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Pharmacology of antidepressants

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The pharmacology of antidepressants is not entirely clear.

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).[1] It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters.[1] All antidepressants that have entered the market before 2011 have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway.[1]

Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants.[2][3] Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to a fortnight) antidepressant effects.[3] Monoamine precursor depletion also fails to alter mood.[4][5][6] To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses.[2][3][7][8] Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.[9]

Monoamine hypothesis

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Main article: Monoamine hypothesis

In 1965, Joseph Schildkraut postulated the Monoamine Hypothesis when he posited an association between low levels of neurotransmitters and depression.[10] By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

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.[11] 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[12]

Although there is evidence that antidepressants inhibit the reuptake of serotonin,[13] 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,[14] 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 downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.[medical citation needed]

Hypothalamic-pituitary-adrenal axis

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One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not known whether this HPA axis dysregulation is reactive or causative for depression. A 2003 briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function.[15]

A 2011 study combines aspects of the HPA axis theory and the neurogenic theory (see below). The researchers showed that mice under unpredictable chronic mild stress (a well-known animal model of depression) have impaired hippocampal neurogenesis and greatly reduced ability of the hippocampus to regulate the HPA axis, causing ahedonia as measured by the Cookie Test. Administration of fluoxetine (an SSRI) without removing the stressor causes increased hippocampal neurogenesis, normalization of the HPA axis, and improvement of ahedonia. If X-ray irradiation is used on the hippocampus before drug treatment to prevent neurogenesis, no improvement of ahedonia occurs. However, if an irradiated mouse is given a corticotropin-releasing factor 1 antagonist – a drug that directly targets the HPA axis – ahedonia is improved. Combined with the fact that irridiation without stressing does not impair hippocampal control of the HPA axis, the authors conclude that fluoxetine works by improving hippocampal neurogenesis, which then helps restore the HPA axis, in turn leading to improvements in depression symptoms such as ahedonia.[16]

Neurogenic adaptations

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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.[17] A broader view is that antidepressants help by increasing neuroplasticity in general.[18]

Chronic use of SSRI antidepressant increased neurogenesis in the hippocampus of rats and mice.[19][20][21] Other antidepressant treatments also appear associated with hippocampal neurogenesis and/or neuroplasticity: electroconvulsive therapy, which is known to be highly effective for depression, is associated with higher BDNF expression in the hippocampus[22] as well as global rewiring;[23] lithium and valporate, two mood stabilizers occasionally used as add-on treatment, are associated with increased survival and proliferation of neurons.[22] Ketamine (see also esketamine), a new fast-acting antidepressant, can increase the number of dendritic spines and restore aspects of functional connectivity after a single infusion.[24]

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).[25]

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).[26]

Studies on human patients have used imaging approaches to measure the changes in density and volume of specific brain areas. The grey matter volume of parts of the brain are differently increased or decreased by SSRI use.[27] It appears possible to use brain imaging to predict which patients are likely to respond to SSRI antidepressants.[28]

Anti-inflammatory and immunomodulation

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Further information: Cytokine

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.[29][30][31][32][33]

Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes, may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones.[32] SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10), as well as TNF-alpha and interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.[34][35][36][37][38]

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.[39][40]

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.[41] 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.[42]

Pharamacological data

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Receptor affinity

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Main articles: Tricyclic antidepressants § Binding profiles, Tetracyclic antidepressants § Binding profiles, Serotonin antagonists and reuptake inhibitors § Binding profiles, Serotonin–norepinephrine reuptake inhibitors § Activity profiles, Monoamine reuptake inhibitors § Binding profiles, and Selective serotonin reuptake inhibitor § Sigma receptor ligands

A variety of monoaminergic antidepressants have been compared below:[1][43][44][45][46][47]

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.

Pharmacokinetics

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Sources:[48][49][50][51]

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[52]
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

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References

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