Chemistry:Pharmacology of antidepressants

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Short description: Antidepressant pharmacology hypotheses

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 had the monoamine hypothesis as their initial 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 2 weeks) antidepressant effects.[3][4] Monoamine precursor depletion also fails to alter mood.[5][6][7] 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][8][9] 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.[10]

Monoamine hypothesis

In 1965, Joseph Schildkraut published a review article stating that several researchers had found an association between depression and deficiency of the catecholamine family of monoamine neurotransmitters, which they had begun calling the "catecholamine hypothesis",[11] also known as the monoamine hypothesis.[12]


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.[13] 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[14]

Although there is evidence that antidepressants inhibit the reuptake of serotonin,[15] 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,[16] 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.

Hypothalamic-pituitary-adrenal axis

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.[17]

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 anhedonia 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 anhedonia. If X-ray irradiation is used on the hippocampus before drug treatment to prevent neurogenesis, no improvement of anhedonia occurs. However, if an irradiated mouse is given a corticotropin-releasing factor 1 antagonist – a drug that directly targets the HPA axis – anhedonia is improved. Combined with the fact that irradiation 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 anhedonia.[18]

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.[19] A broader view is that antidepressants help by increasing neuroplasticity in general.[20]

Chronic use of SSRI antidepressant increased neurogenesis in the hippocampus of rats and mice.[21][22][23] 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[24] as well as global rewiring;[25] lithium and valporate, two mood stabilizers occasionally used as add-on treatment, are associated with increased survival and proliferation of neurons.[24] 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.[26]

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).[27]

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).[28]

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.[29] It appears possible to use brain imaging to predict which patients are likely to respond to SSRI antidepressants.[30]

Anti-inflammatory and immunomodulation

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.[31][32][33][34][35]

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.[34] 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.[36][37][38][39][40]

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties. Antidepressants are now standard of care in chronic neuropathic pain.[41] Antidepressants also work in mouse models of both neuropathic and inflammatory pain.[42] In addition, tramadol is an opioid with SNRI-like activity; it retains some analgesic potency when administered with the opioid antagonist naloxone, indicating a role of its non-opioid activities.[43]

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.[44] 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.[45]

Pharmacological data

Receptor affinity

A variety of monoaminergic antidepressants have been compared below:[1][46][47][48][49][50]

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

Sources:[51][52][53]

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[54]
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

  1. ↑ 1.0 1.1 1.2 1.3 Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. 2011. ISBN 978-0-07-162442-8. 
  2. ↑ 2.0 2.1 "The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression". Metabolic Brain Disease 24 (1): 27–53. March 2009. doi:10.1007/s11011-008-9118-1. PMID 19085093. 
  3. ↑ 3.0 3.1 3.2 "Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders". Neuropharmacology 62 (1): 63–77. January 2012. doi:10.1016/j.neuropharm.2011.07.036. PMID 21827775. 
  4. ↑ Ma, Shuangshuang; Chen, Min; Jiang, Yihao; Xiang, Xinkuan; Wang, Shiqi; Wu, Zuohang; Li, Shuo; Cui, Yihui et al. (October 2023). "Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb". Nature 622 (7984): 802–809. doi:10.1038/s41586-023-06624-1. ISSN 1476-4687. PMID 37853123. 
  5. ↑ "Effect of acute tryptophan depletion on mood and appetite in healthy female volunteers". Journal of Psychopharmacology 8 (1): 8–13. January 1994. doi:10.1177/026988119400800102. PMID 22298474. 
  6. ↑ "The effect of tryptophan depletion on mood in medication-free, former patients with major affective disorder". Neuropsychopharmacology 16 (4): 294–297. April 1997. doi:10.1016/s0893-133x(96)00262-x. PMID 9094147. 
  7. ↑ "Effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients symptomatically stable on lithium". The British Journal of Psychiatry 177 (5): 447–451. November 2000. doi:10.1192/bjp.177.5.447. PMID 11059999. 
  8. ↑ "Epigenetics, depression and antidepressant treatment". Current Pharmaceutical Design 18 (36): 5879–5889. 2012. doi:10.2174/138161212803523590. PMID 22681167. 
  9. ↑ "Epigenetic mechanisms of depression and antidepressant action". Annual Review of Pharmacology and Toxicology 53 (1): 59–87. January 2013. doi:10.1146/annurev-pharmtox-010611-134540. PMID 23020296. 
  10. ↑ "Acute neural effects of selective serotonin reuptake inhibitors versus noradrenaline reuptake inhibitors on emotion processing: Implications for differential treatment efficacy". Neuroscience and Biobehavioral Reviews 37 (8): 1786–1800. September 2013. doi:10.1016/j.neubiorev.2013.07.010. PMID 23886514. https://cronfa.swan.ac.uk/Record/cronfa26248. 
  11. ↑ "The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965". The Journal of Neuropsychiatry and Clinical Neurosciences 7 (4): 524–33; discussion 523–4. 1995. doi:10.1176/jnp.7.4.524. PMID 8555758. 
  12. ↑ Hirschfeld, Robert M. A. (2000-03-31). "History and Evolution of the Monoamine Hypothesis of Depression". The Journal of Clinical Psychology 61 (Supplement): 4–6. PMID 10775017. https://www.psychiatrist.com/jcp/history-evolution-monoamine-hypothesis-depression. Retrieved 2024-12-21. 
  13. ↑ "CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls". European Neuropsychopharmacology 20 (1): 18–24. January 2010. doi:10.1016/j.euroneuro.2009.10.003. PMID 19896342. 
  14. ↑ "Serotonin and depression: a disconnect between the advertisements and the scientific literature". PLOS Medicine 2 (12). December 2005. doi:10.1371/journal.pmed.0020392. PMID 16268734. 
  15. ↑ "Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs". The Journal of Clinical Psychiatry 59 (Suppl 15): 4–12. 1998. PMID 9786305. 
  16. ↑ "A systematic review of comparative efficacy of treatments and controls for depression". PLOS ONE 7 (7). 2012. doi:10.1371/journal.pone.0041778. PMID 22860015. Bibcode: 2012PLoSO...741778K. 
  17. ↑ "Depression, stress and the adrenal axis". Journal of Neuroendocrinology 15 (8): 811–812. August 2003. doi:10.1046/j.1365-2826.2003.01058.x. PMID 12834443. 
  18. ↑ "Antidepressants recruit new neurons to improve stress response regulation.". Molecular Psychiatry 16 (12): 1177–88. December 2011. doi:10.1038/mp.2011.48. PMID 21537331. 
  19. ↑ "Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment". Hippocampus 16 (3): 239–249. 2006. doi:10.1002/hipo.20156. PMID 16425236. 
  20. ↑ Rădulescu, I; Drăgoi, AM; Trifu, SC; Cristea, MB (October 2021). "Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review).". Experimental and Therapeutic Medicine 22 (4): 1131. doi:10.3892/etm.2021.10565. PMID 34504581. 
  21. ↑ "Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus". The Journal of Neuroscience 20 (24): 9104–9110. December 2000. doi:10.1523/JNEUROSCI.20-24-09104.2000. PMID 11124987. 
  22. ↑ "Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro". European Journal of Pharmacology 411 (1–2): 67–70. January 2001. doi:10.1016/S0014-2999(00)00904-3. PMID 11137860. 
  23. ↑ "Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists". European Neuropsychopharmacology 16 (7): 521–537. October 2006. doi:10.1016/j.euroneuro.2006.01.007. PMID 16517129. 
  24. ↑ 24.0 24.1 Hanson, ND; Owens, MJ; Nemeroff, CB (December 2011). "Depression, antidepressants, and neurogenesis: a critical reappraisal.". Neuropsychopharmacology 36 (13): 2589–602. doi:10.1038/npp.2011.220. PMID 21937982. 
  25. ↑ "The Neurobiological Effects of Electroconvulsive Therapy Studied Through Magnetic Resonance: What Have We Learned, and Where Do We Go?". Biological Psychiatry 91 (6): 540–549. March 2022. doi:10.1016/j.biopsych.2021.05.023. PMID 34274106. 
  26. ↑ Catharine H. Duman; Ronald S. Duman (2015). "Spine synapse remodeling in the pathophysiology and treatment of depression". Neuroscience Letters 601: 20–29. doi:10.1016/j.neulet.2015.01.022. PMID 25582786. 
  27. ↑ "Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum". Neuroscience 134 (4): 1309–1316. 2005. doi:10.1016/j.neuroscience.2005.05.003. PMID 15994025. 
  28. ↑ "Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats". Psychopharmacology 182 (1): 104–115. October 2005. doi:10.1007/s00213-005-0055-y. PMID 16010541. 
  29. ↑ Seiger, R; Gryglewski, G; Klöbl, M; Kautzky, A; Godbersen, G M; Rischka, L; Vanicek, T; Hienert, M et al. (23 July 2021). "The Influence of Acute SSRI Administration on White Matter Microstructure in Patients Suffering From Major Depressive Disorder and Healthy Controls". International Journal of Neuropsychopharmacology 24 (7): 542–550. doi:10.1093/ijnp/pyab008. PMID 33667309.  – history of structure research summarized in "Introduction"
  30. ↑ Fu, Cynthia H. Y.; Antoniades, Mathilde; Erus, Guray; Garcia, Jose A.; Fan, Yong; Arnone, Danilo; Arnott, Stephen R.; Chen, Taolin et al. (12 January 2024). "Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo". Nature Mental Health 2 (2): 164–176. doi:10.1038/s44220-023-00187-w. PMID 38948238. 
  31. ↑ "Cytokine profiles in bipolar affective disorder: focus on acutely ill patients". Journal of Affective Disorders 90 (2–3): 263–267. February 2006. doi:10.1016/j.jad.2005.11.015. PMID 16410025. 
  32. ↑ "[Antidepressants and cytokines--clinical and experimental studies"] (in Polish). Psychiatria Polska 39 (5): 921–936. 2005. PMID 16358592. http://www.psychiatriapolska.pl/uploads/PPt39n5s921Obuchowicz.pdf. 
  33. ↑ "Interleukin-6 genetic polymorphism and Chinese major depression". Neuropsychobiology 52 (4): 202–205. 2005. doi:10.1159/000089003. PMID 16244501. 
  34. ↑ 34.0 34.1 "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation 12 (5): 255–269. 2005. doi:10.1159/000087104. PMID 16166805. 
  35. ↑ "Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6". Psychiatry Research 134 (3): 251–258. April 2005. doi:10.1016/j.psychres.2004.01.014. PMID 15892984. 
  36. ↑ "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". European Neuropsychopharmacology 16 (7): 481–490. October 2006. doi:10.1016/j.euroneuro.2005.11.011. PMID 16388933. 
  37. ↑ "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio". Journal of Clinical Psychopharmacology 21 (2): 199–206. April 2001. doi:10.1097/00004714-200104000-00012. PMID 11270917. 
  38. ↑ "The immunoregulatory effects of antidepressants". Human Psychopharmacology 16 (1): 95–103. January 2001. doi:10.1002/hup.191. PMID 12404604. 
  39. ↑ "The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". International Immunopharmacology 5 (3): 609–618. March 2005. doi:10.1016/j.intimp.2004.11.008. PMID 15683856. 
  40. ↑ "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice". International Immunopharmacology 6 (6): 903–907. June 2006. doi:10.1016/j.intimp.2005.12.007. PMID 16644475. https://www.arca.fiocruz.br/handle/icict/2741. 
  41. ↑ "Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society". Pain Research & Management 12 (1): 13–21. 2007. doi:10.1155/2007/730785. PMID 17372630. 
  42. ↑ "Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition". Neuropharmacology 51 (7–8): 1172–1180. December 2006. doi:10.1016/j.neuropharm.2006.08.005. PMID 17045620. 
  43. ↑ "Mechanistic and functional differentiation of tapentadol and tramadol". Expert Opinion on Pharmacotherapy 13 (10): 1437–1449. July 2012. doi:10.1517/14656566.2012.696097. PMID 22698264. 
  44. ↑ "Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response". Journal of Pharmacy & Pharmaceutical Sciences 9 (3): 292–306. 2006. PMID 17207413. https://www.ualberta.ca/~csps/JPPS9_3/Kulmatycki/Kul_Jam.htm. 
  45. ↑ "Cytokines: abnormalities in major depression and implications for pharmacological treatment". Human Psychopharmacology 19 (6): 397–403. August 2004. doi:10.1002/hup.609. PMID 15303243. 
  46. ↑ "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology 340 (2–3): 249–258. December 1997. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821. 
  47. ↑ "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". The Journal of Pharmacology and Experimental Therapeutics 283 (3): 1305–1322. December 1997. doi:10.1016/S0022-3565(24)37161-7. PMID 9400006. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9400006. 
  48. ↑ "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology 114 (4): 559–565. May 1994. doi:10.1007/BF02244985. PMID 7855217. 
  49. ↑ Essentials of clinical psychopharmacology. American Psychiatric Pub. 2006. p. 7. ISBN 978-1-58562-243-6. 
  50. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Oct 4]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: "PDSP Database - UNC". http://pdsp.med.unc.edu/pdsp.php. 
  51. ↑ "Therapeutic Goods Administration – Home page". Department of Health (Australia). https://www.ebs.tga.gov.au/. 
  52. ↑ "electronic Medicines Compendium – Home page". Datapharm. http://www.medicines.org.uk/emc/. [full citation needed][full citation needed]
  53. ↑ (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07- Pharmacological Basis of Therapeutics. 
  54. ↑ Pharmacotherapy of Depression (2nd ed.). New York, NY: Humana Press. 2011. doi:10.1007/978-1-60327-435-7. ISBN 978-1-60327-434-0. 
  55. ↑ Product Information: ELAVIL(R) oral tablets injection, amitriptyline oral tablets injection. Zeneca Pharmaceuticals, Wilmington, DE, 2000.



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