Trimipramine


Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. 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. Similarly to other TCAs, however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

Medical uses

Trimipramine's primary use in medicine is in the treatment of major depressive disorder, especially where sedation is helpful due to its prominent sedative effects. The drug is also an effective anxiolytic, and can be used in the treatment of anxiety. 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. In particular, it does not suppress REM sleep, and dreams are said to "brighten" during treatment.
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.
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 against placebo for treatment of insomnia at 4weeks of 0.55. The certainty of evidence was rated as very low, and no data were available for longer-term treatment. For comparison, the other sedating antihistamines assessed, doxepin and doxylamine, had effect sizes at 4weeks of 0.30 and 0.47 , respectively.
The effective dosage of trimipramine in depression is 150 to 300mg/day. Doses of trimipramine used for insomnia range from 25 to 200mg/day. However, it has been advised that doses be kept as low as possible, and a low dose of 25mg/day has been recommended.

Contraindications

Contraindications include:
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. 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. Somnolence is the most common side effect of the drug. Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present. Such effects, in any case, may be treated with bethanechol.
It is described as being associated with minimal or no orthostatic hypotension, at least in comparison to clomipramine, in spite of its potent and comparable activity as an alpha-1 blocker. However, it has also been said to have a rate of orthostatic hypotension similar to that of other TCAs. Trimipramine is said to be less epileptogenic than other TCAs, although seizures have still been reported in association with it. It is also less cardiotoxic than other TCAs and cardiotoxicity is said to be minimal, with a "very favorable profile".
Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later. However, on tests done on Drosophila melanogaster, nongenotoxic TCAs, and genotoxic TCAs were identified.

List of side effects

Common adverse effects include:
  • Sedation — especially common with trimipramine compared to the other TCAs
  • Anticholinergic effects including:
  • 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:
Rare adverse effects include:
Compared to other TCAs, trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors but less dangerous than bupropion in cases of overdose.

Interactions

Trimipramine should not be given with sympathomimetic agents such as epinephrine, ephedrine, isoprenaline, norepinephrine, phenylephrine and phenylpropanolamine.
Barbiturates may increase the rate of metabolism.
Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.

Pharmacology

Pharmacodynamics

The mechanism of action of trimipramine in terms of its antidepressant effects differs from that of other TCAs and is not fully clear. The mechanism of action of its anxiolytic effects is similarly unclear. Trimipramine is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine, and unlike most other TCAs, has been claimed to be devoid of clinically significant monoamine reuptake inhibition. The effects of the drug are thought to be mainly due to receptor antagonism as follows:
  • Very strong: H1
  • Strong: 5-HT2A, α1-adrenergic
  • Moderate: D2, mACh
  • Weak: 5-HT2C, D1, α2-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, tetracyclic antidepressants , monoamine oxidase inhibitors , and selective serotonin reuptake inhibitors. In addition, trimipramine has been found to possess greater anxiolytic effects than other TCAs such as amitriptyline and doxepin in head-to-head comparisons. Indeed, its prominent anxiolytic effects have been said to distinguish it from most other TCAs. The atypicality of trimipramine in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression.
The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.

Monoamine reuptake inhibition

Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with trimipramine, and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. found a relatively high KD of 149 nM for the SERT in human HEK293 cells, but other authors and a more recent study with an improved design have not had the same findings. In the most recent study, by Haenisch et al., 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 to study interactions as opposed to actual functional reuptake inhibition.
Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition. In what was the only study to date to have assessed the activity profiles of the metabolites of trimipramine, Haenisch et al. 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. 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. However, desmethyltrimipramine still showed only very weak inhibition of the NET.
Therapeutic concentrations of trimipramine are between 0.5 and 1.2 μM and hence significant monoamine reuptake inhibition would not be expected with it or its metabolites. 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. 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. 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. That said, blockade of the 5-HT2A, 5-HT2C, and α2-adrenergic receptors, as with mirtazapine, has also been implicated in antidepressant effects.
In any case, there is also clinical and animal evidence that trimipramine does not inhibit the reuptake of monoamines. Unlike other TCAs, it does not downregulate β3-adrenergic receptors, which is likely the reason that it does not cause orthostatic hypotension. It can be safely combined with MAOIs apparently without risk of serotonin syndrome or hypertensive crisis. Indeed, in rabbits, whereas hyperpyrexia 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.