Search

Research conducted over the past 2 decades has enhanced the validity and expanded the applications of microdosing and other phase 0 approaches in drug development. Phase 0 approaches can accelerate drug development timelines and reduce attrition in clinical development by increasing the quality of candidates entering clinical development and by reducing the time to "go‐no‐go" decisions. This can be done by adding clinical trial data (both healthy volunteers and patients) to preclinical candidate selection, and by applying methodological and operational advantages that phase 0 have over traditional approaches. The main feature of phase 0 approaches is the limited, subtherapeutic exposure to the test article. This means a reduced risk to research volunteers, and reduced regulatory requirements, timelines, and costs of first‐in‐human (FIH) testing. Whereas many operational aspects of phase 0 approaches are similar to those of other early phase clinical development programs, they have some unique strategic, regulatory, ethical, feasibility, economic, and cultural aspects. Here, we provide a guidance to these operational aspects and include case studies to highlight their potential impact in a range of clinical development scenarios. [ABSTRACT FROM AUTHOR]

Pharmacoproteomics is the study of disease-modifying and toxicity parameters associated with therapeutic drug administration, using analysis of quantitative and temporal changes to specific, predetermined, and select proteins, or to the proteome as a whole. Pharmacoproteomics is a rapidly evolving field, with progress in analytic technologies enabling processing of complex interactions of large number of unique proteins and effective use in clinical trials. Nevertheless, our analysis of clinicaltrials.gov and PubMed shows that the application of proteomics in early-phase clinical development is minimal and limited to few therapeutic areas, with oncology predominating. We reviewthe history, technologies, current usage, challenges, and potential for future use, and conclude with recommendations for integration of pharmacoproteomic in early-phase drug development. [ABSTRACT FROM AUTHOR]

Background: A public that is an informed partner in clinical research is important for ethical, methodological, and operational reasons. There are indications that the public is unaware or misinformed, and not sufficiently engaged in clinical research but studies on the topic are lacking. PARTAKE – Public Awareness of Research for Therapeutic Advancements through Knowledge and Empowerment is a program aimed at increasing public awareness and partnership in clinical research. The PARTAKE Survey is a component of the program. Objective: To study public knowledge and perceptions of clinical research. Methods: A 40-item questionnaire combining multiple-choice and open-ended questions was administered to 175 English- or Hindi-speaking individuals in 8 public locations representing various socioeconomic strata in New Delhi, India. Results: Interviewees were 18–84 old (mean: 39.6, SD±16.6), 23.6% female, 68.6% employed, 7.3% illiterate, 26.3% had heard of research, 2.9% had participated and 58.9% expressed willingness to participate in clinical research. The following perceptions were reported (% true/% false/% not aware): ‘research benefits society’ (94.1%/3.5%/2.3%), ‘the government protects against unethical clinical research’ (56.7%/26.3%/16.9%), ‘research hospitals provide better care’ (67.2%/8.7%/23.9%), ‘confidentiality is adequately protected’ (54.1%/12.3%/33.5%), ‘participation in research is voluntary’ (85.3%/5.8%/8.7%); ‘participants treated like ‘guinea pigs’’ (20.7%/53.2%/26.0%), and ‘compensation for participation is adequate’ (24.7%/12.9%/62.3%). Conclusions: Results suggest the Indian public is aware of some key features of clinical research (e.g., purpose, value, voluntary nature of participation), and supports clinical research in general but is unaware of other key features (e.g., compensation, confidentiality, protection of human participants) and exhibits some distrust in the conduct and reporting of clinical trials. Larger, cross-cultural surveys are required to inform educational programs addressing these issues. [ABSTRACT FROM AUTHOR]

In 2004 the Food and Drug Administration issued a warning on the risk of suicidality in children and adolescents receiving antidepressants. This was followed by reports of changes in antidepressant prescription patterns, suicidality and other aggressive behaviors, but debate is continuing regarding the nature and magnitude of these changes. We examined a large physician database for impact of the warning on antidepressant prescriptions, suicidality and other aggressive behaviors in major depressive disorder (MDD) and anxiety disorders in adult and pediatric patients. We analyzed electronic database covering over 100,000 patients, treated in Pre- (before 2003) and Post- (after 2004) warning periods. We compared strength of the association between the measures and the time period with two tests. Multivariate logistic regression analyses were performed to ascertain the unique effect of each parameter. Of 10,089 MDD (61.0 %) and anxiety disorders (39.0 %) patients, 65.2 % received antidepressant prescription and 16.1 % were pediatric patients. In post-warning period, there was a greater reduction in adult versus pediatric antidepressant prescription rates. Logistic modeling showed greater likelihood of antidepressant prescription in MDD as compared with anxiety disorders in post-warning period. Pediatric patients were more likely than adults to receive fluoxetine during the post-warning period. There was an overall reduction in suicidality and other aggressive behaviors in the post-warning period. Regulatory warnings may have had an impact on antidepressant benefit/risk assessment and consequent utilization, therapeutic effects, and adverse events. Our observations suggest that psychiatrists may heed regulatory warnings, but may also exert professional independence and discrimination in their application. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate gender differences in the clinical presentation of generalized anxiety disorder (GAD) and response to sertraline treatment. MethodsAdult outpatients who met DSM-IV criteria for GAD with a minimum Hamilton rating scale for anxiety (HAM-A) total score ≥ 18 were randomized to 12 weeks of double-blind treatment with flexible doses (50–150 mg) of sertraline (n = 182; female, 59%) or placebo (n = 188; female, 51%). ResultsClinical presentation of GAD was very similar in men and women in terms of the severity of the HAM-A psychic factor, severity of concomitant depression symptoms, duration of GAD, quality of life and impairment in physical health. Women had an earlier age of onset and higher HAM-A somatic factor scores compared with men. For both men and women, treatment with sertraline resulted in greater change from baseline to endpoint on the HAM-A compared with placebo (adjusted change ± SE: men: -12.1 ± 0.9 vs -8.8 ± 0.9; women: -11.4 ± 0.8 vs -7.1 ± 0.9, p < 0.001); the interaction between gender and treatment group was not significant, nor was there a significant difference between the average change from baseline for men compared with women. Similarly, responder rates based upon clinical global impression—improvement (CGI-I) scores at endpoint showed no significant interaction between gender and treatment, nor was there a significant difference in the response rates by gender; however, the response rate of sertraline compared with placebo was significantly different (p < 0.0001) (men: 64% vs 40%; women: 62% vs 34%). Similar findings were evident at week 4 assessment and for completers (week 12). Overall, sertraline was well tolerated by both men and women. DiscussionWomen and men with GAD showed similar clinical presentations, with the exception that women had an earlier age of onset and reported more somatic anxiety symptoms. Sertraline was an effective and well tolerated treatment for GAD in both men and women. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Age of onset may affect clinical features and prognosis in elderly patients with major depression (MDD), but there is a lack of such data in elderly patients with dysthymic disorder (DD) and systematic comparisons of late onset MDD and DD have not been conducted. Methods: In a Late Life Depression Clinic, patients≥60 years old who met DSM-III-R or DSM-IV criteria for MDD or DD were studied. The 24-item Hamilton Rating Scale for Depression (HRSD) and SCID-P were completed, family history was obtained, and medical illnesses were assessed. Results: In the total sample (n=370; 211 MDD and 159 DD), compared to early onset patients, late onset (onset≥60 years) patients had a higher rate of cardiovascular disease (χ2=4.12, df=1, P<0.05), lower rate of anxiety disorder (χ2=4.19, df=1, P<0.05), and a lower rate of family history of affective disorder (χ2=9.37, df=1, P<0.002). Late onset DD patients were more likely to have cardiovascular disease than early onset DD patients (χ2=5.63, df=1, P<0.02), but the rate of cardiovascular disease did not differ between late and early onset MDD patients (χ2=0.35, df=1, P<0.6). Late onset MDD patients were less likely to have a family history of affective disorder than early onset MDD patients (χ2=10.71, df=1, P<0.001). Prevalence of anxiety disorders did not differ between the early and late onset MDD patients (χ2=0.07, df=1, P<0.79), but was more common in the early onset DD compared to the late onset DD patients (17.98% versus 4.29%, χ2=6.98, df=1, P<0.01). Late onset DD did not differ from late onset MDD in the rates of cardiovascular disease, anxiety disorders, and family history of affective disorder. Excluding patients with double depression (n=32) did not alter the cardiovascular or family history findings, but the difference in anxiety disorders between early and late onset DD patients was no longer significant. Limitations: Academic clinic sample results may not generalize to community populations. Conclusions: In the elderly, late-onset DD is typically different from early onset DD. Cerebrovascular disease appears to play a role in the etiology of late onset DD. The similarities between late onset DD and late onset MDD suggest a single condition along a continuum. [Copyright &y& Elsevier]

ObjectiveTo examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. Methods and materialsPatients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score ≥2 in at least one domain), were treated with donepezil (5–10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50–200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. Results24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as ≥;50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. ConclusionSertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

To report on the efficacy, safety, and tolerability of sertraline in the treatment of elderly depres-sed patients with and without comorbid medical illness. Multicenter. Randomized, double-blind, placebo-controlled study. A total of 752 patients aged 60 and older with diagnosis of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis. Outcome measures included the 17-item Hamilton Depression Scale (HAMD); the Clinical Global Depression—Severity/Improvement (CGI-S/CGI-I); efficacy and safety/adverse event assessments; Quality of Life, Enjoyment, and Satisfaction Questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Status Survey. In the overall sample, sertraline was superior to placebo on all three primary outcome measures, HAMD, and overall clinical severity and change (CGI-S/CGI-I). Furthermore, therapeutic response to sertraline was comparable in those with or without medical comorbidity, and there were no treatment-by–comorbidity group interactions. Sertraline was also associated with a faster time to response than placebo in the comorbid group ( P<.006). Sertraline-treated patients in the comorbid group had similar adverse events and discontinuations when compared to those in the noncomorbid group. Sertraline was efficacious in reducing depressive symptomatology, regardless of the presence of comorbid medical illness. Sertraline was safe and well tolerated by patients with or without medical illness. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the effects of antidepressants on cognitive functioning in elderly depression.Methods: Data were pooled for elderly participants with major depression from two double-blind 12-week studies (n = 444) comparing sertraline to fluoxetine and to nortriptyline. A cognitive battery was performed pre-treatment and post-treatment that included the Shopping List Task (SLT), which quantifies short-term and long-term memory storage and retrieval, and the Digit Symbol Substitution Test (DSST), which measures visual tracking, motor performance, and coding.Results: Older age, male gender, higher systolic blood pressure, and higher illness severity were associated with lower performance on specific cognitive measures at baseline. For the entire group, improved depression and a lower anticholinergic side effect (dry mouth and constipation) severity were associated with statistically significant improvement in the SLT and DSST. The correlations between improvements in depression and improvement in tested cognitive function were highest for sertraline followed by nortriptyline and then fluoxetine.Conclusions: Acute improvement in depression is associated with cognitive improvement as measured by the SLT and DSST. Prospective studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes in geriatric depression. [ABSTRACT FROM AUTHOR]

Objectives. To analyze the effects of antidepressants on cognitive functioning in elderly depression. Methods. Data were pooled for elderly participants with major depression from two double-blind 12-week studies (n = 444) comparing sertraline to fluoxetine and to nortriptyline. A cognitive battery was performed pre-treatment and post-treatment that included the Shopping List Task (SLT), which quantifies short-term and long-term memory storage and retrieval, and the Digit Symbol Substitution Test (DSST), which measures visual tracking, motor performance, and coding. Results. Older age, male gender, higher systolic blood pressure, and higher illness severity were associated with lower performance on specific cognitive measures at baseline. For the entire group, improved depression and a lower anticholinergic side effect (dry mouth and constipation) severity were associated with statistically significant improvement in the SLT and DSST. The correlations between improvements in depression and improvement in tested cognitive function were highest for sertraline followed by nortriptyline and then fluoxetine. Conclusions. Acute improvement in depression is associated with cognitive improvement as measured by the SLT and DSST. Prospective studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes in geriatric depression. [ABSTRACT FROM AUTHOR]