[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.
[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][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.
[9] Dry mouth is the most common anticholinergic side effect, but others like constipation, urinary retention, and blurred vision are also present.
[18][19] 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.
[9] Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11–15 years later.
[22] Trimipramine should not be given with sympathomimetic agents such as epinephrine (adrenaline), ephedrine, isoprenaline, norepinephrine (noradrenaline), phenylephrine and phenylpropanolamine.
[10][7][6] The effects of the drug are thought to be mainly due to receptor antagonism as follows:[20][28][26] 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.
[7] The major metabolite of trimipramine, desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants.
[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 human HEK293 cells,[24] but other authors and a more recent study with an improved design have not had the same findings.
[25] Trimipramine is extensively metabolized, so its metabolites may contribute to its pharmacology, including potentially to monoamine reuptake inhibition.
[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 the blood–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.
[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] 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][25] Unlike various other TCAs, trimipramine shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission.
[7][42] As such, blockade of inhibitory dopamine autoreceptors and hence facilitation of dopaminergic signaling could be involved in the antidepressant effects of trimipramine.
[44] Trimipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.
[60][61] 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.