Doxepin and imipramine: Effect on catecholamine inhibition of ganglionic transmission
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Doxepin
Desipramine
The possibility that desipramine might prove to be a rapidly acting antidepressant was first raised by laboratory studies. In 1959 desipramine was isolated as a metabolite of imipramine (Hermann et al., 1959; Hermann and Pulver, 1960), and a series of papers then followed (Brodie et al., 1961; Gillette et al., 1961; Sulser et al., 1962) in which it was shown that reserpine-induced inactivity in the rat can be more rapidly reversed by desipramine than by imipramine. This was referred to (Gillette et al., 1961) as an experimental demonstration of the relative rapidity of the “antidepressant” action of the two drugs. Other experimental reports should however warn against incautious interpretation of laboratory findings. Garattini et al . (1962) showed that desipramine is not responsible for all the actions of imipramine: in mice, leptazol convulsions are inhibited by the latter but not by the former drug. Dingell et al . (1964) were able to show considerable species differences in the rate at which imipramine is converted to desipramine and in the rate at which desipramine is then destroyed. Their paper also emphasizes the paucity of information on the metabolism of imipramine in human subjects.
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Rats were given imipramine-N-oxide as single intramuscular injection and then as repeated oral doses. Imipramine-N-oxide and the metabolites imipramine and desipramine were analysed in the blood cells, plasma and brain tissue. The concentration of imipramine-N-oxide increased simultaneously in the brain and blood, reaching a peak 45 minutes after a single dose. Imipramine was the quantitatively predominant metabolite in the blood cells and brain, while desipramine reached a higher concentration than imipramine in the plasma. Samples taken at different times after oral doses during continuous treatment showed fairly constant concentrations of imipramine-N-oxide and desipramine in the brain, whereas the concentration of imipramine was more fluctuating.
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• In a double-blind study of depressed patients treated with imipramine hydrochloride, levels of imipramine and desipramine were measured in plasma and in CSF. Levels of both drugs in CSF were approximately 10% of plasma levels, but the levels in the two body fluids were highly correlated. The levels of both drugs were approximately equal in plasma, but desipramine predominated in CSF (imipramine/desipramine ratio of 0.8). The imipramine-induced alteration in CSF levels of the serotonin metabolite (5-hydroxy-indoleacetic acid [5HIAA]) correlated with imipramine levels but not with desipramine. For the group of patients showing a clear antidepressant response, the mean drug levels were nearly double those of the nonresponder group, a difference that did not quite reach statistical significance in this relatively small sample. The desipramine levels showed no responder-nonresponder difference, while theratioof imipramine/desipramine was significantly higher among the responders. On the average this particular patient group had relatively low pretreatment levels of 5HIAA in CSF, an observation that may partially account for the relatively low overall response rate to imipramine.
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Blood pressure measurements were collected from 36 depressed geriatric outpatients (ages 55 to 81 years) enrolled in a double-blind, placebo-controlled study of the efficacy of doxepin and imipramine. Mean systolic postural changes were 25.9 mm Hg for imipramine, significantly higher than the 10.5 mm Hg for doxepin, and 12.4 mm Hg for placebo. The orthostatic drop in the imipramine group was only weakly related to dose and did not correlate with amount of pretreatment orthostatic hypotension or with duration of treatment. The increased orthostatic hypotension occurred early in treatment and at low doses of imipramine. Accordingly, caution is advised in the use of imipramine for the elderly.
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Abstract Regional distribution of imipramine, desipramine and specific [3H]desipramine binding sites in the rat brain after acute and chronic treatment of rats with imipramine has been investigated. Both substances were distributed unevenly within rat brain after single and prolonged administration of imipramine. This was partly connected with the regional cerebral blood flow, lipid content in the regions and lipophilicity of the substances investigated. It was also found that the number of specific [3H]desipramine binding sites was different in the various brain areas, and that prolonged administration of imipramine led to a decrease of their number in some of those regions. No correlation was found between the regional cerebral distribution of desipramine and the regional density of specific [3H]desipramine binding sites.
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ABSTRACT– A study examining the relationship between plasma levels of tricyclic antidepressants (TCA), clinical response, and side effects was performed in patients with major affective disorder. Patients received either desmethylimipramine (DMI) (150–200 mg/day) or doxepin (200 mg/day) for 4 weeks. No significant correlations were found between plasma levels and either clinical response or side effects when males and females were analyzed together. A significant correlation between plasma levels and response was found in females taking desmethylimipramine. Support for the finding that females may show a stronger relationship than males between clinical response and plasma TCA levels is provided from analysis of previous studies in the literature.
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Abstract Imipramine and desipramine injected intracerebrally increase the temperature of fully reserpinised rats. Desipramine is more effective than imipramine in this. The effect of imipramine seems to be independent of the formation of desipramine in the brain. That imipramine, injected intraperitoneally, leads to an accumulation of brain desipramine has been confirmed.
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