No abstract

No abstract

Olanzapine treatment resulted in significantly greater psychopathology improvement and higher response and completion rates than ziprasidone treatment, while ziprasidone was superior for weight change and lipid profile.

the US Food and Drug Administration (FDA) approved aducanumab (Aduhelm; Biogen Inc), the first new drug for the treatment of Alzheimer disease in 2 decades. Alzheimer disease, the sixth leading cause of death in the US, is a neurodegenerative disease leading to a progressive, irreversible destruction of neurons resulting in loss of cognitive function and memory. Over time, patients develop severe dementia, loss of independence, and death. 1 Unfortunately, pharmacologic treatment options have been extremely limited, with the few previously approved drugs providing only symptomatic improvement, but not modifying disease progression. Undoubtedly, there is a substantial unmet medical need in patients with Alzheimer disease. In this Viewpoint, we discuss the complexities of the data supporting the aducanumab application and the rationale for the FDA's decision to grant it accelerated approval.Aducanumab is administered monthly as an intravenous infusion. The drug is an IgG1 anti-amyloid-β (Aβ) antibody targeting Aβ aggregates-a pathological hallmark of Alzheimer disease-with binding intended to lead to Aβ plaque clearance. The decision to approve this drug was based on our review of data in the application, including 3 clinical studies providing the primary evidence concerning the effectiveness of this drug: study 103 (NCT01677572), study 301 (NCT02477800), and study 302 (NCT02484547). The first (study 103) was an early-phase randomized sequential cohort doubleblind study with 197 participants, evaluating doses up to 10 mg/kg every 4 weeks. Results showed clear dosedependent and time-dependent reduction in Aβ plaque and dose-related improvements in standard Alzheimer disease end points, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB) and the Mini Mental Status Examination (MMSE), with statistical significance at the 10 mg/kg dose for both of these end points.The other 2 studies (301 and 302) were randomized double-blind placebo-controlled, similarly designed, adequate, and well-controlled phase 3 studies, which included 1647 and 1638 participants, respectively. These studies provided conflicting results. Study 302 showed significant improvement in CDR-SB and 3 other secondary end points at the high dose (now the approved dose of 10 mg/kg after titration). These secondary end points (Alzheimer Disease Assessment Scale, Cognitive Subscale [13 items; ADAS-Cog 13]; Alzheimer Disease Cooperative Study, Activities of Daily Living Inventory [Mild Cognitive Impairment version; ADCS-ADL-MCI] and MMSE) evaluate cognitive function, memory, and social and personal functioning using different approaches and scales. They are only modestly correlated with the primary end point (CDR-SB) and each other; of note, the P values for the differences between

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a ␥-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients ( 2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.