Nortriptyline blood levels and clinical outcome: meta-analysis of published studies

Abstract

INTRODUCTION: An optimum range has been suggested for nortriptyline blood levels, above or below which patients respond poorly or do not respond at all to treatment. METHODS: A meta-analysis of published studies was performed to verify the existence of an optimal blood concentration range or therapeutic window in nortriptyline-treated depression patients. A MEDLINE search through the years 1970-1999 was carried out to identify original papers and review articles. Data concerning blood levels and percentage improvement were obtained concerning all included pacients. Univariate and multivariate analyses were performed for data comparison. Possible confounding variables, such as pre-treatment, setting (in or outpatients), and duration of treatment were also evaluated. RESULTS: From the 22 published studies found, only six of them with patients' individual data were included. We found an optimal range for nortriptyline concentrations (OR= 2.25, 95% CI = 1.15 to 4.39, p= 0.02). CONCLUSIONS: There may be a biphasic relationship of efficacy to plasma concentrations of nortriptyline, with a therapeutic window between 46 to 236 ng/ml.

c-Fos expression identifies brain areas activated in response to nortriptyline

“…1 Nicotine increases phosphorylation of CREB (P-CREB) in the ventral tegmental area, 1 while nicotine withdrawal decreases P-CREB. 2 Nicotine-induced P-CREB increase is absent in MOR À/À knockout (KO) mice and is also blocked by the MOR antagonist naloxone in wild-type mice. 1 The MOR promoter has a cAMPresponsive element that binds P-CREB, which is thought to drive expression of MOR.…”

“…1,2 Our group has demonstrated that there is a biphasic curvilinear relationship between plasma levels of nortriptyline and behavior, using the tail suspension test, 3 an animal model employed to screen for drugs with antidepressant effects. Although noradrenergic drugs are known to induce c-Fos expression in central neurons, only one study has investigated the effects of nortriptyline on the expression of brain c-Fos.…”