Pharmacodynamics +<unk>  Site Ki/IC50 (nM) Species Ref 149–2,110 Human 2,450–4,990 Human ≥3,780 Human 5-HT1A 8,000 Human 5-HT1D >10,000 Pig 5-HT2A 32 Human 5-HT2C 537 Pig 5-HT3 9,120 Rat α1 24 Human α2 680 Human D1 347 Pig D2 143–210 Human/ D3 D4 275 Undefined H1 0.27–1.48 Human H2 41 Human H3 >100,000 Human H4 43,700 Human 58 Human Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. The mechanism of action of<unk>  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.<unk>  is a very weak reuptake inhibitor of serotonin, norepinephrine, and dopamine (see below), 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,<unk>  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). In addition,<unk>  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<unk>  in relation to its lack of monoamine reuptake inhibition is described as challenging the monoamine hypothesis of depression. The major metabolite of<unk> , desmethyltrimipramine, is considered to possess pharmacological activity similar to that of other demethylated tertiary amine TCA variants. Monoamine reuptake inhibition +<unk>  and Type Species Tissue Year/Ref 8,200 1,000 6,800 IC50 (nM) Rat Brain 1977 2,500 510 3,400 Ki (nM) Rat Brain 1984 149 2,450 3,780 KD (nM) Human 293 1997 2,110 4,990 55,600 IC50 (nM) Human 293 2011 Studies have generally found only very weak inhibition of serotonin and norepinephrine reuptake with<unk> , and the drug has been described by various authors as devoid of monoamine reuptake inhibition. Richelson & Pfenning (1984) found a relatively high Ki for the NET of 510 nM in rat brain synaptosomes and Tatsumi et al. (1997) 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. (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). +<unk> , metabolites, and Compound<unk>  5.675 5.302 >30 μM Desmethyltrimipramine 5.206 5.535 4.530 2-Hydroxytrimipramine >30 μM 4.960 4.585<unk> -N-oxide 5.445 4.930 5.027 Values are pIC50. The higher the value, the morestrongly the drug binds to the site.<unk>  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<unk> , Haenisch et al. (2011) assayed desmethyltrimipramine, 2-hydroxytrimipramine, and<unk> -N-oxide in addition to<unk>  and found that these metabolites showed IC50 values for the SERT, NET, and DAT similar to those of<unk>  (see table to the right). Like other secondary amine TCAs, desmethyltrimipramine was slightly more potent than<unk>  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<unk>  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. However, these concentrations are nearly 2-fold higher if the active metabolites of<unk>  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,<unk>  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<unk> . 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<unk>  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 (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<unk>  and an MAOI, likely due to<unk> 's lack of serotonin reuptake inhibition. Antihistamine activity<unk>  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). The TeCA mianserin (Ki = 0.40) and the TCA amitriptyline (Ki = 1.0) are also very potent H1 receptor antagonists, whereas other TCAs and TeCAs are less potent. These TCAs and TeCAs, including<unk> , are far more potent than the standard antihistamine diphenhydramine (approximately 800 times for doxepin and 250 times for<unk> , and are among the most potent antihistamines available.<unk>  is also an antagonist of the H2 receptor with lower potency and has been found to be effective in the treatment of duodenal ulcers. As a hypnotic Blockade of the H1 receptor is responsible for the sedative effects of<unk>  and other TCAs and their effectiveness in the treatment of insomnia. Most antidepressants suppress REM sleep, in parallel with their alleviation of depressive symptoms (although suppression of REM sleep is not required for antidepressant effects). This includes TCAs (e.g., amitriptyline, nortriptyline), TeCAs (e.g., mianserin, maprotiline), MAOIs (e.g., clorgiline, pargyline), and SSRIs (e.g., fluoxetine, zimelidine, indalpine).<unk>  is unique in that it is an exception and produces antidepressant effects without compromising or otherwise affecting REM sleep. Even long-term treatment with<unk>  for up to 2 years has not been found to suppress REM sleep. In addition,<unk>  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. In clinical studies,<unk>  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. It also improved subjectively perceived sleep quality and well-being during daytime. Monitoring of patients upon discontinuation of<unk>  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<unk>  withdrawal. Antidopaminergic activity +<unk>  and clozapine Site<unk>  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 1D i (nM). The higher the value,the more strongly the drug binds to the site.<unk>  is a weak but significant antagonist of the dopamine D1 and D2 receptors, and also binds to the D4 receptor (Ki = 275 nM). Its affinities for various monoamine receptors including the D2 and 5-HT2A receptors closely resemble those of the atypical antipsychotic clozapine. In accordance, high doses of<unk>  have been found to have antipsychotic effects in schizophrenic patients, notably without causing extrapyramidal symptoms, and<unk>  has recently been found to be effective in reducing psychotic symptoms in patients with delusional depression. The lack of extrapyramidal symptoms with<unk>  may be related to its affinity for the D4 receptor, these both being properties it shares with clozapine. Unlike other TCAs, but reminiscent of antipsychotics,<unk>  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. These findings are suggestive of important antidopaminergic actions of<unk> . Unlike various other TCAs,<unk>  shows marked antagonism of presynaptic dopamine autoreceptors, potentially resulting in increased dopaminergic neurotransmission. This effect has also been observed
Trimipramine
Carpipramine
Clomipramine
Desipramine
Imipramine
Sertraline
Citalopram
Chlorpromazine