Clinical and biochemical results of a fatal case of desipramine intoxication

Bickel, Marcel H.; Brochon, R.; Friolet, B; Herrmann, Bernhard G.; Stofer, A. R.

doi:10.1007/bf00403984

Cited by 28 publications

(7 citation statements)

References 7 publications

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“…In fact, in vivo neuroimaging studies using spectroscopy, which are only possible with antidepressants containing fluorine atoms such as fluoxetine and fluvoxamine, have consistently described steadystate brain concentrations of these drugs in the micromolar range (Bolo et al, 2000). Moreover, brain concentrations of tricyclics in humans, largely derived from postmortem studies following overdoses, have described brain-toplasma concentration ratios ranging from eightfold, at higher plasma concentrations, to 125-fold, at lower plasma concentrations (Sunshine and Baeumler, 1963;Bickel et al, 1967;Avella et al, 2004). Therefore, considering that the plasma concentrations of tricyclics in patients taking therapeutic doses range 100-250 ng/ml (ie approximately 0.4-0.9 mM for desipramine and amitryptiline, and 0.3-0.8 mM for clomipramine), even a conservative estimate of a brain-to-plasma concentration of 10 would lead to micromolar concentrations of tricyclic antidepressants in the brain of patients.…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

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The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoidsFbut this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region ( + 31%; p ¼ 0.045); in contrast, in abcb1ab (À/À) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (À45%; p ¼ 0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (À/À) mice, but in abcb1ab (À/À) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (À/À) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the 'physiological' levels of untreated mice (À39%; p ¼ 0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (À9 to À23%), but had no effect on 11b-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.

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Section: Discussionmentioning

confidence: 99%

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

Yau

Noble

Thomas

et al. 2007

Neuropsychopharmacol

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“…Therefore, to examine the regional CMP distribution in the brain, the T/M ratio is studied on each brain region here. There are several reports concerning the uneven distribution and different kinetics of TCAs in the rat brains and postmortem specimens (Cassano and Hans,son 1966;Bickel et al 1967;Sherman and Allers 1980;Van Wijk and Korf 1982;Friedman and Cooper 1983;Masada et al 1984;Kurata et al 1986;Yufu 1987). It is generally agreed that in the single-dose experiment the uptake of the TCAs is high in the cerebral cortex and striatum but low in the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

Distribution of clomipramine in various brain regions of rats under steady-state serum concentrations

1988

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The clomipramine (CMP) distribution in 12 regions of rat brain was investigated 2 and 7 days after subcutaneous minipump implantation. The results of serial blood samplings during 7 days indicated that steady-state CMP serum levels were achieved from experimental day 2. The regional CMP distributions in the brains were uneven on both the 2nd and 7th experimental days. On both test days the CMP concentrations were higher in the cerebral cortex and hippocampus than those in the other regions, and those in the cerebellum and bulbus olfactorius and septum were lower. When the serial fluctuations of the CMP levels were examined in 12 brain regions, there were significant differences between days 2 and 7 in the following four regions: the anterior basal ganglia, hypothalamus, bulbus olfactorius + septum and amygdala.

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“…In fact, in vivo neuroimaging studies using spectroscopy, which are only possible with antidepressants containing fluorine atoms such as fluoxetine and fluvoxamine, have consistently described steady-state brain concentrations of these drugs in the micromolar range (Bolo et al, 2000). Moreover, brain concentrations of tricyclics in humans, largely derived from post-mortem studies after overdoses, have described brain-to-plasma concentration ratios ranging from 8-fold, at higher plasma concentrations, to 125-fold, at lower plasma concentrations (Bickel et al, 1967;Avella et al, 2004;Sunshine and Baeumler, 1963). Therefore, considering that the plasma concentrations of tricyclics in patients taking therapeutic doses range from 100 to 250 ng/ml (that is, approximately 0.3À0.8 mM for clomipramine), even a conservative estimate of a brain-to-plasma concentration of 10-fold would lead to micromolar concentrations of tricyclic antidepressants in the brain of patients.…”

Section: Sirmentioning

confidence: 99%