Effect of age on the relative efficacy of clozapine in schizophrenia.

OBJECTIVE Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. METHOD Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. RESULTS 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, p =0.79 CI -0.03 - 0.03). Individual patient data was available for 2 studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. CONCLUSION The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide meta-analysable data for future use

Advancing understanding of land–atmosphere interactions by breaking discipline and scale barriers

Vegetation and atmosphere processes are coupled through a myriad of interactions linking plant transpiration, carbon dioxide assimilation, turbulent transport of moisture, heat and atmospheric constituents, aerosol formation, moist convection, and precipitation. Advances in our understanding are hampered by discipline barriers and challenges in understanding the role of small spatiotemporal scales. In this perspective, we propose to study the atmosphere–ecosystem interaction as a continuum by integrating leaf to regional scales (multiscale) and integrating biochemical and physical processes (multiprocesses). The challenges ahead are (1) How do clouds and canopies affect the transferring and in-canopy penetration of radiation, thereby impacting photosynthesis and biogenic chemical transformations? (2) How is the radiative energy spatially distributed and converted into turbulent fluxes of heat, moisture, carbon, and reactive compounds? (3) How do local (leaf-canopy-clouds, 1 m to kilometers) biochemical and physical processes interact with regional meteorology and atmospheric composition (kilometers to 100 km)? (4) How can we integrate the feedbacks between cloud radiative effects and plant physiology to reduce uncertainties in our climate projections driven by regional warming and enhanced carbon dioxide levels? Our methodology integrates fine-scale explicit simulations with new observational techniques to determine the role of unresolved small-scale spatiotemporal processes in weather and climate models