Journal Digest
How Antidepressants Make New Brain Cells
A recent study used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Sertraline increases human hippocampal neurogenesis via a glucocorticoid receptor (GR)-dependent mechanism that requires protein kinase A (PKA) signaling, GR phosphorylation, and activation of a specific set of genes, suggest data from that study.
Using an in vitro model allowed the investigators to separate the direct effects of antidepressants on progenitor cells from any potential indirect effect—such as endogenous glucocorticoid production—which would be present in an in vivo model. The selective serotonin reuptake inhibitor sertraline was chosen first for evaluation because it is one of the most clinically effective antidepressants. Then the group performed confirmatory replication experiments using the tricyclic antidepressants amitriptyline and clomipramine.
These data may point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans, and identification of this mechanism may allow manipulation of neurogenesis, thereby possibly counteracting some of the neurobiological disturbances in depression, wrote the authors.
Anacker C, Zunszain P, Cattaneo A, et al.: Antidepressants Increase Human Hippocampal Neurogenesis by Activating the Glucocorticoid Receptor. Mol Psychiatry. 2011 Apr 12 [Epub ahead of print]. The full text is posted at <www.nature.com/mp/journal/vaop/ncurrent/full/mp201126a.html>.
Adolescent Group Therapy Not Cost-Effective for Self-Harm
Group psychotherapy is not a cost-effective addition to routine care offered for adolescents with self-harming behaviors, according to the results of a British study. Researchers evaluated adolescents aged 12 to 17 with at least two episodes of self-harm—nonaccidental overdose of drugs or other toxic substances or nonaccidental self-inflicted injuries such as scratching, cutting, burning, or strangulation—within the previous 12 months. In the northwest United Kingdom, 366 adolescents were evaluated at eight child and adolescent mental health service facilities. Children who were not English speaking or who had low-weight anorexia nervosa, acute psychosis, substantial learning difficulties (defined by the need for specialist school), or current containment in secure care were excluded from the study.
The researchers considered a primary outcome of frequency of subsequent repeated episodes of self-harm. Secondary outcomes were severity of subsequent self-harm, mood disorder, suicidal ideation, and global functioning. Total costs of health care, social care, education, and criminal justice efforts, as well as family-related costs and productivity losses, were recorded.
The addition of a targeted group-therapy program did not improve self-harm outcomes for adolescents who repeatedly self-harmed, nor was there evidence of cost-effectiveness, although the outcomes to end point for the cohort as a whole were better than current clinical expectations.
Green J, Wood A, Kerfoot M, et al.: Group Therapy for Adolescents With Repeated Self-Harm: Randomised Controlled Trial With Economic Evaluation. BMJ. 2011 Apr 1 [Epub ahead of print]. The full text is posted at <www.bmj.com/content/342/bmj.d682>.
Fixed Hippocampal Volume Assessed In Schizophrenia Patients/Siblings
Fixed hippocampal volume loss seen in childhood-onset schizophrenia, which is not shared by healthy siblings, appears to be related to the illness. Decreased hippocampal volume is not strongly genetically related but represents an important intermediate disease phenotype.
Anatomic brain magnetic resonance scans were obtained in childhood-onset schizophrenia probands, their nonpsychotic full siblings, and matched healthy comparison subjects aged 10 to 29 years. Total, left, and right hippocampal volumes were measured using FreeSurfer software and analyzed using a linear mixed-model regression covarying for sex and intracranial volume.
As a whole, these studies suggest that hippocampal volumes may be differentially affected, depending on the stage and type of psychosis, but fail to provide convincing evidence about the use of hippocampal volume as a familial/trait marker, according to the researchers.
Mattai A, Hosanagar A, Weisinger B, et al.: Hippocampal Volume Development in Healthy Siblings of Childhood-Onset Schizophrenia Patients. 2011 Am J Psychiatry. 168(4):427-435.The full text is posted at <http://ajp.psychiatryonline.org/cgi/reprint/168/4/427>.
Donepezil Reduces Apathy Emergence in Alzheimer's
Symptomatic improvement is the most common measure of treatment efficacy, but a recent study evaluated treatment for patients with Alzheimer's disease in terms of reduced emergence of a symptom. Apathy is typically the earliest neuropsychiatric symptom to manifest in Alzheimer's, and researchers sought to determine whether donepezil treatment is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's and to explore relationships between donepezil's effects on apathy and other neuropsychiatric inventory (NPI)–measured behavioral symptoms.
Two randomized, double-blind, parallel-group, placebo-controlled studies that were sufficiently similar to allow data pooling were derived from all donepezil Alzheimer's clinical trials. NPI data were available for 490 patients (249 receiving placebo; 241 receiving donepezil), and they were included in the analysis; a score from 10 to 26 at baseline on the Mini-Mental Status Examination was also an inclusion requirement. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency x severity) of at least three. Of all NPI items, apathy had the highest proportion of subjects scoring 3 or more at baseline, and treatment with the cholinesterase inhibitor donepezil appeared to result in a significant reduction over six months of the emergence of apathy.
These data suggest that a prospective clinical trial in patients with early Alzheimer's that includes apathy as a primary outcome measure may be warranted, said the authors. The study was funded by Pfizer and Eisai.
Waldemar G, Gauthier S, Jones R, et al.: Effect of Donepezil on Emergence of Apathy in Mild to Moderate Alzheimer's Disease. Int J Psychiatry. 2011; 26(2):150-157. The full text is posted at <http://onlinelibrary.wiley.com/doi/10.1002/gps.2507/pdf>.
Memantine's Benefit Questioned
Memantine, indicated for moderate to severe Alzheimer's, is frequently prescribed off label, either alone or with a cholinesterase inhibitor, for mild Alzheimer's and mild cognitive impairment, but its effectiveness is questionable. U.S. and European manufacturers of memantine have published meta-analyses claiming the beneficial effects of the drug for mild to severe cases of Alzheimer's. But recently, Lon Schneider, M.D., of the University of Southern California Keck School of Medicine, and colleagues systematically searched only manufacturer-sponsored meta-analyses, registries, presentations, and publications for randomized, placebo-controlled, parallel-group clinical trials of memantine in those patients with mild to moderate Alzheimer's. The search identified three trials that included 431 patients with mild Alzheimer's and 697 patients with moderate Alzheimer's. Using several scales, the researchers assessed cognition, global change, functional activities, and behavior. They concluded that there were no significant differences between memantine and placebo on any outcome for patients with mild Alzheimer's, either within any trial or when data were combined.
"Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild Alzheimer's, and there is meager evidence for its efficacy in moderate Alzheimer's," the authors concluded.
Schneider L, Dagerman K, Higgins J, et al.: Lack of Evidence for the Efficacy of Memantine in Mild Alzheimer Disease. Arch Neurol. 2011 Apr 11. [Epub ahead of print]. An abstract is posted at <http://archneur.ama-assn.org/cgi/content/abstract/archneurol.2011.69>.
