Imipramine

Imipramine is a tricyclic antidepressant that has been used since the 1950s. Its primary mechanism of
action is to inhibit the reuptake of serotonin and norepinephrine, thus elevating the levels of
these neurotransmitters in the brain. Recently, epigenetic effects of imipramine have been noted,
providing a deeper understanding into the therapeutic effect of this drug. Because dysfunction
of BDNF is often implicated in the etiology of depression, Tsankova et al. [31] investigated the
effectiveness of imipramine on epigenetic regulation of the BDNF gene in the hippocampi of mice.
Chronic social defeat led to repression of histone dimethylation of H3K27 at the BDNF exon 3 and 4
promoters, continuing for a month after social defeat. Chronic treatment with imipramine could not
reverse this, even though the depression-like behaviors disappeared. However, chronic imipramine
did lead to hyperacetylation of H3 at the BDNF promoters, mediated by downregulation of HDAC5.
Moreover, the efficacy of imipramine was blocked by overexpression of HDAC5, suggesting that
downregulation of HDAC5 may be essential to the efficacy of imipramine. The authors suggested that,
because histone H3 hypermethylation was not affected by imipramine, this remains a possible target
for antidepressant therapy. Imipramine also influences epigenetic regulation in the nucleus
accumbens by largely reversing repression of dimethylation of H3K9 and H3K27 in the nucleus
accumbens and increased phospho–CREB binding induced by social defeat stress. The global pattern
of H3 dimethylation in the nucleus accumbens of mice that did not develop depression-like behaviors
strongly resembled the dimethylation profile of mice that received chronic imipramine treatment
after social defeat. This may indicate that resilient animals somehow naturally overcome the effects
of stress on gene expression in the accumbens. Of course, the genes that show dimethylation in
resilient mice, but not in mice treated with imipramine, could also be investigated as novel targets
for antidepressant medication [32].
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Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal
and Cardiovascular
K.E. Browman, G.B. Fox, in Comprehensive Medicinal Chemistry II, 2007
6.05.6.3.1 Structure–activity relationships
Imipramine (Figure 3) is a TCA. Imipramine is comprised of a tricyclic nucleus (including two phenyl
rings and a central cycloheptadien ring). A short side chain and a terminal amine group are additional
structural features characterizing imipramine and related members of the same chemical
series.90 The short side chain and the terminal amine group appear to be the conditions that are
important for antidepressant activity. The tertiary amines, including imipramine, are more selective
for SERT than NET, while the secondary amines, including nortriptyline, are more NET-selective.86
Bupropion hydrochloride (Figure 3) is an aminoketone antidepressant related to the
phenylisopropylamines.86 Bupropion appears to act as an indirect dopamine agonist as well as having
specific noradrenergic effects, being a functional NET inhibitor.
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Neuropsychopharmacology of Hyperkinetic Children
RACHEL GITTELMAN-KLEIN, in Neuro-Psychopharmacology, 1979
Tricyclics
Imipramine has been demonstrated to improve the behavior of hyperkinetic children (Greenberg and
co-workers, 1975; Rapoport and co-workers, 1974) and offers certain practical advantages in that it is
long-acting, eliminating or reducing the need for multiple dosages through the day. Further, clinical
side-effects are reported to be negligible. However, as with the phenothiazines, the effect of
imipramine is not as complete as with stimulants and many children fail to sustain their initially good
response (Gittelman-Klein, 1974). There have been recent reports of cardiotoxic EKG effects with
imipramine treatment in children thereby limiting the potential usefulness of high dosage of this drug
(for a review see Saraf and coworkers, 1978).
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Enuresis*
S.K. Anand, C.D. Berkowitz, in Encyclopedia of Stress (Second Edition), 2007
TCA
Imipramine has been the principal TCA used for enuresis, but other TCAs are also effective. The
mechanism of action is unknown. The starting dose of imipramine is 25 mg (which may be increased
to a maximum of 50 mg for 8- to 12-year-olds and 75 mg for >12 years old) 1 h before bed time. A trial
period of 2 to 4 weeks is adequate to assess effectiveness. The initial success rate is about 40–60%
with a relapse rate of 50–70% upon discontinuation.
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Psychotropic drugs
Christof Schaefer, in Drugs During Pregnancy and Lactation (Second Edition), 2007
Imipramine
Imipramine has a half-life of 6–20 hours. Up to 95% is bound to plasma protein. With a dose of
200mg imipramine a day, a maximum of 29μg/l of imipramine and 35μg/l of desipramine (metabolite)
were measured in the milk (Sovner 1979). By contrast, in four mothers in a newer study taking 75–
150mg daily, active ingredient concentrations of up to 600μg/l were measured in the milk. Most of
the values, however, were significantly under 300μg/l (Yoshida 1997A). Based on these data, a
maximum of 90μg/kg per day, or 7% of the maternal weight-related dosage, could be calculated for
the baby. However, on average, it is below 2% (survey in Weissman 2004).