Pharmacology of antidepressants

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 currently marketed antidepressants 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]

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 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. This briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function.[16]

Monoamine hypothesis

In 1965, Joseph Schildkraut postulated the Monoamine Hypothesis when he posited an association between low levels of neurotransmitters and depression.[17] 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.[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-HT_2Areceptors, 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-HT_2A receptors evolved as a saturation signal (people who use 5-HT_2A 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-HT_2A 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-HT_2A 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-HT_2A receptors or by overstimulating them until they decrease via tolerance.

Receptor affinity

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][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	0.34	56.7	574	22000	108	4600	>10000	>35000	>10000	19000	32000	?	?
Protriptyline	19.6	1.41	2100	60	25	130	6600	?	26	?	?	?	?
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)	?	?	?	?	?
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

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.[27][28][29][30][31]

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.[30] 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.[32][33][34][35][36]

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

Sources:[41][42][43][44]

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%)	CYP3A4 CYP2C19 CYP2D6[46]	?
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	CYP2D6 CYP2C19 CYP3A3 CYP3A4	?
Imipramine	High	12 (30)	18	175-300	1-2 hr	90%	Urine	CYP1A2 CYP2C19 CYP2D6	?
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%)	CYP3A4 CYP2C19	CYP1A2 (weak)
Escitalopram	80%	27-32	20	40-80	3.5-6.5 hr	56%	Urine (8%)	CYP3A4 CYP2C19	CYP2D6 (weak)
Fluoxetine	72%	24-72 (single doses), 96-144 (repeated dosing)	12-43	100-500	6-8 hr	95%	Urine (15%)	CYP2D6	CYP2C19 (weak–moderate) CYP2D6 (strong) CYP3A4 (weak–moderate)
Fluvoxamine	53%	18	25	100-200	3-8 hr	80%	Urine (85%)	CYP2D6 CYP1A2 CYP3A4 CYP2C9	CYP1A2 (strong) CYP2C9 (moderate) CYP3A4 (weak) CYP2C19 (strong) CYP2B6 (weak)
Paroxetine	?	17	8.7	30-100	5.2-8.1 (IR); 6-10 hr (CR)	93-95%	Urine (64%), faeces (36%)	CYP2D6	CYP2D6 (strong) CYP2B6 (strong) CYP1A2 (weak) CYP2C9 (weak) CYP2C19 (weak) CYP3A4 (weak)
Sertraline	44%	23-26 (66)	?	25-50	4.5-8.4 hr	98%	Urine (12-14% unchanged), faeces (40-45%)	CYP2B6 CYP2D6	CYP2D6 (weak–moderate) CYP2C19 (weak–moderate)
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 CYP1A2	CYP2D6 (moderate)
Levomilnacipran	92%	12	387-473 L	?	6-8 hr	22%	Urine (76%; 58% as unchanged drug & 18% as N-desmethyl metabolite)	CYP3A4 CYP2C8 CYP2C19 CYP2D6 CYP2J2	?
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%)	CYP1A2 CYP2C9 CYP2C19	?
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%)	CYP1A2 CYP2D6 CYP3A4	?
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)	CYP3A4 CYP2C19 CYP2D6	?
Vortioxetine	?	66	2600 L	?	7-11 hr	98%	Urine (59%), faeces (26%)	CYP2D6 CYP3A4 CYP3A5 CYP2C19 CYP2C9 CYP2A6 CYP2C8 CYP2B6	?

See also

• Atypical antidepressant
• STAR*D

References

1. Brunton, L. L.; Chabner, Bruce; Knollmann, Björn C., eds. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.
2. Maes, M; Yirmyia, R; Noraberg, J; Brene, S; Hibbeln, J; Perini, G; Kubera, M; Bob, P; Lerer, B; Maj, M (March 2009). "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. doi:10.1007/s11011-008-9118-1. PMID 19085093.
3. Sanacora, G; Treccani, G; Popoli, M (January 2012). "Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders". Neuropharmacology. 62 (1): 63–77. doi:10.1016/j.neuropharm.2011.07.036. PMC 3205453. PMID 21827775.
4. Cowen; Salkovskis; Oldman; Walsh; Laver (January 1994). "Effect of acute tryptophan depletion on mood and appetite in healthy female volunteers". J. Psychopharmacol. 8 (1): 8–13. doi:10.1177/026988119400800102. PMID 22298474.
5. Leyton; Young; Blier; Ellenbogen; Palmour; Ghadirian; Benkelfat (April 1997). "The effect of tryptophan depletion on mood in medication-free, former patients with major affective disorder". Neuropsychopharmacology. 16 (4): 294–297. doi:10.1016/s0893-133x(96)00262-x. PMID 9094147.
6. Hughes; Dunne; Young (November 2000). "Effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients symptomatically stable on lithium". Br J Psychiatry. 177 (5): 447–451. doi:10.1192/bjp.177.5.447. PMID 11059999.
7. Menke A, Klengel T, Binder EB (2012). "Epigenetics, depression and antidepressant treatment". Current Pharmaceutical Design. 18 (36): 5879–5889. doi:10.2174/138161212803523590. PMID 22681167.
8. Vialou, V; Feng, J; Robison, AJ; Nestler, EJ (January 2013). "Epigenetic mechanisms of depression and antidepressant action". Annual Review of Pharmacology and Toxicology. 53 (1): 59–87. doi:10.1146/annurev-pharmtox-010611-134540. PMC 3711377. PMID 23020296.
9. Kempa; Outhreda; Hawkshead; Wagerd; Dasa; Malhia (2013). "Acute neural effects of selective serotonin reuptake inhibitors versus noradrenaline reuptake inhibitors on emotion processing: Implications for differential treatment efficacy" (PDF). Neuroscience and Biobehavioral Reviews. 37 (8): 1786–1800. doi:10.1016/j.neubiorev.2013.07.010. PMID 23886514.
10. Warner-Schmidt, Jennifer L.; Duman, Ronald S. (2006). "Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment". Hippocampus. 16 (3): 239–49. doi:10.1002/hipo.20156. PMID 16425236.
11. Malberg, Jessica E.; Eisch, Amelia J.; Nestler, Eric J.; Duman, Ronald S. (2000). "Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus". The Journal of Neuroscience. 20 (24): 9104–10. doi:10.1523/JNEUROSCI.20-24-09104.2000. PMC 6773038. PMID 11124987.
12. Manev, Hari; Uz, Tolga; Smalheiser, Neil R; Manev, Radmila (2001). "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. doi:10.1016/S0014-2999(00)00904-3. PMID 11137860.
13. Carboni, Lucia; Vighini, Miriam; Piubelli, Chiara; Castelletti, Laura; Milli, Alberto; Domenici, Enrico (2006). "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): 521–37. doi:10.1016/j.euroneuro.2006.01.007. PMID 16517129.
14. Uz, T.; Ahmed, R.; Akhisaroglu, M.; Kurtuncu, M.; Imbesi, M.; Dirim Arslan, A.; Manev, H. (2005). "Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum". Neuroscience. 134 (4): 1309–16. doi:10.1016/j.neuroscience.2005.05.003. PMID 15994025.
15. Zhang, Han-Ting; Huang, Ying; Mishler, Kathleen; Roerig, Sandra C.; O'Donnell, James M. (2005). "Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats". Psychopharmacology. 182 (1): 104–15. doi:10.1007/s00213-005-0055-y. PMID 16010541.
16. Pariante, CM (2003). "Depression, stress and the adrenal axis". Journal of Neuroendocrinology. 15 (8): 811–2. doi:10.1046/j.1365-2826.2003.01058.x. PMID 12834443.
17. Schildkraut, JJ (1995). "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. doi:10.1176/jnp.7.4.524. PMID 8555758.
18. Moreno, Francisco A.; Parkinson, Damian; Palmer, Craig; Castro, Wm. Lesley; Misiaszek, John; El Khoury, Aram; Mathé, Aleksander A.; Wright, Ron; Delgado, Pedro L. (2010). "CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls". European Neuropsychopharmacology. 20 (1): 18–24. doi:10.1016/j.euroneuro.2009.10.003. PMC 2794896. PMID 19896342.
19. Lacasse, Jeffrey R.; Leo, Jonathan (2005). "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature". PLoS Medicine. 2 (12): e392. doi:10.1371/journal.pmed.0020392. PMC 1277931. PMID 16268734.
20. Murphy, DL; Andrews, AM; Wichems, CH; Li, Q; Tohda, M; Greenberg, B (1998). "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. PMID 9786305.
21. Khan, Arif; Faucett, James; Lichtenberg, Pesach; Kirsch, Irving; Brown, Walter A. (2012). Holscher, Christian (ed.). "A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression". PLoS ONE. 7 (7): e41778. Bibcode:2012PLoSO...741778K. doi:10.1371/journal.pone.0041778. PMC 3408478. PMID 22860015.
22. Tatsumi, Masahiko; Groshan, Karen; Blakely, Randy D; Richelson, Elliott (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
23. Owens, Michael J.; Morgan, W. Neal; Plott, Susan J.; Nemeroff, Charles B. (1997). "Neurotransmitter Receptor and Transporter Binding Profile of Antidepressants and Their Metabolites". The Journal of Pharmacology and Experimental Therapeutics. 283 (3): 1305–22. PMID 9400006.
24. Cusack, Bernadette; Nelson, Albert; Richelson, Elliott (1994). "Binding of antidepressants to human brain receptors: Focus on newer generation compounds". Psychopharmacology. 114 (4): 559–65. doi:10.1007/BF02244985. PMID 7855217.
25. Schatzberg, Alan F.; Nemeroff, Charles B. (2006). Essentials of clinical psychopharmacology. American Psychiatric Pub. p. 7. ISBN 978-1-58562-243-6.
26. National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Oct 4]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: "Archived copy". Archived from the original on 2013-11-08. Retrieved 2013-10-26.CS1 maint: archived copy as title (link)
27. O'Brien, Sinead M.; Scully, Paul; Scott, Lucinda V.; Dinan, Timothy G. (2006). "Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients". Journal of Affective Disorders. 90 (2–3): 263–7. doi:10.1016/j.jad.2005.11.015. PMID 16410025.
28. Obuchowicz, Ewa; Marcinowska, Agnieszka; Herman, Zbigniew S. (2005). "Leki przeciwdepresyjne a cytokiny – badania kliniczne i doświadczalne" [Antidepressants and cytokines – clinical and experimental studies] (PDF). Psychiatria Polska (in Polish). 39 (5): 921–36. PMID 16358592.
29. Hong, Chen-Jee; Yu, Younger W.-Y.; Chen, Tai-Jui; Tsai, Shih-Jen (2005). "Interleukin-6 Genetic Polymorphism and Chinese Major Depression". Neuropsychobiology. 52 (4): 202–5. doi:10.1159/000089003. PMID 16244501.
30. Elenkov, Ilia J.; Iezzoni, Domenic G.; Daly, Adrian; Harris, Alan G.; Chrousos, George P. (2005). "Cytokine Dysregulation, Inflammation and Well-Being". Neuroimmunomodulation. 12 (5): 255–69. doi:10.1159/000087104. PMID 16166805.
31. Kubera, Marta; Maes, Michael; Kenis, Gunter; Kim, Yong-Ku; Lasoń, Władysław (2005). "Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor α and interleukin-6". Psychiatry Research. 134 (3): 251–8. doi:10.1016/j.psychres.2004.01.014. PMID 15892984.
32. Diamond, Michael; Kelly, John P.; Connor, Thomas J. (2006). "Antidepressants suppress production of the Th1 cytokine interferon-γ, independent of monoamine transporter blockade". European Neuropsychopharmacology. 16 (7): 481–90. doi:10.1016/j.euroneuro.2005.11.011. PMID 16388933.
33. Kubera, Marta; Lin, Ai-Hua; Kenis, Gunter; Bosmans, Eugene; Van Bockstaele, Dirk; Maes, Michael (2001). "Anti-Inflammatory Effects of Antidepressants Through Suppression of the Interferon-γ/Interleukin-10 Production Ratio". Journal of Clinical Psychopharmacology. 21 (2): 199–206. doi:10.1097/00004714-200104000-00012. PMID 11270917.
34. Maes, Michael (2001). "The immunoregulatory effects of antidepressants". Human Psychopharmacology: Clinical and Experimental. 16 (1): 95–103. doi:10.1002/hup.191. PMID 12404604.
35. Maes, Michael; Kenis, Gunter; Kubera, Marta; De Baets, Mark; Steinbusch, Harry; Bosmans, Eugene (2005). "The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". International Immunopharmacology. 5 (3): 609–18. doi:10.1016/j.intimp.2004.11.008. PMID 15683856.
36. Brustolim, D.; Ribeiro-Dos-Santos, R.; Kast, R.E.; Altschuler, E.L.; Soares, M.B.P. (2006). "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): 903–7. doi:10.1016/j.intimp.2005.12.007. PMID 16644475.
37. Moulin, DE; Clark, AJ; Gilron, I; Ware, MA; Watson, CP; Sessle, BJ; Coderre, T; Morley-Forster, PK; et al. (2007). "Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society". Pain Research & Management. 12 (1): 13–21. doi:10.1155/2007/730785. PMC 2670721. PMID 17372630.
38. Jones, Carrie K.; Eastwood, Brian J.; Need, Anne B.; Shannon, Harlan E. (2006). "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): 1172–80. doi:10.1016/j.neuropharm.2006.08.005. PMID 17045620.
39. Kulmatycki, Kenneth M.; Jamali, Fakhreddin (2006). "Drug disease interactions: Role of inflammatory mediators in depression and variability in antidepressant drug response". Journal of Pharmacy & Pharmaceutical Sciences. 9 (3): 292–306. PMID 17207413.
40. O'Brien, Sinead M.; Scott, Lucinda V.; Dinan, Timothy G. (2004). "Cytokines: Abnormalities in major depression and implications for pharmacological treatment". Human Psychopharmacology: Clinical and Experimental. 19 (6): 397–403. doi:10.1002/hup.609. PMID 15303243.
41. "Therapeutic Goods Administration – Home page". Department of Health (Australia). Retrieved 27 November 2013.
42. "electronic Medicines Compendium – Home page". Datapharm. Retrieved 28 November 2013.
43. "Medscape Multispecialty – Home page". WebMD. Retrieved 27 November 2013.
44. Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
45. Ciraulo, DA; Shader, RI, eds. (2011). Pharmacotherapy of Depression. SpringerLink (2nd ed.). New York, NY: Humana Press. doi:10.1007/978-1-60327-435-7. ISBN 978-1-60327-434-0.
46. Product Information: ELAVIL(R) oral tablets injection, amitriptyline oral tablets injection. Zeneca Pharmaceuticals, Wilmington, DE, 2000.