Trimipramine's primary use in medicine is in the treatment ofmajor depressive disorder,[11][12] especially wheresedation is helpful due to its prominent sedative effects.[12] The drug is also an effectiveanxiolytic, and can be used in the treatment ofanxiety.[8][9] In addition to depression and anxiety, trimipramine is effective in the treatment of insomnia, and unlike most otherhypnotics, does not alter the normal sleep architecture.[8] In particular, it does not suppressREM sleep, anddreams are said to "brighten" during treatment.[8][13]
A majorsystematic review andnetwork meta-analysis of medications for the treatment of insomnia published in 2022 found that trimipramine had aneffect size (standardized mean difference (SMD)) againstplacebo for treatment of insomnia at 4weeks of 0.55 (95%CITooltip confidence interval –0.11 to 1.21).[14] Thecertainty 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 anddoxylamine, 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]
The side effects of trimipramine have been said to be similar to those of other tertiary amine TCAs, with a preponderance ofanticholinergic andsedative 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 ofnorepinephrine 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 likeconstipation,urinary retention, andblurred vision are also present.[9] Such effects, in any case, may be treated withbethanechol.[18][19]
It is described as being associated with minimal or noorthostatic hypotension, at least in comparison toclomipramine,[6][7] in spite of its potent and comparable activity as analpha-1 blocker.[20][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 lessepileptogenic than other TCAs, althoughseizures have still been reported in association with it.[7] It is also lesscardiotoxic 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.[21] However, on tests done onDrosophila melanogaster, nongenotoxic TCAs (amitriptyline, maprotiline, nortriptyline, and protriptyline), andgenotoxic TCAs (amoxapine, clomipramine, desipramine, doxepin, imipramine, and trimipramine) were identified.[21]
The majormetabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.[25]
Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine,[25] 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[32] and Tatsumi et al. (1997) found a relatively high KD of 149 nM for the SERT in humanHEK293 cells,[24] but other authors and a more recent study with an improved design have not had the same findings.[25] 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 ofradioligand binding in isolated membranes (KD) to study interactions as opposed to actual functional reuptake inhibition (IC50).[25]
Values arepIC50. The higher the value, the more strongly the drug binds to the site.
Trimipramine is extensivelymetabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition.[25][33] 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).[25][33] 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.[25] However, desmethyltrimipramine still showed only very weak inhibition of the NET.[25]
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.[25] 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 theblood–brain barrier and accumulate in the brain to levels of up to 10-fold those in the periphery.[25] 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.[25][33] 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.[25] That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as withmirtazapine,[34] has also been implicated in antidepressant effects.[35][10][36]
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 notdownregulateβ3-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 ofserotonin syndrome orhypertensive crisis.[7] Indeed, in rabbits, whereashyperpyrexia (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 potentantihistamine; it has the third highest affinity for theH1 receptor (Ki = 0.27 nM) aftermirtazapine (Ki = 0.14 nM) anddoxepin (Ki = 0.24 nM) among the TCAs andtetracyclic antidepressants (TeCAs).[20][37] The TeCAmianserin (Ki = 0.40) and the TCAamitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists,[20][37][38] whereas other TCAs and TeCAs are less potent.[10] These TCAs and TeCAs, including trimipramine, are far more potent than the standard antihistaminediphenhydramine (approximately 800 times for doxepin and 250 times for trimipramine),[39] and are among the most potent antihistamines available.[38][40]
Trimipramine is also an antagonist of theH2 receptor with lower potency and has been found to be effective in the treatment ofduodenal ulcers.[9]
Blockade of the H1 receptor is responsible for thesedative effects of trimipramine and other TCAs and their effectiveness in the treatment ofinsomnia.[41]
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.[42] In addition, trimipramine has been found to decrease nocturnalcortisol levels to normal and to normalize cortisol response in depressed patients; hence, it normalizes thehypothalamic–pituitary–adrenal axis, whereas imipramine and other antidepressants tend to increase nocturnal cortisol secretion.[27]
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 dopamineD1 andD2 receptors, and also binds to theD4 receptor (Ki = 275 nM).[6][25] Its affinities for variousmonoamine receptors including the D2 and 5-HT2A receptors closely resemble those of theatypical antipsychoticclozapine.[6] In accordance, high doses of trimipramine have been found to haveantipsychotic effects inschizophrenic patients, notably without causingextrapyramidal symptoms, and trimipramine has recently been found to be effective in reducing psychotic symptoms in patients withdelusional depression.[6][25] 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.[27] Unlike other TCAs, but reminiscent of antipsychotics, trimipramine has been found to markedly increase plasmaprolactin 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 importantantidopaminergic actions of trimipramine.[6][25]
Unlike various other TCAs, trimipramine shows marked antagonism ofpresynapticdopamineautoreceptors, potentially resulting in increaseddopaminergicneurotransmission.[7] This effect has also been observed with low-potency tricyclic antipsychotics likethioridazine andchlorprothixene.[7] Notably, these two antipsychotics have been claimed many times to also possess antidepressant effects.[7][42] As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine.[7][42] However, other authors have attributed the claimed antidepressant effects of antipsychotics like the two previously mentioned toα2-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.[42]
Thetime 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.[43] Theterminal 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 aracemic compound with twoenantiomers.[1]CYP2C19 is responsible for thedemethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, andCYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively.[44] CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.[44]
Trimipramine was developed byRhône-Poulenc.[54] It was patented in 1959 and first appeared in the literature in 1961.[54] The drug was first introduced for medical use in 1966, inEurope.[54][55] It was not introduced in theUnited States until later in 1979 or 1980.[56][57]
Trimipramine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, whiletrimipramine maleate is itsUSANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[52][53][58][59] Its generic name inLatin istrimipraminum, inGerman istrimipramin, and inSpanish istrimipramina.[53][59]
Trimipramine is marketed throughout the world mainly under the brand name Surmontil.[53][59] Other notable brand names of trimipramine have included Herphonal, Rhotrimine, Sapilent, Stangyl, and Tydamine.[53][59]
The sedative effects of Trimipramine in off-prescription, recreational use are described in the 1987 filmWithnail 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."[62]
^Schredl M, Berger M, Riemann D. The effect of trimipramine on dream recall and dream emotions in depressive outpatients. Psychiatry Res. 2009 May 30;167(3):279-86. doi: 10.1016/j.psychres.2008.03.002. Epub 2009 Apr 28. PMID 19403177.
^Kachur JF, Allbee WE, Gaginella TS. Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro. J Pharmacol Exp Ther. 1988 May;245(2):455-9. PMID: 2896792.
^abcdefghiRichelson E, Nelson A (1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro".J. Pharmacol. Exp. Ther.230 (1):94–102.PMID6086881.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved7 May 2022.
^abcdeTatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".Eur. J. Pharmacol.340 (2–3):249–58.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^abcWander TJ, Nelson A, Okazaki H, Richelson E (1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro".Eur. J. Pharmacol.132 (2–3):115–21.doi:10.1016/0014-2999(86)90596-0.PMID3816971.
^abCusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds".Psychopharmacology.114 (4):559–65.doi:10.1007/bf02244985.PMID7855217.S2CID21236268.
^abcdAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H1R, H2R, H3R, and H4R receptors with 34 antidepressants and antipsychotics".Naunyn-Schmiedeberg's Arch. Pharmacol.385 (2):145–70.doi:10.1007/s00210-011-0704-0.PMID22033803.S2CID14274150.
^Randrup A, Braestrup C (1977). "Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression".Psychopharmacology.53 (3):309–14.doi:10.1007/bf00492370.PMID408861.S2CID8183053.
^abRichelson E, Pfenning M (1984). "Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake".Eur. J. Pharmacol.104 (3–4):277–86.doi:10.1016/0014-2999(84)90403-5.PMID6499924.
^Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies".Thérapie.60 (5):441–60.doi:10.2515/therapie:2005065.PMID16433010.
^Krystal AD, Richelson E, Roth T (2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications".Sleep Med Rev.17 (4):263–72.doi:10.1016/j.smrv.2012.08.001.PMID23357028.
^Ostad Haji E, Hiemke C, Pfuhlmann B (2012). "Therapeutic drug monitoring for antidepressant drug treatment".Curr. Pharm. Des.18 (36):5818–27.doi:10.2174/138161212803523699.PMID22681162.
^abEap CB, Bender S, Gastpar M, et al. (2000). "Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients".Ther Drug Monit.22 (2):209–14.doi:10.1097/00007691-200004000-00012.PMID10774635.
^Acta Pharmacologica Et Toxicologica: Supplement. Munksgaard. 1985.Triraipramine, butriptylin, and propizepine have a methyl substituent at the 2'-position of the sidechain, e.g. trimipramine is a 2'-methyl-imipramine.
^Dawkins K, Manji HK, Potter WZ (20 September 1994)."Pharmacodynamics of Antidepressants". In Cutler NR, Sramek JJ, Narang PK (eds.).Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. pp. 160–.ISBN978-0-471-95052-3.
^abcAndersen J, Kristensen AS, Bang-Andersen B, Strømgaard K (2009). "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters".Chem. Commun. (25):3677–92.doi:10.1039/b903035m.PMID19557250.
