Imipramine and desipramine

Pankey et al.21 described a rapid, reliable, and specific enzyme multiplied immunoassay technique (EMIT ) for amitriptyline, nortriptyline, imipramine, and desipramine in sera. To overcome crossreactivity, solid phase extraction was included in sample pretreatment. Disposable 1 mL columns packed with covalently labeled silica gel were conditioned with HPLC-grade methanol (1 mL) and then with de-ionized or distilled water (1 mL). Serum (calibrator, control, or patient sample, 500 L) was applied onto the column, eluted to waste, washed with 900 /uL of wash solution containing acetonitrile (236.1 g/L) and ion-pairing reagent in acetate buffer, pH 4.2, washed with 500 fiL of mobile phase solution containing acetonitrile (393.5 g/L) in methanolic phosphate buffer, pH 7.0,... 

Pankey, S. et al. 1986. Quantitative homogeneous enzyme immunoassays for amitriptyline, nortriptyline, imipramine, and desipramine. Clin Chem. 32 768. 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Chuang DM, Gao X-M, Paul SM N-methyl-D-aspartate exposure blocks glutamate toxicity in cultured cerebellar granule cells. Mol Pharmacol 42 210-216, 1992 Chugh Y, Saha N, Sankaranarayanan A, et al Enhancement of memory retrieval and attenuation of scopolamine-induced amnesia following administration of S-HTj antagonist ICS 205-930. Pharmacol Toxicol 69 105-106, 1991 Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146, 1981 Ciraulo DA, Barnhill JG, Jaffe JH Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers. Pharmacol Ther 43 539-548, 1988... 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

Fluvoxamine increases the systemic availability of oral melatonin, probably by reducing its first-pass clearance (34). In a crossover study in seven healthy subjects, serum melatonin concentrations were increased by fluvoxamine but not citalopram (35). In another study fluoxetine, paroxetine, citalopram, imipramine, and desipramine did not affect the biotransformation of melatonin at therapeutic concentrations in vitro (36). 

Fluoxetine, in addition to its antidepressant property, has been used as an appetite suppressant. Imipramine and desipramine have been used as antibulimic substances. 

Mass spectrometric detection has also been directly interfaced with microchip separations for drug detection. These studies, detecting imipramine and desipramine in fortified human plasma, show analysis of spiked analytes in clinical sample matrices for drug detection [3]. These widely used tricyclic antidepressants inhibit the reuptake of the neurotransmitters serotonin and norepinephrine in the central nervous system. Unfortunately, the 5-mg/mL detection limit found for these antidepressants with this method is not low enough to detect typical clinical levels of the drugs. Combinatorial library characterization and preclinical drug delivery studies should benefit, however, since the concentra-... 

Quantification. Gas Chromatography. In plasma imipramine and desipramine, detection limit 10 ng/ml, AFID—S. Dawling and R. A. Braithwaite, J. Chromat., 1978,146 Biomed. AppL, 3, 449-456. 

Gas Chromatography-Mass Spectrometry. In serum or plasma imipramine and desipramine, sensitivity 4 ng/ml—D. Alkalay et aL, Biomed. Mass Spectrom., 1979, 6, 200-204. 

Toxicity. In adults the estimated minimum lethal dose is 1 g, although fatalities have occurred with less and patients have survived the ingestion of as much as 5 g. In children, as little as 350 mg may be fatal. Blood concentrations greater than 0.5 jj-g/ml (imipramine and desipramine) may cause toxic effects and imipramine concentrations of 0.8 to 4.5 to 13 pg/ml have been associated with fatalities. 

Abernethy DR, Greenblatt DJ, Shader RI. Imipramine and desipramine disposition in the elderly. J Pharmacol Exp Ther 1985 232 183-8. 

There are few reports on the excretion of antidepressant drugs in breast milk, even though postpartum depression is relatively common. In a 32-year-old woman who took imi-pramine 200 mg/day from 1 month postpartum imipramine and desipramine were detectable in breast milk (135). There have also been reports that amitriptyline (136), desipramine (137), and nortriptyline (138,139) were detectable in the milk of nursing mothers and in the plasma of the mothers and infants. Neither parent compound nor metabolite were detected in infants serum, except for two infants who had low concentrations of 10-hydroxynortriptyline. There were no adverse effects in any of the infants. The use of antidepressants during lactation has been reviewed, including 15 studies in which serum concentrations of antidepressants were obtained from nursing infants (140). 

Sovner R, Orsulak PJ. Excretion of imipramine and desipramine in human breast milk. Am J Psychiatry 1979 136(4A) 451-2. 

Koyama et al. (1996) evaluated the steady-state plasma levels of imipramine and desipramine in 28 Japanese patients with depression after they had received fixed doses of imipramine for a minimum of 2 weeks to phenotype for CYP2C19 metabolizer status. The authors found that the mean desipramine concentration-to-imipramine concentration ratio (N-demethylation index) was significantly reduced in patients who were designated PMs, compared with those who were designated EMs. 

Koyama E, Tanaka T, Chiba K, et al Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4 -hydroxylation status in Japanese depressive patients. J Clin Psycho-pharmacol 16 286-293,1996... 

NSRI Antidepressants. Nonselective serotonin reuptake inhibitors (NSRI)also block the reuptake of norepinephrine. Several of the old tricyclic antidepressants belong in this category. Imipramine and desipramine reduce REM sleep because of the increased norepinephrine levels at postsynaptic receptors caused by reduced reuptake of norepinephrine. 

Among NSAI agents, indomethacin inhibits the rat kidney PGDH. Imipramine and desipramine,... 

KK Midha, C Charette, JK Cooper, IJ McGilveray. Comparison of a new GLC-AFID method with a GLC-MS selected ion monitoring technique and a radioimmunoassay for the determination of plasma concentrations of imipramine and desipramine. J Anal Toxicol 4 237, 1980. 

Tricyclic antidepressants Alprazolam has been found to increase imipramine and desipramine serum levels by about 25%. The mechanism is unknown. ... 

Venlafaxine is a virtually non-selective inhibitor of the uptake of 5-HT and NE by rat brain synaptosomes. It is structurally related to gamfexine a compound with antidepressant and psychostimulant properties (fig. 4). The potency of venlafaxine to inhibit in vitro monoamine uptake is the same range as that of imipramine and desipramine under the experimental conditions described by Muth et al. [45] and Yardley et al. [46]. 

Part of the explanation for the increased C3S1S depression is that both alcohol and some of the tricyclics, particularly amitriptyline, cause drowsiness and other CNS depressant effeets, which can be additive with the effects of alcohol. The sedative effects have been reported to be greatest with amitriptyline, then doxepin and imipramine, followed by nortriptyline, and least with amoxapine, clomipramine, desipramine, and protriptyline. In addition acute alcohol intake causes marked increases (100 to 200%) in the plasma levels of amitriptyline, probably by inhibiting its first pass metabolism. Alcohol-induced liver damage could also result in impaired amitriptyline metabolism. The lower serum levels of imipramine and desipramine seen in abstinent alcoholics are attributable to induction of the cytochrome P450 isoenzymes by alcohol. ... 

Spina E, Avenoso A, Campo GM, Scordo MG, Caputi AP, Pemcca E. Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects. BrJ Clin Pharmacol (1997) 43,315-8. 

Spina E, Avenoso A Campo GM, Caputi AP, Perucca E. Decreased plasma concentrations of imipramine and desipramine following cholestyramine intake in depressed patients. TherDrug Monit 99A) 6, 432-4. 

Disulflram reduces the clearance of imipramine and desipramine. The concurrent use of amitriptyline and disulflram has been reported to cause a therapeutically useful Increase In the effects of disulflram but organic brain syndrome has been seen In two patients. 

Bresen K, Gram LF. Quinidine inhibits the 2-hydroxylation of imipramine and desipramine, but not the demethylation of imipramine. EurJClin Pharmacol (1989) 37,155-60. 

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