Pharmacodynamics +<unk>  (and metabolite) Site Species Ref 0.14–0.28 40 Human/rat 38–53.7 0.32 Human/rat ≥2,190 2,100 Human/rat 5-HT1A ≥7,000 19,000 Human/ 5-HT1B >10,000 Human 5-HT1D >10,000 Human 5-HT2A 27–35.5 130 Human/ 5-HT2B 5-HT2C 64.6 Human 5-HT3 460–985 Rodent 5-HT6 53.8 Rat 5-HT7 127 Rat α1 3.2–38 190 Human/ α2 525–3,200 1,800 Human/ β 22,000 16,000 Undefined D1 219 320 Human/ D2 77.6–190 1,200 Human/ D3 30–50.1 Human D4 D5 H1 13–31 450 Human/ H2 209 Human H3 9,770 Human H4 5,750 Human 37 92 Human/ σ1 546 Rat 130 () Human Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.<unk>  is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI); that is, it blocks the reuptake of these neurotransmitters back into neurons by preventing them from interacting with their transporters, thereby increasing their extracellular concentrations in the synaptic cleft and resulting in increased serotonergic and noradrenergic neurotransmission. In addition,<unk>  also has antiadrenergic, antihistamine, antiserotonergic, antidopaminergic, and anticholinergic activities. It is specifically an antagonist of the α1-adrenergic receptor, the histamine H1 receptor, the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, the dopamine D1, D2, and D3 receptors, and the muscarinic acetylcholine receptors (M1–M5). Like other TCAs,<unk>  weakly blocks voltage-dependent sodium channels as well. Although<unk>  shows around 100- to 200-fold preference in affinity for the serotonin transporter (SERT) over the norepinephrine transporter (NET), its major active metabolite, desmethylclomipramine (norclomipramine), binds to the NET with very high affinity (Ki = 0.32 nM) and with dramatically reduced affinity for the SERT (Ki = 31.6 nM). Moreover, desmethylclomipramine circulates at concentrations that are approximately twice those of<unk> . In accordance, occupancy of both the SERT and the NET has been shown with<unk>  administration in positron emission tomography studies with humans and non-human primates. As such,<unk>  is in fact a fairly balanced SNRI rather than only a serotonin reuptake inhibitor (SRI). The antidepressant effects of<unk>  are thought to be due to reuptake inhibition of serotonin and norepinephrine, while serotonin reuptake inhibition only is thought to be responsible for the effectiveness of<unk>  in the treatment of OCD. Conversely, antagonism of the H1, α1-adrenergic, and muscarinic acetylcholine receptors is thought to contribute to its side effects. Blockade of the H1 receptor is specifically responsible for the antihistamine effects of<unk>  and side effects like sedation and somnolence (sleepiness). Antagonism of the α1-adrenergic receptor is thought to cause orthostatic hypotension and dizziness. Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of<unk>  like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death. On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain. The exceptionally strong serotonin reuptake inhibition of<unk>  likely precludes the possibility of its antagonism of serotonin receptors (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signaling by these receptors. In accordance, while serotonin receptor antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome,<unk>  is nonetheless capable of inducing this syndrome. In fact, while all TCAs are SRIs and serotonin receptor antagonists to varying extents, the only TCAs that are associated with serotonin syndrome are<unk>  and to a lesser extent its dechlorinated analogue imipramine, which are the two most potent SRIs of the TCAs (and in relation to this have the highest ratios of serotonin reuptake inhibition to serotonin receptor antagonism). As such, whereas other TCAs can be combined with monoamine oxidase inhibitors (with caution due to the risk of hypertensive crisis from NET inhibition; sometimes done in treatment-resistant depressives),<unk>  cannot be due to the risk of serotonin syndrome and death. Unlike the case of its serotonin receptor antagonism, orthostatic hypotension is a common side effect of<unk> , suggesting that its blockade of the α1-adrenergic receptor is strong enough to overcome the stimulatory effects on the α1-adrenergic receptor of its NET inhibition. Serotonergic activity + Comparison of SERT-active antidepressants Medication Dosage(mg/day) ()(hours) (ng/mL) / SERTratio Amitriptyline 4.3 34.5 100–200 16 (30) 100–250 23–58 Amoxapine 58.5 16.1 200–300 8 (30) 200–500 3.4–8.5 Butriptyline 1,360 5,100 ? ? ? ?<unk>  0.14–0.28 37 100–200 32 (70) 150–500 536–3,570 Desipramine 17.5 0.8 100–200 30 125–300 7.1–17 Dosulepin 8.3 45.5 150–225 25 (34) 50–200 6.0–24 Doxepin 66.7 29.4 100–200 18 (30) 150–250 2.2–3.7 Imipramine 1.4 37 100–200 12 (30) 175–300 125–214 Iprindole 1,620 1,262 ? ? ? ? Lofepramine 70.0 5.4 ? ? ? ? Nortriptyline 18.5 4.4 75–150 31 60–150 3.2–8.1 Protriptyline 19.6 1.4 15–40 80 100–250 5.1–13 Trimipramine 149 2,450 75–200 16 (30) 100–300 0.67–2.0 Citalopram 1.4 5,100 20–40 36 75–150 54–107 Escitalopram 1.1 7,840 10–20 30 40–80 36–73 Fluoxetine 0.8 244 20–40 53 (240) 100–500 125–625 Fluvoxamine 2.2 1,300 100–200 18 100–200 45–91 Paroxetine 0.34 40 20–40 17 30–100 300–1,000 Sertraline 0.4 417 100–150 23 (66) 25–50 83–167 Duloxetine 1.6 11.2 80–100 11 ? ? Milnacipran 123 200 ? ? ? ? Venlafaxine 9.1 535 75–225 5 (11) ? ? The values for the SERT and NET are Ki (nM). Note that in the Cp / SERT ratio,free versus protein-bound drug concentrations are not accounted for. + occupancy by SRIs at<unk> nically approved dosages Medication Dosage range(mg/day) ~80% occupancy(mg/day) Ratio (dosage /80% occupancy) Citalopram 20–40 40 0.5–1 Escitalopram 10–20 10 1–2 Fluoxetine 20–80 20 1–4 Fluvoxamine 50–300 70 0.71–5 Paroxetine 10–60 20 0.5–3 Sertraline 25–200 50 0.5–4 Duloxetine 20–60 30 0.67–2 Venlafaxine 75–375 75 1–5<unk>  50–250 10 5–25<unk>  is a very strong SRI. Its affinity for the SERT was reported in one study using human tissues to be 0.14 nM, which is considerably higher than that of other TCAs. For example, the TCAs with the next highest affinities for the SERT in the study were imipramine, amitriptyline, and dosulepin (dothiepin), with Ki values of 1.4 nM, 4.3 nM, and 8.3 nM, respectively. In addition,<unk>  has a terminal half-life that is around twice as long as that of amitriptyline and imipramine. In spite of these differences however,<unk>  is used<unk> nically at the same usual dosages as other serotonergic TCAs (100–200 mg/day). It achieves typical circulating concentrations that are similar in range to those of other TCAs but with an upper limit that is around twice that of amitriptyline and imipramine. For these reasons,<unk>  is the most potent SRI among the TCAs and is far stronger as an SRI than other TCAs at typical<unk> nical dosages. In addition,<unk>  is more potent as an SRI than any selective serotonin reuptake inhibitors (SSRIs), it is more potent than paroxetine, which is the strongest SSRI. A positron emission tomography study found that a single low dose of 10 mg<unk>  to healthy volunteers resulted in 81.1% occupancy of the SERT, which was comparable to the 84.9% SERT occupancy by 50 mg fluvoxamine. In the study, single doses of 5 to 50 mg<unk>  resulted in 67.2 to 94.0% SERT occupancy while single doses of 12.5 to 50 mg fluvoxamine resulted in 28.4 to 84.9% SERT occupancy. Chronic treatment with higher doses was able to achieve up to 100.0% SERT occupancy with<unk>  and up to 93.6% SERT occupancy with fluvoxamine. Other studies have found 83% SERT occupancy with 20 mg/day paroxetine and 77% SERT occupancy with 20 mg/day citalopram. These results indicate that very low doses of<unk>  are able to substantially occupy the SERT and that<unk>  achieves higher occupancy of the SERT than SSRIs at comparable doses. Moreover,<unk>  may be able to achieve more complete occupancy of the SERT at high doses, at least relative to fluvoxamine. If the ratios of the 80% SERT occupancy dosage and the approved<unk> nical dosage range are calculated and compared for SSRIs, SNRIs, and<unk> , it can be deduced that<unk>  is by far the strongest SRI used medically. The lowest approved dosage of<unk>  can be estimated to be roughly comparable in SERT occupancy to the maximum approved dosages of the strongest SSRIs and SNRIs. Because their mechanism of action was originally not known and dose-ranging studies were never conducted, first-generation antipsychotics were dramatically overdosed in patients. It has been suggested that the same may have been true for<unk>  and other TCAs. Obsessive–compulsive disorder<unk>  was the first drug that was investigated for and found to be effective in the treatment of OCD. In addition, it was the first drug to be approved by the in the United States for the treatment of OCD. The effectiveness of<unk>  in the treatment of OCD is far greater than that of other TCAs, which are comparatively weak SRIs; a meta-analysis found pre- versus post-treatment effect sizes of 1.55 for
Clomipramine
Trimipramine
Desipramine
Carpipramine
Imipramine
Sertraline
Citalopram
Escitalopram