The data reviewed present a case for increasing the dose of clozapine in non-responsive patients to achieve a plasma level of at least 350-420 ng mL-1. Non-response at these levels, however, should not preclude a further upward titration of dose. This should occur unless (i) clinical response is obtained at a lower dose, (ii) intolerable side effects occur, or (iii) a daily dose of 900 mg is reached.
The data reviewed present a case for increasing the dose of clozapine in non-responsive patients to achieve a plasma level of at least 350-420 ng mL-1. Non-response at these levels, however, should not preclude a further upward titration of dose. This should occur unless (i) clinical response is obtained at a lower dose, (ii) intolerable side effects occur, or (iii) a daily dose of 900 mg is reached.
We read with interest the study of Sachdev et al., 1 who reported an association between elevated homocysteine levels and brain atrophy in healthy elderly subjects. To our knowledge, this observation is the second report about a linkage between increased homocysteine levels and brain volume reduction. Recently, radiologic evidence of temporal atrophy progression in patients with AD has been found to be significant greater among those patients with higher plasma homocysteine levels. 2 In addition to these findings we would like to emphasize the influence of elevated homocysteine levels in chronic alcoholism on alcoholism-related brain shrinkage. Chronic alcohol consumption leads, among other lesions, to cortical and subcortical cerebral atrophy (e.g., cerebral white matter, corpus callosum, hippocampal area, cerebellar vermis). 3 However, the precise mechanisms on which the alcohol-related brain tissue changes are based have yet to be fully explained. There is evidence that chronic alcoholism is associated with hyperhomocysteinemia. 4 In a recent volumetric MRI study including 52 chronic alcoholics we observed that pathologic raised levels of plasma homocysteine showed the most significant correlation to brain volume reduction. 5 These results further support the abovementioned observations. The decrease in homocysteine possibly may explain why brain atrophy no longer progresses during abstinence, taking into account that homocysteine levels steadily decrease during alcohol withdrawal. 4 Therefore, increased levels of homocysteine in patients with brain atrophy may have important implications for understanding the pathogenesis of neurodegenerative disorders. The results of these studies highlight the need for further research on whether neuroprotection against elevated homocysteine levels (e.g., NMDA antagonists) or the lowering of homocysteine (e.g., fortification) will protect patients from neuronal cell loss or brain atrophy. The relationship between increased homocysteine levels, their causes (e.g., common genetic polymorphisms such as methylenetetrahydrofolate reductase mutations) and neurotoxicity warrants further study.
Clinicians in Australia and New Zealand who wish to know their patients' plasma-clozapine levels can be confident that the result of the assay is unlikely to vary with the choice of centre or the operator who performs the assay.
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