Pharmacology of antidepressants
The
Neurogenic adaptations
The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants.[10] Chronic use of antidepressant increased neurogenesis in the hippocampus of rats.[11][12][13] Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes).[14]
The delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment, including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs).[15]
Hypothalamic-pituitary-adrenal axis
One manifestation of depression is an altered
Monoamine hypothesis
In 1965, Joseph Schildkraut postulated the
Serotonin levels in the human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response.[18] Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin levels in the brain and symptoms of depression have not been linked[19]
Although there is evidence that antidepressants inhibit the reuptake of serotonin,[20] norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants,[21] and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.
While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2Areceptors, suggesting it is too simplistic to say serotonin is a "happy neurotransmitter". In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as
Receptor affinity
A variety of monoaminergic antidepressants have been compared below:[1][22][23][24][25][26]
Compound | SERT | NET | DAT | H1 | mACh | α1 | α2 | 5-HT1A |
5-HT2A |
5-HT2C |
D2 |
MT1A | MT1B |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Agomelatine | ? | ? | ? | ? | ? | ? | ? | ? | ? | 631 | ? | 0.1 | 0.12 |
Amitriptyline | 3.13 | 22.4 | 5380 | 1.1 | 18 | 24 | 690 | 450 | 4.3 | 6.15 | 1460 | ? | ? |
Amoxapine | 58 | 16 | 4310 | 25 | 1000 | 50 | 2600 | ? | 0.5 | 2 | 20.8 | ? | ? |
Atomoxetine | 43 | 3.5 | 1270 | 5500 | 2060 | 3800 | 8800 | 10900 | 1000 | 940 | >35000 | ? | ? |
Bupropion | 9100 | 52600 | 526 | 6700 | 40000 | 4550 | >35000 | >35000 | >10000 | >35000 | >35000 | ? | ? |
Buspirone | ? | ? | ? | ? | ? | 138 | ? | 5.7 | 138 | 174 | 362 | ? | ? |
Butriptyline | 1360 | 5100 | 3940 | ? | ? | ? | ? | ? | ? | ? | ? | ? | ? |
Citalopram | 1.38 | 5100 | 28000 | 380 | 1800 | 1550 | >10000 | >10000 | >10000 | 617 | ? | ? | ? |
Clomipramine | 0.14 | 45.9 | 2605 | 31.2 | 37 | 39 | 525 | >10000 | 35.5 | 64.6 | 119.8 | ? | ? |
Desipramine | 17.6 | 0.83 | 3190 | 110 | 196 | 100 | 5500 | >10000 | 113.5 | 496 | 1561 | ? | ? |
Dosulepin | 8.6 | 46 | 5310 | 4 | 26 | 419 | 12 | 4004 | 152 | ? | ? | ? | ? |
Doxepin | 68 | 29.5 | 12100 | 0.24 | 83.3 | 23.5 | 1270 | 276 | 26 | 8.8 | 360 | ? | ? |
Duloxetine | 0.8 | 5.9 | 278 | 2300 | 3000 | 8300 | 8600 | 5000 | 504 | 916 | >10000 | ? | ? |
Escitalopram | 0.8-1.1 | 7800 | 27400 | 2000 | 1240 | 3900 | >1000 | >1000 | >1000 | 2500 | >1000 | ? | ? |
Etoperidone | 890 | 20000 | 52000 | 3100 | >35000 | 38 | 570 | 85 | 36 | 36 | 2300 | ? | ? |
Femoxetine | 11 | 760 | 2050 | 4200 | 184 | 650 | 1970 | 2285 | 130 | 1905 | 590 | ? | ? |
Fluoxetine | 1.0 | 660 | 4176 | 6250 | 2000 | 5900 | 13900 | 32400 | 197 | 255 | 12000 | ? | ? |
Fluvoxamine | 1.95 | 1892 | >10000 | >10000 | 240000 | 1288 | 1900 | >10000 | >10000 | 6700 | >10000 | ? | ? |
Imipramine | 1.4 | 37 | 8300 | 37 | 46 | 32 | 3100 | >10000 | 119 | 120 | 726 | ? | ? |
Lofepramine | 70 | 5.4 | 18000 | 360 | 67 | 100 | 2700 | 4600 | 200 | ? | 2000 | ? | ? |
Maprotiline | 5800 | 11.1 | 1000 | 1.7 | 560 | 91 | 9400 | ? | 51 | 122 | 665 | ? | ? |
Mazindol | 100 | 1.2 | 19.7 | 600 | ? | ? | ? | ? | ? | ? | ? | ? | ? |
Mianserin | 4000 | 71 | 9400 | 1.0 | 500 | 74 | 31.5 | 1495 | 3.21 | 2.59 | 2052 | ? | ? |
Milnacipran | 94.1 | 111 | >10000 | ? | ? | ? | ? | ? | ? | ? | ? | ? | ? |
Mirtazapine | >10000 | 4600 | >10000 | 0.14 | 794 | 608 | 20 | 18 | 69 | 39 | 5454 | ? | ? |
Nefazodone | 400 | 490 | 360 | 24000 | 11000 | 48 | 640 | 80 | 8.6 | 72 | 910 | ? | ? |
Nisoxetine | 610 | 5.1 | 382 | ? | 5000 | ? | ? | ? | 620 | ? | ? | ? | ? |
Nomifensine | 2941 | 22.3 | 41.1 | 2700 | >10000 | 1200 | 6744 | 1183 | 937 | >10000 | >10000 | ? | ? |
Nortriptyline | 16.5 | 4.37 | 3100 | 15.1 | 37 | 55 | 2030 | 294 | 5 | 8.5 | 2570 | ? | ? |
Oxaprotiline | 3900 | 4.9 | 4340 | ? | ? | ? | ? | ? | ? | ? | ? | ? | ? |
Paroxetine | 0.08 | 56.7 | 574 | 22000 | 108 | 4600 | >10000 | >35000 | >10000 | 19000 | 32000 | ? | ? |
Protriptyline | 19.6 | 1.41 | 2100 | 60 | 25 | 130 | 6600 | ? | 26 | ? | ? | ? | ? |
Quetiapine | >10,000 | >10,000 | >10,000 | 7 | ? | 22 | 3,630 | 376 | 99 | 2502 | 245 | ? | ? |
Reboxetine | 274 | 13.4 | 11500 | 312 | 6700 | 11900 | >10000 | >10000 | >10000 | 457 | >10000 | ? | ? |
Sertraline | 0.21 | 667 | 25.5 | 24000 | 625 | 370 | 4100 | >35000 | 1000 | 1000 | 10700 | ? | ? |
Trazodone | 367 | >10000 | >10000 | 220 | >35000 | 42 | 320 | 118 | 35.8 | 224 | 4142 | ? | ? |
Trimipramine | 149 | 2450 | 3780 | 1.4 | 58 | 24 | 680 | ? | ? | ? | ? | ? | ? |
Venlafaxine | 7.7 | 2753 | 8474 | >35000 | >35000 | >35000 | >35000 | >35000 | >35000 | >10000 | >35000 | ? | ? |
Vilazodone | 0.1 | ? | ? | ? | ? | ? | ? | 2.3 | ? | ? | ? | ? | ? |
Viloxazine | 17300 | 155 | >100000 | ? | ? | ? | ? | ? | ? | ? | ? | ? | ? |
Vortioxetine | 1.6 | 113 | >1000 | ? | ? | ? | ? | 15 (Agonist) | ? | 180 | ? | ? | ? |
Zimelidine | 152 | 9400 | 11700 | ? | ? | ? | ? | ? | ? | ? | ? | ? | ? |
The values above are expressed as equilibrium dissociation constants in nanomoles/liter. A smaller dissociation constant indicates more affinity. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors.
Anti-inflammatory and immunomodulation
This section may be too technical for most readers to understand.(November 2013) |
Recent studies show
Studies also show that the chronic secretion of
Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.[37][38]
These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy.[39] Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.[40]
Pharmacokinetics
Drug | Bioavailability | t1/2 (hr) for parent drug (active metabolite) | Vd (L/kg unless otherwise specified) | Cp (ng/mL) parent drug (active metabolite) | Tmax | Protein binding Parent drug (active metabolite(s)) | Excretion | Enzymes responsible for metabolism | Enzymes inhibited[45] |
---|---|---|---|---|---|---|---|---|---|
Tricyclic antidepressant (TCAs) | |||||||||
Amitriptyline | 30–60% | 9–27 (26–30) | ? | 100–250 | 4 hr | >90% (93–95%) | Urine (18%) | ? | |
Amoxapine | ? | 8 (30) | 0.9–1.2 | 200–500 | 90 mins | 90% | Urine (60%), faeces (18%) | ? | ? |
Clomipramine | 50% | 32 (70) | 17 | 100–250 (230–550) | 2–6 hr | 97–98% | Urine (60%), faeces (32%) | CYP2D6 | ? |
Desipramine | ? | 30 | ? | 125–300 | 4–6 hr | ? | Urine (70%) | CYP2D6 | ? |
Doxepin | ? | 18 (30) | 11930 | 150–250 | 2 hr | 80% | Urine | ? | |
Imipramine | High | 12 (30) | 18 | 175–300 | 1–2 hr | 90% | Urine | ? | |
Lofepramine | 7% | 1.7–2.5 (12–24) | ? | 30–50 (100–150) | 1 hr | 99% (92%) | Urine | CYP450 | ? |
Maprotiline | High | 48 | ? | 200–400 | 8–24 hr | 88% | Urine (70%); faeces (30%) | ? | ? |
Nortriptyline | ? | 28–31 | 21 | 50–150 | 7–8.5 hr | 93–95% | Urine, faeces | CYP2D6 | ? |
Protriptyline | High | 80 | ? | 100–150 | 24–30 hr | 92% | Urine | ? | ? |
Tianeptine | 99% | 2.5–3 | 0.5–1 | ? | 1–2 hr | 95–96% | Urine (65%) | ? | ? |
Trimipramine | 41% | 23–24 (30) | 17–48 | 100–300 | 2 hr | 94.9% | Urine | ? | ? |
Monoamine oxidase inhibitors (MAOIs)
| |||||||||
Moclobemide | 55–95% | 2 | ? | ? | 1–2 hr | 50% | Urine, faeces (<5%) | ? | MAOA |
Phenelzine | ? | 11.6 | ? | ? | 43 mins | ? | Urine | MAOA | MAO |
Tranylcypromine | ? | 1.5–3 | 3.09 | ? | 1.5–2 hr | ? | Urine | MAO | MAO |
Selective serotonin reuptake inhibitors (SSRIs)
| |||||||||
Citalopram | 80% | 35–36 | 12 | 75–150 | 2–4 hr | 80% | Urine (15%) | CYP1A2 (weak) | |
Escitalopram | 80% | 27–32 | 20 | 40–80 | 3.5–6.5 hr | 56% | Urine (8%) | CYP2D6 (weak) | |
Fluoxetine | 72% | 24–72 (single doses), 96–144 (repeated dosing) | 12–43 | 100–500 | 6–8 hr | 95% | Urine (15%) | CYP2D6 | |
Fluvoxamine | 53% | 18 | 25 | 100–200 | 3–8 hr | 80% | Urine (85%) | ||
Paroxetine | ? | 17 | 8.7 | 30–100 | 5.2–8.1 (IR); 6–10 hr (CR) | 93–95% | Urine (64%), faeces (36%) | CYP2D6 | |
Sertraline | 44% | 23–26 (66) | ? | 25–50 | 4.5–8.4 hr | 98% | Urine (12–14% unchanged), faeces (40–45%) | ||
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
| |||||||||
Desvenlafaxine | 80% | 11 | 3.4 | ? | 7.5 hr | 30% | Urine (69%) | CYP3A4 | CYP2D6 (weak) |
Duloxetine | High | 11–12 | 3.4 | ? | 6 hr (empty stomach), 10 hr (with food) | >90% | Urine (70%; <1% unchanged), faeces (20%) | CYP2D6 (moderate) | |
Levomilnacipran | 92% | 12 | 387–473 L | ? | 6–8 hr | 22% | Urine (76%; 58% as unchanged drug & 18% as N-desmethyl metabolite) | ? | |
Milnacipran | 85-90% | 6-8 (L-isomer), 8-10 (D-isomer) | 400 L | ? | 2–4 hr | 13% | Urine (55%) | ? | ? |
Venlafaxine | 45% | 5 (11) | 7.5 | ? | 2-3 hr (IR), 5.5–9 hr (XR) | 27–30% (30%) | Urine (87%) | CYP2D6 | CYP2D6 (weak) |
Others | |||||||||
Agomelatine | ≥80% | 1–2 hr | 35 L | ? | 1–2 hr | 95% | Urine (80%) | ? | |
Bupropion | ? | 8–24 (IR; 20, 30, 37), 21±7 (XR) | 20–47 | 75–100 | 2 hr (IR), 3 hr (XR) | 84% | Urine (87%), faeces (10%) | CYP2B6 | CYP2D6 (moderate) |
Mianserin | 20-30% | 21–61 | ? | ? | 3 hr | 95% | Faeces (14–28%), urine (4–7%) | CYP2D6 | ? |
Mirtazapine | 50% | 20–40 | 4.5 | ? | 2 hr | 85% | Urine (75%), faeces (15%) | ? | |
Nefazodone | 20% (decreased by food) | 2–4 | 0.22–0.87 | ? | 1 hr | >99% | Urine (55%), faeces (20–30%) | CYP3A4 | ? |
Reboxetine | 94% | 12–13 | 26 L (R,R diastereomer), 63 L (S,S diastereomer) | ? | 2 hr | 97% | Urine (78%; 10% as unchanged) | CYP3A4 | ? |
Trazodone | ? | 6–10 | ? | 800–1600 | 1 hr (without food), 2.5 hr (with food) | 85–95% | Urine (75%), faeces (25%) | CYP2D6 | ? |
Vilazodone | 72% (with food) | 25 | ? | ? | 4–5 hr | 96–99% | Faeces (2% unchanged), urine (1% unchanged) | ? | |
Vortioxetine | ? | 66 | 2600 L | ? | 7–11 hr | 98% | Urine (59%), faeces (26%) | ? |
See also
References
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