treatment with both doses of lurasidone or with QXR-600 mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥ 20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80 mg (65%; p < 0.001), lurasidone 160 mg (79%; p < 0.001), and QXR-600 mg (79%; p < 0.001) compared with placebo (41%). The proportion of patients experiencing ≥ 7% weight gain was 4% for each lurasidone group, 15% for the QXR-600 mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600 mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p < 0.001), LDL cholesterol (p < 0.01), and triglycerides (p < 0.05). Conclusions Lurasidone 80 mg and 160 mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.
To determine whether overall treatment time affects outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small-cell lung carcinoma (NSCLC).
Data were analyzed from 3 ...prospective Radiation Therapy Oncology Group trials (RTOG 91-06, 92-04, and 94-10) in which immediate concurrent chemoradiation (cisplatin-based) was the primary therapy for good-performance status Stage III (and selected inoperable Stage II) NSCLC. "Short" overall treatment time (per protocol) was defined as completing treatment within 5 days of plan; other patients were considered to have had "prolonged" treatment time (protocol violation); treatment time was also analyzed as a continuous variable in a multivariate model. Actuarial analysis was performed for overall survival, progression-free survival, freedom from local-regional progression, and toxicity.
A total of 474 patients were analyzed. Median follow-up for surviving patients was 6.1 years. Treatment time was delivered per protocol in 387 (82%), whereas 87 patients (18%) had a prolonged treatment time. Long treatment time was significantly associated with severe acute esophagitis. Median survival was slightly better in patients completing treatment on time (19.5 months vs. 14.8 months), but this did not reach statistical significance (p = 0.15) in the univariate analysis. However, in the multivariate analysis of treatment time as a continuous variable, prolonged treatment time was significantly associated with poorer survival (p = 0.02), indicating a 2% increase in the risk of death for each day of prolongation in therapy. Histology (squamous fared worse) and performance status were also significant in the multivariate model.
This retrospective analysis demonstrates a correlation between prolonged overall radiotherapy treatment time and survival in patients with locally advanced NSCLC, even when concurrent chemotherapy is used. Further study of novel radiation-chemotherapy dose/fractionation regimens is warranted.
Schizophrenia is characterized by high suicide risk and low awareness of disorder. Although awareness has benefits for medication compliance and clinical outcome, it is unclear how it may relate to ...suicide risk in this population.
This multicenter investigation assessed awareness and suicide-related behavior in 980 patients with schizophrenia or schizoaffective disorder. Patients were followed over 2 years and assessed by blinded raters for suicide-related events.
Awareness of psychiatric condition at baseline was associated with increased risk of suicide events over the follow-up. This effect was mediated by depression and hopelessness levels. By contrast, changes in awareness associated with treatment decreased the risk of suicide.
Although some patients may become depressed after acknowledging the clinical handicaps of their disorder, treatment-related changes in awareness are generally associated with a positive outcome relative to suicide risk. The complex interactions and mediation effects of these clinical variables require careful monitoring.
This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80mg/day and 160mg/day) in the treatment of an acute exacerbation of schizophrenia.
Participants, who ...were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6weeks of fixed-dose, double-blind treatment with lurasidone 80mg (n=125), lurasidone 160mg (n=121), quetiapine XR 600mg (QXR-600mg; n=119; active control included to test for assay sensitivity), or placebo (n=121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure).
Treatment with both doses of lurasidone or with QXR-600mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80mg (65%; p<0.001), lurasidone 160mg (79%; p<0.001), and QXR-600mg (79%; p<0.001) compared with placebo (41%). The proportion of patients experiencing ≥7% weight gain was 4% for each lurasidone group, 15% for the QXR-600mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p<0.001), LDL cholesterol (p<0.01), and triglycerides (p<0.05).
Lurasidone 80mg and 160mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.
Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective ...patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome.
In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001.
Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings.
The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.
The prognostic significance of traditional and newer tumor cell-related biologic parameters, like deoxyribonucleic acid ploidy (flow cytometry), proliferative activity (expression of proliferating ...cell nuclear antigen by immunohistochemistry), mitotic count, and intratumoral or peritumoral (or both) blood or lymphatic vessel invasion by tumor cells was investigated in 95 consecutive patients who had T1 N0 M0 non-small-cell lung cancer and who had operation alone between 1975 and 1985. The median follow-up for the entire group is now 8.3 years, and overall 5-, 10-, and 15-year-survivals were 75%, 69%, and 61%, respectively. Twenty-two patients died of either local (n = 3) or systemic (n = 19) recurrent non-small-cell lung cancer, 5 of non-cancer-related causes, 2 of new primary lung cancer, and 1 of an extrathoracic cancer. By multivariate analysis, blood vessel invasion by tumor cells (p = 0.0001) and mitotic count (p = 0.016) were independent predictors of survival; by contrast, the disease-free survival was influenced only by blood vessel invasion (p = 0.0004). The relative risk of death of recurrent non-small-cell lung cancer for low-risk patients (n = 79) was 13.3 (95% confidence interval, 6.1 to 28.7) times lower than that of high-risk patients (n = 16) (p < 0.0001). The relative risk of manifesting recurrent disease as distant metastasis for high-risk patients was 25.64 (95% confidence intervals, 8.4 to 77.6) times higher than that of their low-risk counterparts (p < 0.0001). These results provide a rationale for effective systemic adjuvant treatment in completely resected T1 N0 M0 non-small-cell lung cancer tailored to the individual patients’ risk of development of recurrent non-small-cell lung cancer. (J Thorac Cardiovasc Surg 1993;106:80-9)
Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson's disease (PDD). However, since anticholinergic drugs have a role in the management of tremor ...in patients with Parkinson's disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD.
The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine.
During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson's Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worsening parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Post-hoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study.
Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.
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