Trimipramine's primary use in medicine is in the treatment of
major depressive disorder,[11][12] especially where
sedation is helpful due to its prominent sedative effects.[12] The drug is also an effective
anxiolytic, and can be used in the treatment of
anxiety.[8][9] In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most other
hypnotics, does not alter the normal sleep architecture.[8] In particular, it does not suppress
REM sleep, and
dreams are said to "brighten" during treatment.[8][13]
A major
systematic review and
network meta-analysis of medications for the treatment of insomnia published in 2022 found that trimipramine had an
effect size (
standardized mean difference (SMD)) against
placebo for treatment of insomnia at 4weeks of 0.55 (95%
CITooltip confidence interval –0.11 to 1.21).[14] The
certainty of evidence was rated as very low, and no data were available for longer-term treatment (3months).[14] For comparison, the other sedating antihistamines assessed,
doxepin and
doxylamine, had effect sizes (SMD) at 4weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.47 (95% CI 0.06 to 0.89) (moderate certainty evidence), respectively.[14]
The effective dosage of trimipramine in depression is 150 to 300mg/day.[9] Doses of trimipramine used for insomnia range from 25 to 200mg/day.[15][16][17] However, it has been advised that doses be kept as low as possible, and a low dose of 25mg/day has been recommended.[15]
Any degree of heart block or other cardiac arrhythmias
Mania
Severe liver disease
During breastfeeding
Hypersensitivity to trimipramine or to any of the excipients
Side effects
The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance of
anticholinergic and
sedative effects.[9] However, trimipramine has also been said to be associated with a different side effect profile compared to other TCAs and in general with fewer side effects, chiefly due to its lack of
norepinephrine reuptake inhibition and relatively lower anticholinergic effects (although it is still a potent anticholinergic).[7][9]Somnolence is the most common side effect of the drug.[9]Dry mouth is the most common anticholinergic side effect, but others like
constipation,
urinary retention, and
blurred vision are also present.[9]
It is described as being associated with minimal or no
orthostatic hypotension, at least in comparison to
clomipramine,[6][7] in spite of its potent and comparable activity as an
alpha-1 blocker.[18][9] However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs.[9] Trimipramine is said to be less
epileptogenic than other TCAs, although
seizures have still been reported in association with it.[7] It is also less
cardiotoxic than other TCAs[7] and cardiotoxicity is said to be minimal, with a "very favorable profile".[9]
Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later.[19] However, on tests done on
Drosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), and
genotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.[19]
The major
metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.[23]
Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine,[23] and the drug has been described by various authors as devoid of monoamine reuptake inhibition.[10] Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes[30] and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in human
HEK293 cells,[22] but other authors and a more recent study with an improved design have not had the same findings.[23] In the most recent study, by Haenisch et al. (2011), the researchers suggested that the discrepant findings from the Tatsumi et al. study were due to methodological differences, in particular the use of
radioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).[23]
Values are
pIC50. The higher the value, the more strongly the drug binds to the site.
Trimipramine is extensively
metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition.[23][31] In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and trimipramine-N-oxide in addition to trimipramine and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of trimipramine (see table to the right).[23][31] Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than trimipramine in its norepinephrine reuptake inhibition but less potent in its inhibition of serotonin reuptake.[23] However, desmethyltrimipramine still showed only very weak inhibition of the NET.[23]
Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM (150–350 ng/mL) and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites.[23] However, these concentrations are nearly 2-fold higher if the active metabolites of trimipramine are also considered, and studies of other TCAs have found that they cross the
blood–brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery.[23] As such, trimipramine and its metabolites might at least partially inhibit reuptake of serotonin and/or norepinephrine, though not of dopamine, at therapeutic concentrations, and this could be hypothesized to contribute at least in part to its antidepressant effects.[23][31] This is relevant as Haenisch et al. has stated that these are the only actions known at present which could explain or at least contribute to the antidepressant effects of trimipramine.[23] That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with
mirtazapine,[32] has also been implicated in antidepressant effects.[33][10][34]
In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines.[7] Unlike other TCAs, it does not
downregulateβ3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension.[7][6] It can be safely combined with MAOIs apparently without risk of
serotonin syndrome or
hypertensive crisis.[7] Indeed, in rabbits, whereas
hyperpyrexia (a symptom of serotonin syndrome) occurs with imipramine and an MAOI and to a lesser extent with amitriptyline and an MAOI, it does not occur at all with trimipramine and an MAOI, likely due to trimipramine's lack of serotonin reuptake inhibition.[7]
Trimipramine is a very potent
antihistamine; it has the third highest affinity for the
H1 receptor (Ki = 0.27 nM) after
mirtazapine (Ki = 0.14 nM) and
doxepin (Ki = 0.24 nM) among the TCAs and
tetracyclic antidepressants (TeCAs).[18][35] The TeCA
mianserin (Ki = 0.40) and the TCA
amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists,[18][35][36] whereas other TCAs and TeCAs are less potent.[10] These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistamine
diphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine),[37] and are among the most potent antihistamines available.[36][38]
Trimipramine is also an antagonist of the
H2 receptor with lower potency and has been found to be effective in the treatment of
duodenal ulcers.[9]
As a hypnotic
Blockade of the H1 receptor is responsible for the
sedative effects of trimipramine and other TCAs and their effectiveness in the treatment of
insomnia.[39]
Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects).[6] This includes TCAs (e.g., amitriptyline,
nortriptyline), TeCAs (e.g.,
mianserin, maprotiline), MAOIs (e.g.,
clorgiline,
pargyline), and SSRIs (e.g., fluoxetine,
zimelidine,
indalpine).[6] Trimipramine is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep.[6][9] Even long-term treatment with trimipramine for up to 2 years has not been found to suppress REM sleep.[40] In addition, trimipramine has been found to decrease nocturnal
cortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes the
hypothalamic–pituitary–adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.[25]
In clinical studies, trimipramine has been found in doses of 50 to 200 mg/day to significantly increase sleep efficiency and total sleep time and to decrease waking time for up to 3 weeks in patients with insomnia.[6] It also improved subjectively perceived sleep quality and well-being during daytime.[6] Monitoring of patients upon discontinuation of trimipramine found that it did not cause rebound insomnia or worsening of sleep quality in subjective evaluations of sleep, although objective measurements found total sleep time below baseline in a subset of patients during trimipramine withdrawal.[6]
Values are pKi (nM). The higher the value, the more strongly the drug binds to the site.
Trimipramine is a weak but significant antagonist of the dopamine
D1 and
D2 receptors, and also binds to the
D4 receptor (Ki = 275 nM).[6][23] Its affinities for various
monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the
atypical antipsychoticclozapine.[6] In accordance, high doses of trimipramine have been found to have
antipsychotic effects in
schizophrenic patients, notably without causing
extrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients with
delusional depression.[6][23] The lack of extrapyramidal symptoms with trimipramine may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine.[25] Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasma
prolactin levels (a marker of D2 receptor antagonism) at a dose of 75 mg/day and to increase nocturnal prolactin secretion at doses of 75 and 200 mg/day.[6] These findings are suggestive of important
antidopaminergic actions of trimipramine.[6][23]
Unlike various other TCAs, trimipramine shows marked antagonism of
presynapticdopamineautoreceptors, potentially resulting in increased
dopaminergicneurotransmission.[7] This effect has also been observed with low-potency tricyclic antipsychotics like
thioridazine and
chlorprothixene.[7] Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects.[7][40] As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine.[7][40] However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned to
α2-adrenergic receptor antagonism, although trimipramine specifically has only weak affinity for this receptor.[7] Aside from antidepressant effects, low doses of antipsychotics have been found to increase REM sleep, and so dopamine autoreceptor antagonism could be involved in the unique effects of trimipramine in terms of REM sleep and sleep architecture.[40]
Pharmacokinetics
The
time to peak concentrations following a dose is 2 to 4 hours.[9] The typical antidepressant therapeutic range of trimipramine concentrations is 150 to 300 ng/mL.[41] The
terminal half-life of trimipramine has been variously reported to be as little as 8 hours (in plasma)[7] and as long as 24 hours.[9] In any case, the terminal half-life of trimipramine is described as shorter than that of other TCAs, which makes it ideal for use in the treatment of insomnia.[9][7]
Trimipramine is a
racemic compound with two
enantiomers.[1]CYP2C19 is responsible for the
demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and
CYP2D6 is responsible for the 2-
hydroxylation of (
D)- and (
L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively.[42] CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.[42]
Trimipramine was developed by
Rhône-Poulenc.[52] It was patented in 1959 and first appeared in the literature in 1961.[52] The drug was first introduced for medical use in 1966, in
Europe.[52][53] It was not introduced in the
United States until later in 1979 or 1980.[54][55]
Society and culture
Generic names
Trimipramine is the
generic name of the drug and its
INNTooltip International Nonproprietary Name,
USANTooltip United States Adopted Name,
BANTooltip British Approved Name, and
DCFTooltip Dénomination Commune Française, while trimipramine maleate is its
USANTooltip United States Adopted Name,
USPTooltip United States Pharmacopeia,
BANMTooltip British Approved Name, and
JANTooltip Japanese Accepted Name.[50][51][56][57] Its generic name in
Latin is trimipraminum, in
German is trimipramin, and in
Spanish is trimipramina.[51][57]
Brand names
Trimipramine is marketed throughout the world mainly under the brand name Surmontil.[51][57] Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.[51][57]
Availability
Trimipramine is no longer marketed in
Australia, though it was previously.[58][59]
In film
The sedative effects of Trimipramine in off-prescription, recreational use are described in the 1987 film
Withnail and I where the eponymous character declares "This is the plan. We get in there and get wrecked, then we'll eat a pork pie, then we'll drop a couple of Surmontil-50's each. That means we'll miss out Monday but come up smiling Tuesday morning."[60]
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