Dental implant treatment in patients with cancer on high-dose antiresorptive medication: A prospective feasibility study with 2 years follow-up.

OBJECTIVES: Dental implant treatment is considered contraindicated in patients with cancer on high-dose antiresorptive medication (HDAR). The aim of this prospective, feasibility study was to evaluate implant treatment in patients with cancer on HDAR, in terms of implant survival, implant success, and oral health-related quality of life (OHLQoL) after 2 years of loading. MATERIALS AND METHODS: Implants were inserted in three groups of HDAR patients: (1) Previous tooth extraction, no medication-related osteonecrosis of the jaw (MRONJ), (2) Previous MRONJ, now healed, (3) Existing MRONJ, planned surgical resection. Implants were placed without adjunctive bone or soft tissue argumentation. Abutment operation was performed after ≥12 weeks. Prosthetic treatment was initiated ≥14 weeks. Survival and success rate were determined, and OHLQoL was analyzed with OHIP-49 and QLQ-H&N35 questionnaires. Patients were seen for 6 months, 1- and 2 years follow-up. RESULTS: Twenty-two patients, 39 implants, completed the implant-based prosthetic treatment. Implant-supported crowns and overdentures were fabricated. Thirteen patients (59%) with 23 implants (59%) completed 2 years follow-up. Overall implant survival and success rate after 2 years of loading were 100% and 97.4%, respectively. OHLQoL for the patients increased in all groups after the treatment, a substantial increase was seen in group 3. Two patients developed MRONJ, but not related to the implant treatment. CONCLUSION: Dental implant treatment, with high survival and success rate and increased post-treatment OHLQoL, is feasible in HDAR patients after 2 years of loading. Caution with general recommendations should be exercised.

The Integrated Alzheimer's Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial.

The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia.

Delayed-Start Analyses in the Phase 3 Solanezumab EXPEDITION3 Study in Mild Alzheimer's Disease.

OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer's disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer's Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer's Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS).

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

Olanzapine versus risperidone. A prospective comparison of clinical and economic outcomes in schizophrenia.

OBJECTIVE: To compare the clinical and economic outcomes associated with olanzapine and risperidone treatment for schizophrenia. DESIGN AND SETTING: An international, multicentre, double-blind, prospective study. To facilitate economic comparisons, our sample was restricted to patients enrolled in US sites. 150 patients with a Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV) diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder were randomised to therapy with either olanzapine 10 to 20 mg/day (n = 75) or risperidone 4 to 12 mg/day (n = 75) for a maximum of 28 weeks. In addition to tolerability and efficacy assessments, use of health services was assessed at baseline and prospectively, at 8-week intervals and at study completion. Clinically important response, defined as a 40% improvement in the Positive and Negative Syndrome Scale total score, maintenance of response and rates of treatment-emergent extrapyramidal symptoms were compared between groups. Direct medical costs were estimated by assigning standardised prices to resource units. Median total, inpatient/outpatient service and medication acquisition costs were compared between treatment groups. MAIN OUTCOME MEASURES AND RESULTS: The mean modal dosages for the olanzapine and risperidone treatment groups were 17.7 +/- 3.4 mg/day and 7.9 +/- 3.2 mg/day, respectively. Olanzapine-treated patients were more likely to maintain response compared with risperidone-treated patients (p = 0.048). In addition, a smaller proportion of olanzapine-treated patients required anticholinergic therapy compared with risperidone-treated patients (25.3 vs 45.3%; p = 0.016). Total per patient medical costs over the study interval were $US2843 (1997 values) [36%] lower in the olanzapine treatment group than in the risperidone treatment group (p = 0.342). Medication costs were significantly higher for olanzapine-treated patients ($US2513 vs $US1581; p < 0.001), but this difference was offset by a reduction of $US3774 (52%) in inpatient/outpatient service costs for olanzapine-treated patients in comparison with risperidone-treated patients ($US3516 vs $US7291, p = 0.083). Median cost findings were consistent with results observed using other robust measures of central tendency and provide conservative estimates of potential savings that may be obtained from olanzapine therapy. CONCLUSIONS: In this study, olanzapine-treated patients experienced clinical improvements that translated into savings in costs of care for both inpatient and outpatient services. These savings offset the difference in medication acquisition cost between olanzapine and risperidone.

The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone.

BACKGROUND: Depressive symptoms are common during the course of schizophrenia and may carry prognostic relevance. METHODS: From a 28-week prospective, double-blind, randomized study of olanzapine and risperidone, a post hoc evaluation of changes on the Positive and Negative Syndrome Scale (PANSS) depression cluster (PDC) and the subsequent risk of relapse were analyzed by logistic regression. RESULTS: Olanzapine was associated with a significantly higher categorical rate of improvement on the PANSS depression cluster (> or = 7 points) (p < .05). Although the baseline severity of depressive symptoms was not a significant predictor of relapse, the degree of acute (8-week) mood improvement on the PANSS depression cluster (but neither negative or positive symptom changes) was related to the probability of a subsequent psychotic relapse. Acute mood improvement with olanzapine was inversely related to a nonsignificantly lower risk of relapse. However, an opposite and significant relationship was observed among risperidone-treated subjects. Risperidone-treated subjects with a greater degree of acute mood change were both 3.58 times more likely to relapse than their risperidone counterparts who had experienced less mood improvement (p = .008) and 8.55 times more likely than olanzapine-treated subjects who had had similar mood improvements (p = .001). CONCLUSIONS: These data suggest the underlying pharmacologic differences between the two drugs may bestow different rates of longer-term mood stabilization and relapse prevention. In a second series of analyses, worsening on the PANSS depression cluster in the 4 weeks or less preceding a clinical relapse was a significant prodromal predictor of relapse among all subjects. As a whole, subjects with a worsening on the PDC demonstrated a 1.77 times higher risk of a relapse during the subsequent 4 weeks (p = .001). Among this mood-worsening stratum, risperidone-treated patients were 3.51 times more likely to relapse in those next 4 weeks (p = .005) than their olanzapine counterparts. Future comparative drug studies in this area will further contribute to our understanding of the pathophysiology of mood change and its relationship to psychosis, including clinical relapse and how newer agents may differ in their respective delivery of long-term treatment outcomes.

Should we consider mood disturbance in schizophrenia as an important determinant of quality of life?

BACKGROUND: The main objective in the treatment of schizophrenia should be to optimize individual patient functioning and quality of life. Little is known about the possible relationship of concurrent mood symptoms and quality of life. We hypothesized that the quality of life for people with schizophrenia would be inversely related to the severity of concurrent mood disruption. METHOD: We conducted a post hoc analysis of an international, multicenter, double-blind, 28-week study of 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform, or schizoaffective disorder and were randomized to treatment with either olanzapine or risperidone. Quality of life data were collected at baseline, 8, 16, 24, and 28 weeks or at early discontinuation; Positive and Negative Syndrome Scale (PANSS) data were collected at each visit (weekly to week 8 and monthly thereafter). Correlations were calculated between changes in quality of life (quality of life scale [QLS] total and subscales) and PANSS mood score. Regression models were used to determine the proportion of variability in the QLS total and subscores accounted for by changes in PANSS positive, PANSS negative, and PANSS mood scores. Finally, path analysis was performed to determine the mechanisms used by the PANSS mood scores to affect the QLS total and subscores. RESULTS: Olanzapine demonstrated a significantly greater therapeutic effect on the PANSS mood item than risperidone did. However, mood improvements with either therapy demonstrated correlations of PANSS mood on the QLS total and subscores which were statistically significant, with the strongest correlation against the interpersonal relations (QLS-IPR) subscore. The path analysis results indicate that the PANSS mood item's most significant path in affecting the QLS total and QLS-IPR is direct. CONCLUSION: Changes in the quality of life of schizophrenic patients is inversely related to changes in the concurrent mood disruption. Early therapeutic interventions directed at a broader constellation of schizophrenic symptomatology, including mood, may be helpful in improving an individual patient's quality of life. The possible relative advantages of introducing novel antipsychotic agents earlier in the course of illness for restoration of individual quality of life merit further investigation.

Echoplanar BOLD fMRI of brain activation induced by concurrent transcranial magnetic stimulation.

RATIONALE AND OBJECTIVES: The authors demonstrate the feasibility of combining transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) inside an MR scanner to noninvasively stimulate and image regional brain activity. METHODS: Echoplanar blood oxygen level dependent (BOLD)-based fMRI studies of TMS response were performed on three human volunteers inside a standard 1.5 T MR scanner using independent computer control to interleave echoplanar image acquisition and stimulation of right thumb primary motor cortex with a nonferromagnetic TMS coil. RESULTS: Significant (P< 0.001) response was observed in motor cortex under the TMS coil during stimulation compared to rest, as well in auditory cortex, the latter presumably due to the loud "snap" when the coil was pulsed. CONCLUSIONS: Concurrent TMS stimulation and echoplanar BOLD fMRI imaging is possible. This method has potential for tracing neural circuits with brain imaging, as well as investigating the effects of TMS.

Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders.

Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.