ABSTRACT

There continues to be progress in neurotherapeutics and neuropsychopharmacology with each advancing year. Production of new molecular entities (NME's) remains small, but advances are being made in repurposing agents and extending their indications, obtaining more safety and tolerability data in long term and extension studies, introducing novel trial methodologies that provide insight into how to best to conduct trials and how best to treat diseases, and developing new formulations that improve adherence and decrease the barriers to patient compliance. Advances in how to test potential disease-modifying agents in patients with progressive neurological illnesses is advancing. Promising biomarkers have been identified in some neurological diseases.

ABSTRACT

Dementia, particularly Alzheimer's disease (AD), is increasing by patient population included in clinical trials. The methodology for trials of AD patients have been defined in terms of outcomes, standard measures and analytic techniques. Trial methodology is evolving with experience as new potential therapies become available. Screening criteria, instrumentation choices, duration of trials and analytic strategies may have a profound impact on the conclusions that can be derived from trials. The components of AD trials are reviewed in detail in this chapter.

ABSTRACT

Background: Despite the use of surgery, radiotherapy (RT) and standard chemotherapy, childhood high-grade astrocytoma (HGA) continues to carry a dismal prognosis. In an attempt to identify effective drug combinations and an alternative treatment strategy, the Children's Cancer Group (CCG) conducted a nationwide clinical trial that prospectively evaluated 102 children with HGA and post-operative residual disease for efficacy and toxicity of four courses of high-dose chemotherapy (HDCT) before RT. Design and methods: Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A); ifosfamide/etoposide (Regimen B); or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients received local RT followed by lomustine and vincristine. Results: Of 76 evaluable patients (median age 11.95 years, range 3–20 years), 30 patients relapsed during HDCT and 11 others did not complete HDCT due to toxicity. Non-hematologic serious toxicities were common (29%) and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24 ± 5% at 5 years and did not differ between groups. The 5-year, event-free survival (EFS) for all patients was 8 ± 3% and 14 ± 7% for Regimen A (p = 0.07). Patients who responded to HDCT had a nominally higher survival rate (p = 0.03 for trend). Interpretation: HDCT prior to RT provides no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor, and adversely effects ability to complete RT. Strong consideration should be given to investigating alternative strategies and novel biologic agents for this disease.

ABSTRACT

There is evidence for an association between vascular disease and depression, and in particular between cerebrovascular disease and depression, especially that occurring later in life. Among the diverse psychiatric diseases, the one which is most widely studied concerning the relationship with the vascular system, is depression. The risk relationship between depression and vascular events is a two-way road: the presence of depression increases the cerebrovascular and cardiovascular event risk (worsening its evolution and prognosis, as well) and a patient evidencing cerebrovascular or heart disease, will also show an increase in the risk of suffering depression (Taragano et al., 2005). Depression is a common cause of disability in the elderly. It reduces quality of life and represents a serious public health problem (Beekman et al., 2001; Steffens et al., 2000). Its prevalence in late life is 2–3% for major depression and 12–15% for all depressive syndromes (Beekman et al., 1999).

ABSTRACT

A key obstacle to the development of new drugs to treat the cognitive deficits of schizophrenia was the absence of a standard by which to measure their efficacy. Before granting approval for any new drug for this condition, the US Food and Drug Administration wanted a standard cognitive endpoint based on a broad consensus-based method. To address this obstacle, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) intiative oversaw a process to develop a consensus neurocognitive battery. Its development included a ten-step process that is described in this article.

ABSTRACT

Background: The purpose of this analysis was to compare symptomatic remission rates between risperidone and placebo in a completed randomized controlled trial. Design and Methods: Two hundred ninety (290) adult patients who met DSM-IV criteria for Bipolar I Disorder Manic or Mixed episode were randomized to flexible doses of risperidone or placebo for 3 weeks. An entry Young Mania Rating Scale (YMRS) score of > 20 was required at trial screening and baseline. Time to first onset of remission (as defined as a YMRS score of < 8) was assessed using Cox proportional hazards. Persence or absence of sustained remission was analyzed using logistic regression. Sustained remission was defined as maintaining a YMRS < 8 for the remainder of the trial or until censor. Results: After adjusting for presence of psychosis, baseline YMRS, gender, number of mood cycles in the previous year and treatment,the odds of sustained remission for subjects on risperidone was 5.6 (p < 0.0001). Similarly the adjusted hazard or remission for subjects on rsiperidone was 4.0 (p < 0.0001). Interpretaion: A statistically significant proportion of manic patients receiving risperidone monotherapy achieved symptomatic remission within 3 weeks as compared to placebo.

ABSTRACT

Effective treatments for the prevention of relapse and recurrence of mood episodes in patients with bipolar disorder are essential to reduce the high mortality associated with this condition, and to improve long-term outcomes. While lithium is considered to be effective as a first line maintenance treatment, additional treatment options would provide clinicians with tools to address the needs of individual patients. The efficacy of olanzapine, an atypical antipsychotic, for the prevention of relapse in bipolar disorder has been demonstrated in several randomized controlled double-blind clinical trials, both as monotherapy and in combination with other agents. The data reviewed herein suggest a more robust efficacy of treatment with olanzapine in the prevention of relapse into manic episodes than into depressive episodes. The adverse events observed most frequently in patients treated with olanzapine relative to comparators were related to somnolence (somnolence, fatigue, or hypersomnia) and weight gain (weight gain, or increased appetite). Moreover, a larger proportion of olanzapine-treated patients than comparator-treated patients experienced clinically important weight gain.