The majority of the<unk> s act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission. Notably, with the sole exception of amineptine, the<unk> s have weak affinity for the dopamine transporter (DAT), and therefore have low efficacy as dopamine reuptake inhibitors (DRIs). Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders. In addition to their reuptake inhibition, many<unk> s also have high affinity as antagonists at the 5-HT2 (5-HT2A and 5-HT2C), 5-HT6, 5-HT7, α1-adrenergic, and NMDA receptors, and as agonists at the sigma receptors (σ1 and σ2), some of which may contribute to their therapeutic efficacy, as well as their side effects. The<unk> s also have varying but typically high affinity for antagonising the H1 and H2 histamine receptors, as well as the muscarinic acetylcholine receptors. As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in<unk> s, especially with comorbid anxiety, as it provides a sedative effect. Most, if not all, of the<unk> s also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively. The former property is responsible for the high mortality rate upon overdose seen with the<unk> s via cardiotoxicity. It may also be involved in their efficacy as analgesics, however. In summary,<unk> s can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors. Thus their dangerous side effect profile limits their use in daily practice. Binding profiles The binding profiles of various<unk> s and some metabolites in terms of their affinities (, ) for various receptors and transporters are as follows: + Compound 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7 α1 α2 D2 H1 H2 σ1 σ2 Amineptine >100,000 10,000 1,000–1,400 >100,000 74,000 >100,000 >100,000 >100,000 ≥13,000 >100,000 Amitriptyline 2.8–4.3 19–35 3,250 ≥450 18–23 4.0 65–141 93–123 4.4–24 114–690 196–1,460 0.5–1.1 66 9.6 300 Amoxapine 58 16 4,310 0.5 2.0 6.0–50 41 50 2,600 3.6–160 7.9–25 1,000 Butriptyline ≥1,360 5,100 3,940 7,000 380 570 4,800 1.1 35 Clomipramine 0.14–0.28 38–54 ≥2,190 ≥7,000 27–36 65 54 127 3.2–38 ≥535 78–190 13–31 209 37 546 Desipramine 18–163 0.63–3.5 3,190 ≥6,400 115–350 244–748 >1,000 23–130 ≥1,379 3,400 60–110 1,550 66–198 ≥1,990 ≥1,610 Dibenzepin >10,000 >10,000 ≥1,500 >10,000 >10,000 >10,000 23 1,950 1,750 Dosulepin 8.6–78 46–70 5,310 4,000 152 419 2,400 3.6–4.0 25–26 Doxepin 68–210 13–58 ≥4,600 276 11–27 8.8–200 136 24 28–1,270 360 0.09–1.23 174 23–80 Imipramine 1.3–1.4 20–37 8,500 ≥5,800 80–150 120 190–209 >1,000 32 3,100 620–726 7.6–37 550 46 332–520 327–2,100 Iprindole ≥1,620 1,260 6,530 2,800 217–280 206 2,300 8,600 6,300 100–130 200–8,300 2,100 >10,000 Lofepramine 70 5.4 >10,000 4,600 200 100 2,700 2,000 245–360 4,270 67 2,520 Maprotiline 5,800 11–12 1,000 51 122 50 90 9,400 350–665 0.79–2.0 776 570 Norclomipramine 40 0.45 2,100 19,000 130 190 1,800 1,200 450 92 Northiaden 192 25 2,539 2,623 141 950 25 110 Nortriptyline 15–18 1.8–4.4 1,140 294 5.0–41 8.5 148 55 2,030 2,570 3.0–15 646 37 2,000 Opipramol ≥2,200 ≥700 ≥3,000 >10,000 120 200 6,100 120–300 6.0 4,470 3,300 0.2–50 110 Protriptyline 19.6 1.41 2,100 3,800 70 130 6,600 2,300 7.2–25 398 25 Tianeptine >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 >10,000 Trimipramine 149–2,110 ≥2,450 ≥3,780 8,000 32 537 24 680 143–210 0.27–1.5 41 58 Values are (). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins. With the exception of the sigma receptors, the<unk> s act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters. Tianeptine is included in this list due to it technically being a<unk> , but with a vastly different pharmacology. Therapeutic levels of<unk> s are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM. Plasma protein binding is generally 90% or greater.
Tricyclic antidepressant
Tetracyclic antidepressant
Atypical antidepressant
Heterocyclic antidepressant
Second-generation antidepressant
Antipsychotic
Atypical antipsychotic
Antipsychotic ester