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Trimipramine

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression.[6][7][8][9] It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively.[6][7][8][9] The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor.[10] Similarly to other TCAs, however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.[6][7][8][9]

Trimipramine
Clinical data
Trade namesSurmontil, others
Other namesTrimeproprimine; IF-6120; IL-6001; RP-7162; 2'-Methylimipramine; β-Methylimipramine
AHFS/Drugs.com
MedlinePlusa602010
License data
  • US FDA: Trimipramine
Pregnancy
category
  • AU: C
Routes of
administration
Oral, intramuscular injection, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability41%[2][3][4][5]
Protein binding94.9%[2][3][4][5]
MetabolismHepatic[2][3][4][5]
Elimination half-life23–24 hours[2][3][4][5]
ExcretionRenal[2][3][4][5]
Identifiers
  • (±)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine
CAS Number
PubChem CID
  • 5584
IUPHAR/BPS
  • 7317
DrugBank
  • DB00726 Y
ChemSpider
  • 5382 Y
UNII
  • 6S082C9NDT
KEGG
  • D00394 Y
ChEBI
  • CHEBI:9738 Y
ChEMBL
  • ChEMBL644 Y
CompTox Dashboard (EPA)
  • DTXSID8023715
ECHA InfoCard100.010.917
Chemical and physical data
FormulaC20H26N2
Molar mass294.442 g·mol−1
3D model (JSmol)
  • Interactive image
  • c1cc3c(cc1)CCc2c(cccc2)N3CC(C)CN(C)C
  • InChI=1S/C20H26N2/c1-16(14-21(2)3)15-22-19-10-6-4-8-17(19)12-13-18-9-5-7-11-20(18)22/h4-11,16H,12-15H2,1-3H3 Y
  • Key:ZSCDBOWYZJWBIY-UHFFFAOYSA-N Y
  (verify)

Medical uses edit

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]

Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine, and may be useful in the treatment of psychotic symptoms, such as in delusional depression, schizoaffective disorder or schizophrenia.[6][7]

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 4 weeks 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 (3 months).[14] For comparison, the other sedating antihistamines assessed, doxepin and doxylamine, had effect sizes (SMD) at 4 weeks 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 300 mg/day.[9] Doses of trimipramine used for insomnia range from 25 to 200 mg/day.[15][16][17] However, it has been advised that doses be kept as low as possible, and a low dose of 25 mg/day has been recommended.[15]

Contraindications edit

Contraindications include:[2][3][4][5][11][12]

  • Recent myocardial infarction
  • 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 edit

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]

List of side effects edit

Common adverse effects include:[2][3][4][5][11][12]

  • Sedation — especially common with trimipramine compared to the other TCAs
  • Anticholinergic effects including:
- dry mouth
- blurred vision
- mydriasis
- decreased lacrimation
- constipation
- urinary hesitancy or retention
- reduced GI motility
- tachycardia (high heart rate)
- anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
  • Weight gain
  • Orthostatic hypotension
  • Sexual dysfunction including impotence, loss of libido and other sexual adverse effects
  • Tremor
  • Dizziness
  • Sweating
  • Anxiety
  • Insomnia
  • Agitation
  • Rash

Adverse effects with an unknown incidence includes:[2][3][4][5][11][12]

  • Confusion
  • Nausea
  • Vomiting
  • Extrapyramidal side effects (e.g. parkinsonism, dystonia, etc.)
  • Tinnitus
  • Paraesthesia
  • ECG changes
  • Increased liver function tests

Rare adverse effects include:[2][3][4][5][11][12]

Overdose edit

Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.[20]

Interactions edit

Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.

Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.[2][3][4][5][11][12]

Pharmacology edit

Pharmacodynamics edit

Trimipramine[21]
Site Ki/IC50 (nM) Species Ref
SERTTooltip Serotonin transporter 149–2,110 Human [22][23]
NETTooltip Norepinephrine transporter 2,450–4,990 Human [22][23]
DATTooltip Dopamine transporter ≥3,780 Human [22][23]
5-HT1A 8,000 Human [24]
5-HT1D >10,000 Pig [25]
5-HT2A 32 Human [24]
5-HT2C 537 Pig [25]
5-HT3 9,120 Rat [25]
α1 24 Human [18]
α2 680 Human [18]
D1 347 Pig [25]
D2 143–210 Human/undefined [18][26][25]
D3 ND ND ND
D4 275 Undefined [25]
H1 0.27–1.48 Human [27][18][28]
H2 41 Human [27]
H3 >100,000 Human [27]
H4 43,700 Human [27]
mAChTooltip Muscarinic acetylcholine receptor 58 Human [18]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear.[23][8] The mechanism of action of its anxiolytic effects is similarly unclear.[8] Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below),[23] and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition.[10][7][6] The effects of the drug are thought to be mainly due to receptor antagonism as follows:[18][26][24]

In spite of its atypical nature and different profile of activity, trimipramine has been shown in head-to-head clinical studies to possess equivalent effectiveness to other antidepressants, including but not limited to other TCAs (e.g., amitriptyline, imipramine, doxepin, amineptine), tetracyclic antidepressants (TeCAs) (e.g., maprotiline), monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid), and selective serotonin reuptake inhibitors (e.g., fluoxetine).[6][7] In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons.[8] Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs.[9] The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.[7]

The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.[23]

Monoamine reuptake inhibition edit

Trimipramine and MATs
SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter Type Species Tissue Year/Ref
8,200 1,000 6,800 IC50 (nM) Rat Brain 1977[29]
2,500 510 3,400 Ki (nM) Rat Brain 1984[30]
149 2,450 3,780 KD (nM) Human HEK293 1997[22]
2,110 4,990 55,600 IC50 (nM) Human HEK293 2011[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]

Trimipramine, metabolites, and MATs[23]
Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter
Trimipramine 5.675 5.302 >30 μM
Desmethyltrimipramine 5.206 5.535 4.530
2-Hydroxytrimipramine >30 μM 4.960 4.585
Trimipramine-N-oxide 5.445 4.930 5.027
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 downregulate β3-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]

Antihistamine activity edit

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 edit

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]

Antidopaminergic activity edit

Trimipramine and clozapine[25][6]
Site Trimipramine Clozapine
5-HT2A 7.71 7.84
α1A/B 7.62 8.54
D2 7.24 7.01
D1 6.46 6.58
α2B 6.42 7.08
5-HT2C 6.27 8.40
α2A 5.86 7.10
5-HT3 5.04 7.00
5-HT1A <5.00 6.17
5-HT1D <5.00 5.68
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 antipsychotic clozapine.[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 presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission.[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 edit

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]

Chemistry edit

Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[43] Other dibenzazepine TCAs include imipramine, desipramine, and clomipramine.[43] Trimipramine is a derivative of imipramine with a methyl group added to its side chain[44] and is also known as 2'-methylimipramine or β-methylimipramine.[43][45] The tri- prefix in its name may allude to the fact that its side chain features three methyl groups. Trimipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desmethyltrimipramine being a secondary amine.[46][47] Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, dosulepin (dothiepin), and doxepin.[48][49] The chemical name of trimipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294.434 g/mol.[50] The drug is used commercially as the maleate salt.[50][51] The CAS Registry Number of the free base is 739-71-9 and of the maleate is 521-78-8.[50][51]

History edit

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 edit

Generic names edit

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 edit

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 edit

Trimipramine is no longer marketed in Australia, though it was previously.[58][59]

In film edit

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]

References edit

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trimipramine, sold, under, brand, name, surmontil, among, others, tricyclic, antidepressant, which, used, treat, depression, also, been, used, sedative, anxiolytic, weak, antipsychotic, effects, treatment, insomnia, anxiety, disorders, psychosis, respectively,. Trimipramine sold under the brand name Surmontil among others is a tricyclic antidepressant TCA which is used to treat depression 6 7 8 9 It has also been used for its sedative anxiolytic and weak antipsychotic effects in the treatment of insomnia anxiety disorders and psychosis respectively 6 7 8 9 The drug is described as an atypical or second generation TCA because unlike other TCAs it seems to be a fairly weak monoamine reuptake inhibitor 10 Similarly to other TCAs however trimipramine does have antihistamine antiserotonergic antiadrenergic antidopaminergic and anticholinergic activities 6 7 8 9 TrimipramineClinical dataTrade namesSurmontil othersOther namesTrimeproprimine IF 6120 IL 6001 RP 7162 2 Methylimipramine b MethylimipramineAHFS Drugs comMedlinePlusa602010License dataUS FDA TrimipraminePregnancycategoryAU CRoutes ofadministrationOral intramuscular injection intravenousATC codeN06AA10 WHO Legal statusLegal statusAU S4 Prescription only BR Class C1 Other controlled substances 1 CA only UK POM Prescription only US onlyPharmacokinetic dataBioavailability41 2 3 4 5 Protein binding94 9 2 3 4 5 MetabolismHepatic 2 3 4 5 Elimination half life23 24 hours 2 3 4 5 ExcretionRenal 2 3 4 5 IdentifiersIUPAC name 3 10 11 dihydro 5H dibenzo b f azepin 5 yl N N 2 trimethylpropan 1 amineCAS Number739 71 9 Y 521 78 8 maleate PubChem CID5584IUPHAR BPS7317DrugBankDB00726 YChemSpider5382 YUNII6S082C9NDTKEGGD00394 YChEBICHEBI 9738 YChEMBLChEMBL644 YCompTox Dashboard EPA DTXSID8023715ECHA InfoCard100 010 917Chemical and physical dataFormulaC 20H 26N 2Molar mass294 442 g mol 13D model JSmol Interactive imageSMILES c1cc3c cc1 CCc2c cccc2 N3CC C CN C CInChI InChI 1S C20H26N2 c1 16 14 21 2 3 15 22 19 10 6 4 8 17 19 12 13 18 9 5 7 11 20 18 22 h4 11 16H 12 15H2 1 3H3 YKey ZSCDBOWYZJWBIY UHFFFAOYSA N Y verify Contents 1 Medical uses 2 Contraindications 3 Side effects 3 1 List of side effects 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Monoamine reuptake inhibition 6 1 2 Antihistamine activity 6 1 3 As a hypnotic 6 1 4 Antidopaminergic activity 6 2 Pharmacokinetics 7 Chemistry 8 History 9 Society and culture 9 1 Generic names 9 2 Brand names 9 3 Availability 9 4 In film 10 ReferencesMedical uses editTrimipramine 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 Trimipramine also has some weak antipsychotic effects with a profile of activity described as similar to that of clozapine and may be useful in the treatment of psychotic symptoms such as in delusional depression schizoaffective disorder or schizophrenia 6 7 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 4 weeks 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 3 months 14 For comparison the other sedating antihistamines assessed doxepin and doxylamine had effect sizes SMD at 4 weeks 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 300 mg day 9 Doses of trimipramine used for insomnia range from 25 to 200 mg day 15 16 17 However it has been advised that doses be kept as low as possible and a low dose of 25 mg day has been recommended 15 Contraindications editContraindications include 2 3 4 5 11 12 Recent myocardial infarction Any degree of heart block or other cardiac arrhythmias Mania Severe liver disease During breastfeeding Hypersensitivity to trimipramine or to any of the excipientsSide effects editThe 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 List of side effects edit Common adverse effects include 2 3 4 5 11 12 Sedation especially common with trimipramine compared to the other TCAs Anticholinergic effects including dry mouth blurred vision mydriasis decreased lacrimation constipation urinary hesitancy or retention reduced GI motility tachycardia high heart rate anticholinergic delirium particularly in the elderly and in Parkinson s disease Weight gain Orthostatic hypotension Sexual dysfunction including impotence loss of libido and other sexual adverse effects Tremor Dizziness Sweating Anxiety Insomnia Agitation Rash Adverse effects with an unknown incidence includes 2 3 4 5 11 12 Confusion Nausea Vomiting Extrapyramidal side effects e g parkinsonism dystonia etc Tinnitus Paraesthesia ECG changes Increased liver function tests Rare adverse effects include 2 3 4 5 11 12 Seizures Syndrome of inappropriate secretion of antidiuretic hormone Blood dyscrasias including Agranulocytosis Thrombocytopenia Eosinophilia Leukopenia Myocardial infarction Heart block QTc interval prolongation Sudden cardiac death Depression worsening Suicidal ideationOverdose editMain article Tricyclic antidepressant overdose Compared to other TCAs trimipramine is relatively safe in overdose although it is more dangerous than the selective serotonin reuptake inhibitors SSRIs and serotonin norepinephrine reuptake inhibitors SNRIs but less dangerous than bupropion in cases of overdose 20 Interactions editTrimipramine should not be given with sympathomimetic agents such as epinephrine adrenaline ephedrine isoprenaline norepinephrine noradrenaline phenylephrine and phenylpropanolamine Barbiturates may increase the rate of metabolism Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism 2 3 4 5 11 12 Pharmacology editPharmacodynamics edit See also Pharmacology of antidepressants and Tricyclic antidepressant Binding profiles Trimipramine 21 Site Ki IC50 nM Species Ref SERTTooltip Serotonin transporter 149 2 110 Human 22 23 NETTooltip Norepinephrine transporter 2 450 4 990 Human 22 23 DATTooltip Dopamine transporter 3 780 Human 22 23 5 HT1A 8 000 Human 24 5 HT1D gt 10 000 Pig 25 5 HT2A 32 Human 24 5 HT2C 537 Pig 25 5 HT3 9 120 Rat 25 a1 24 Human 18 a2 680 Human 18 D1 347 Pig 25 D2 143 210 Human undefined 18 26 25 D3 ND ND ND D4 275 Undefined 25 H1 0 27 1 48 Human 27 18 28 H2 41 Human 27 H3 gt 100 000 Human 27 H4 43 700 Human 27 mAChTooltip Muscarinic acetylcholine receptor 58 Human 18 Values are Ki nM The smaller the value the more strongly the drug binds to the site The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear 23 8 The mechanism of action of its anxiolytic effects is similarly unclear 8 Trimipramine is a very weak reuptake inhibitor of serotonin norepinephrine and dopamine see below 23 and unlike most other TCAs has been claimed to be devoid of clinically significant monoamine reuptake inhibition 10 7 6 The effects of the drug are thought to be mainly due to receptor antagonism as follows 18 26 24 Very strong H1 Strong 5 HT2A a1 adrenergic Moderate D2 mACh Weak 5 HT2C D1 a2 adrenergic In spite of its atypical nature and different profile of activity trimipramine has been shown in head to head clinical studies to possess equivalent effectiveness to other antidepressants including but not limited to other TCAs e g amitriptyline imipramine doxepin amineptine tetracyclic antidepressants TeCAs e g maprotiline monoamine oxidase inhibitors MAOIs e g phenelzine isocarboxazid and selective serotonin reuptake inhibitors e g fluoxetine 6 7 In addition trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head to head comparisons 8 Indeed its prominent anxiolytic effects have been said to distinguish it from most other TCAs 9 The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression 7 The major metabolite of trimipramine desmethyltrimipramine is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants 23 Monoamine reuptake inhibition edit Trimipramine and MATs SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter Type Species Tissue Year Ref 8 200 1 000 6 800 IC50 nM Rat Brain 1977 29 2 500 510 3 400 Ki nM Rat Brain 1984 30 149 2 450 3 780 KD nM Human HEK293 1997 22 2 110 4 990 55 600 IC50 nM Human HEK293 2011 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 amp 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 Trimipramine metabolites and MATs 23 Compound SERTTooltip Serotonin transporter NETTooltip Norepinephrine transporter DATTooltip Dopamine transporter Trimipramine 5 675 5 302 gt 30 mM Desmethyltrimipramine 5 206 5 535 4 530 2 Hydroxytrimipramine gt 30 mM 4 960 4 585 Trimipramine N oxide 5 445 4 930 5 027 Values are pIC50 The higher the value the morestrongly 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 mM 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 a2 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 downregulate b3 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 Antihistamine activity edit See also Doxepin As a hypnotic 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 edit 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 Antidopaminergic activity edit Trimipramine and clozapine 25 6 Site Trimipramine Clozapine 5 HT2A 7 71 7 84 a1A B 7 62 8 54 D2 7 24 7 01 D1 6 46 6 58 a2B 6 42 7 08 5 HT2C 6 27 8 40 a2A 5 86 7 10 5 HT3 5 04 7 00 5 HT1A lt 5 00 6 17 5 HT1D lt 5 00 5 68 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 antipsychotic clozapine 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 presynaptic dopamine autoreceptors potentially resulting in increased dopaminergic neurotransmission 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 a2 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 edit 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 Chemistry editTrimipramine is a tricyclic compound specifically a dibenzazepine and possesses three rings fused together with a side chain attached in its chemical structure 43 Other dibenzazepine TCAs include imipramine desipramine and clomipramine 43 Trimipramine is a derivative of imipramine with a methyl group added to its side chain 44 and is also known as 2 methylimipramine or b methylimipramine 43 45 The tri prefix in its name may allude to the fact that its side chain features three methyl groups Trimipramine is a tertiary amine TCA with its side chain demethylated metabolite desmethyltrimipramine being a secondary amine 46 47 Other tertiary amine TCAs include amitriptyline imipramine clomipramine dosulepin dothiepin and doxepin 48 49 The chemical name of trimipramine is 3 10 11 dihydro 5H dibenzo b f azepin 5 yl N N 2 trimethylpropan 1 amine and its free base form has a chemical formula of C20H26N2 with a molecular weight of 294 434 g mol 50 The drug is used commercially as the maleate salt 50 51 The CAS Registry Number of the free base is 739 71 9 and of the maleate is 521 78 8 50 51 History editTrimipramine was developed by Rhone 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 editGeneric names edit 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 Denomination Commune Francaise 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 edit 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 edit Trimipramine is no longer marketed in Australia though it was previously 58 59 In film edit 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 References edit Anvisa 2023 03 31 RDC Nº 784 Listas de Substancias Entorpecentes Psicotropicas Precursoras e Outras sob Controle Especial Collegiate Board Resolution No 784 Lists of Narcotic Psychotropic Precursor and Other Substances under Special Control in Brazilian Portuguese Diario Oficial da Uniao published 2023 04 04 Archived from the original on 2023 08 03 Retrieved 2023 08 16 a b c d e f g h i j PRODUCT INFORMATION SURMONTIL Tablets and Capsules PDF TGA eBusiness Services Aspen Pharmacare Australia Pty Ltd 28 November 2012 Retrieved 30 November 2013 a b c d e f g h i j SURMONTIL trimipramine maleate capsule Duramed Pharmaceuticals Inc DailyMed Duramed Pharmaceuticals Inc December 2012 Retrieved 30 November 2013 a b c d e f g h i j Surmontil Trimip trimipramine dosing indications interactions adverse effects and more Medscape Reference WebMD Retrieved 30 November 2013 a b c d e f g h i j Trimipramine 50mg Capsules Summary of Product Characteristics SPC electronic Medicines Compendium Zentiva 19 November 2012 Retrieved 30 November 2013 a b c d e f g h i j k l m n o p q r s t Berger M Gastpar M 1996 Trimipramine a challenge to current concepts on antidepressives Eur Arch Psychiatry Clin Neurosci 246 5 235 9 doi 10 1007 bf02190274 PMID 8863001 S2CID 29596291 a b c d e f g h i j k l m n o p q r s t u v Gastpar M 1989 Clinical originality and new biology of trimipramine Drugs 38 Suppl 1 43 8 discussion 49 50 doi 10 2165 00003495 198900381 00010 PMID 2693055 S2CID 23302529 a b c d e f g h i Pecknold JC Luthe L 1989 Trimipramine anxiety depression and sleep Drugs 38 Suppl 1 25 31 discussion 49 50 doi 10 2165 00003495 198900381 00007 PMID 2693052 S2CID 20347877 a b c d e f g h i j k l m n o p q r Lapierre YD 1989 A review of trimipramine 30 years of clinical use Drugs 38 Suppl 1 17 24 discussion 49 50 doi 10 2165 00003495 198900381 00006 PMID 2693051 S2CID 22227558 a b c d e Frazer A 1997 Pharmacology of antidepressants J Clin Psychopharmacol 17 Suppl 1 2S 18S doi 10 1097 00004714 199704001 00002 PMID 9090573 a b c d e f Rossi S ed 2013 Australian Medicines Handbook 2013 ed Adelaide The Australian Medicines Handbook Unit Trust ISBN 978 0 9805790 9 3 a b c d e f g Joint Formulary Committee 2013 British National Formulary BNF 65 ed London UK Pharmaceutical Press ISBN 978 0 85711 084 8 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 a b c De Crescenzo F D Alo GL Ostinelli EG Ciabattini M Di Franco V Watanabe N Kurtulmus A Tomlinson A Mitrova Z Foti F Del Giovane C Quested DJ Cowen PJ Barbui C Amato L Efthimiou O Cipriani A July 2022 Comparative effects of pharmacological interventions for the acute and long term management of insomnia disorder in adults a systematic review and network meta analysis Lancet 400 10347 170 184 doi 10 1016 S0140 6736 22 00878 9 hdl 11380 1288245 PMID 35843245 S2CID 250536370 a b Wiegand MH 2008 Antidepressants for the treatment of insomnia a suitable approach Drugs 68 17 2411 7 doi 10 2165 0003495 200868170 00001 PMID 19016570 S2CID 28009108 Everitt H Baldwin DS Stuart B Lipinska G Mayers A Malizia AL Manson CC Wilson S May 2018 Antidepressants for insomnia in adults Cochrane Database Syst Rev 2018 5 CD010753 doi 10 1002 14651858 CD010753 pub2 PMC 6494576 PMID 29761479 Ioachimescu OC El Solh AA June 2012 Pharmacotherapy of insomnia Expert Opin Pharmacother 13 9 1243 60 doi 10 1517 14656566 2012 683860 PMID 22578014 S2CID 9177139 a b c d e f g h i Richelson E Nelson A 1984 Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro J Pharmacol Exp Ther 230 1 94 102 PMID 6086881 a b Sharpe CR Collet JP Belzile E Hanley JA Boivin JF January 2002 The effects of tricyclic antidepressants on breast cancer risk British Journal of Cancer 86 1 92 97 doi 10 1038 sj bjc 6600013 PMC 2746543 PMID 11857018 White N Litovitz T Clancy C December 2008 Suicidal antidepressant overdoses a comparative analysis by antidepressant type Journal of Medical Toxicology 4 4 238 250 doi 10 1007 BF03161207 PMC 3550116 PMID 19031375 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 Retrieved 7 May 2022 a b c d e Tatsumi 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 PMID 9537821 a b c d e f g h i j k l m n o p q r s t u v Haenisch B Hiemke C Bonisch H 2011 Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters Psychopharmacology 217 2 289 95 doi 10 1007 s00213 011 2281 9 PMID 21484238 S2CID 28707541 a b c Wander 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 PMID 3816971 a b c d e f g h i Gross G Xin X Gastpar M 1991 Trimipramine pharmacological reevaluation and comparison with clozapine Neuropharmacology 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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 PMID 6499924 a b c Lopez Munoz F Alamo C 2013 Active metabolites as antidepressant drugs the role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders Front Psychiatry 4 102 doi 10 3389 fpsyt 2013 00102 PMC 3770982 PMID 24062697 Anttila SA Leinonen EV 2001 A review of the pharmacological and clinical profile of mirtazapine CNS Drug Rev 7 3 249 64 doi 10 1111 j 1527 3458 2001 tb00198 x PMC 6494141 PMID 11607047 Celada P Puig M Amargos Bosch M Adell A Artigas F 2004 The therapeutic role of 5 HT1A and 5 HT2A receptors in depression J Psychiatry Neurosci 29 4 252 65 PMC 446220 PMID 15309042 Millan MJ 2005 Serotonin 5 HT2C receptors as a target for the treatment of depressive and anxious states focus on novel therapeutic 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smrv 2012 08 001 PMID 23357028 a b c d Ruther E 1989 Depression circadian rhythms and trimipramine Drugs 38 Suppl 1 1 3 discussion 49 50 doi 10 2165 00003495 198900381 00003 PMID 2693050 S2CID 22636330 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 PMID 22681162 a b Eap 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 PMID 10774635 a b c Ritsner MS 15 February 2013 Appendix 2 List of Pyschotropic Medications Polypharmacy in Psychiatry Practice Volume I Multiple Medication Use Strategies Springer Science amp Business Media pp 270 271 ISBN 978 94 007 5805 6 Lemke TL Williams DA 24 January 2012 Foye s Principles of Medicinal Chemistry Lippincott Williams amp Wilkins pp 606 ISBN 978 1 60913 345 0 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 amp Sons pp 160 ISBN 978 0 471 95052 3 Baumann P Hiemke C 23 February 2012 Central Nervous System Drugs In Anzenbacher P Zanger UM eds Metabolism of Drugs and Other Xenobiotics John Wiley amp Sons pp 302 ISBN 978 3 527 64632 6 Anthony PK Powers CA 2002 Drugs that Affect the Central Neverous System In Anthony PK ed Pharmacology Secrets Elsevier Health Sciences pp 39 ISBN 978 1 56053 470 9 Cowen P Harrison P Burns T 9 August 2012 Drugs and Other Physical Treatments Shorter Oxford Textbook of Psychiatry OUP Oxford pp 532 ISBN 978 0 19 162675 3 a b c d Elks J 14 November 2014 The Dictionary of Drugs Chemical Data Chemical Data Structures and Bibliographies Springer pp 1251 ISBN 978 1 4757 2085 3 a b c d e f Index Nominum 2000 International Drug Directory Taylor amp Francis 2000 p 1067 ISBN 978 3 88763 075 1 a b c Andersen J Kristensen AS Bang Andersen B Stromgaard 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 PMID 19557250 Dawson AH 2004 Cyclic Antidepressant Drugs In Dart RC ed Medical Toxicology Lippincott Williams amp Wilkins pp 836 ISBN 978 0 7817 2845 4 Gelenberg AJ Schoonover SC 29 June 2013 Major psychiatric disorders depression In Gelenberg AJ Bassuk EL Schoonover SC eds The Practitioner s Guide to Psychoactive Drugs Springer Science amp Business Media pp 38 ISBN 978 1 4757 1137 0 Moyer TP Boeckx RL 1 January 1982 Applied Therapeutic Drug Monitoring Fundamentals American Association for Clinical Chemistry p 249 ISBN 978 0 915274 23 9 Morton IK Hall JM 6 December 2012 Concise Dictionary of Pharmacological Agents Properties and Synonyms Springer Science amp Business Media pp 281 ISBN 978 94 011 4439 1 a b c d Trimipramine Uses Side Effects amp Warnings TRIMIPRAMINE Australian Medicines Handbook www mps aust com au MPS Australia 2008 Archived from the original on 4 August 2017 Retrieved 4 August 2017 Tricyclic antidepressants Australian Medicines Handbook Australian Medicines Handbook Australian Medicines Handbook Pty Ltd Retrieved 4 August 2017 IMDB Quotes page IMDB IMDB Retrieved 28 March 2024 Retrieved from https en wikipedia org w index php title Trimipramine amp oldid 1218407195, wikipedia, wiki, book, books, library,

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