Which cyclic antidepressants are superior for the treatment of depressed psoriatic patients? A theoretical molecular approach
Published Web Locationhttps://doi.org/10.5070/D35vt5050c
Which cyclic antidepressants are superior for the treatment of depressed psoriatic patients? a theoretical molecular approachDermatology Department and Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. email@example.com
M R Namazi MD
Dermatology Online Journal 14 (1): 23
Psoriasis, a common skin complaint affecting an estimated 1-3 percent of the world population, has been associated with a range of psychiatric morbidity including depressive disease and case reports of completed suicide . Sharma et al.  reported a depression prevalence of 23.3 percent in psoriatic patients and Gupta et al. reported that about 10 percent of these patients wished to be dead and 5.5 percent had active suicidal ideation . These figures, being astonishingly similar to those of life-threatening medical disorders such as malignancies , elucidate the importance of psychiatric intervention for these patients. Because cyclic antidepressants are frequently employed to treat the depression of these patients, this paper aims to designate the superior agents for this purpose.
Psoriatic plaques are the result of keratinocyte hyperproliferation in association with abnormal epidermal differentiation secondary to the release of cytokines from mononuclear cells accumulating in the epidermis and dermis of the lesions. Psoriasis, therefore, is believed to be a cell-mediated autoimmune disorder .
Biological functions of keratinocyte muscarinic and β-2-adrenergic receptors
Nerve fibers penetrate all vital layers of the human epidermis and contact keratinocyte cell bodies or cilia by membrane-membrane apposition. Secretion of neurotransmitters by neurons could thus affect keratinocytes . Keratinocytes express several types of muscarinic receptors. These receptors are predominantly localized to the basal, proliferating, layer of the epidermis and are believed to negatively control proliferation of the basal cells. PrBCM, an irreversible muscarinic antagonist, has been shown to stimulate keratinocyte proliferation in vitro .
Keratinocytes also express β-2-adrenoceptors, which are believed to induce keratinocyte differentiation and limit keratinocyte proliferation through increase of intracellular cAMP levels [6, 7]. Norepinephrine elicited a 49 percent inhibitory response on proliferation of human keratinocytes in vitro  and topical application of isoprenaline (isoproterenol), a non-selective β-agonist, has been shown to be effective against psoriasis .
In summary, both muscarinic and beta-2-adrenergic receptors limit keratinocyte proliferation.
Biological functions of β-2-adrenergic and muscarinic receptors of the immune cells
It has been shown that lymphocytes and macrophages express β-2-adrenoceptors and that stimulation of these receptors inhibits cellular immune reactions . This explains the improvement of cell-mediated symptoms (e.g., arthritis) of systemic lupus erythematosus patients during confrontation with stressors, including infections . Moreover, the cellular immunodeficiency associated with hemorrhagic shock is believed to result from increased catecholamine release and is reversible by the administration of beta-blockers . Exacerbation of psoriasis during stress may thus be the result of increased release of the neuropeptides, such as calcitonin gene-related peptide, rather than of catecholamines . It should be noted that the effects of catecholamines on the pathomechanism underlying psoriasis is not limited to their action on beta-2-receptors, as these agents also increase prostanoid production and decrease leukotriene production in human polymorphonuclear leukocytes and whole blood, which is not mediated via adrenergic receptors. Decreased prostanoid/leukotriene ratio has been implicated in the pathomechanism of psoriasis .
It has also been shown that peripheral blood lymphocytes contain the acetylcholine biosynthetic and catabolic enzymes, synthesize acetylcholine and express muscarinic cholinergic receptors . These findings suggest the existence of autocrine/paracrine pathways in T-cell-dependent immune responses .
Although stimulation of muscarinic receptors enhanced IL-2 production by the immune cells , it inhibited the cellular immune reactions via inducing the production of PGE2, a potent inhibitor of cellular immune reactions , by CD8+ T-lymphocytes  and decreased the number of IL-2 receptor bearing cells ; these findings were blunted by administration of atropine .
Noteworthy, overexpression of muscaric cholinergic receptors on peripheral blood lymphocytes of asthmatic patients has been implicated in the pathophysiology of this illness, which is characterized by a bias towards the humoral pathway of the immune response .
Conclusively, both β-2 and muscarinc receptors of the immune cells suppress cellular immune responses.
Given that the stimulation of muscarinic and β-2- adrenergic receptors of keratinocytes and immune cells inhibits keratinocyte proliferation as well as cellular immune reactions, the tri- and tetra-cyclic antidepressants (TCAs) exerting the least muscarinic acetylcholine receptor blockade and the most norepinephrine re-uptake blockade (hence producing higher norepinephrine levels in blood and also in the vicinity of keratinocytes and immune cells accumulating in the psoriatic plaques) might be designated as the superior agents for treating the otherwise healthy depressed psoriatic patients and the agents with the reverse effects as the inferior ones.
Desipramine, followed by protryptiline and maprotiline, might thus be designated as the most favorable agents and amitryptiline, followed by trimipramine, as the least favorable agents for this purpose. The other agents of the TCA family lie between these two poles.
Clinical studies on this subject, assessing variations both in mental status and in severity of skin lesions, are warranted.
References1. Gupta MA, Schork NJ, Gupta AK, Kirkby S, Ellis CN. Suicidal ideation in psoriasis. Int J Dermatol 1993; 32: 188-90. PubMed
2. Sharma N, Koranne RV, Singh RK. Psychiatric morbidity in psoriasis and vitiligo: a comparative study. J Dermatol. 2001; 28(8): 419-23. PubMed
3. Namazi MR. Nicotinamide: a potential addition to the anti-psoriatic weaponry. FASEB J (In Press). PubMed
4. Hilliges M, Wang L, Johansson O. Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Invest Dermatol 1995; 104(1): 134-7. PubMed
5. Grando SA. Biological function of keratinocyte cholinergic receptors. J Invest Dermatol Symp Proc 1997; 2: 41-8. PubMed
6. Koizumi H, Yasui C, Fukaya T, Ohkawara A, Ueda T. Beta-adrengergic stimulation induces intracellular Ca++ increase in human epidermal keratinocytes. J Invest Dermatol 1991; 96: 234-7. PubMed
7. Schallreuter KU, Lemke KR, Pittelkow MR, Wood JM, Korner C, Malik R. Catecholamines in human keratinocyte differentiation. J Invest Dermatol Symp Proc 1995; 104: 935-7. PubMed
8. Harper RA, Flaxman BA. Effect of pharamacological agents on human keratinocyte mitosis in vitro II. Inhibition by catecholamines. J Cell Physiol 1975; 86(2 pt 1): 293-9. PubMed
9. Das NS, Chowdary TN, Sobhanadri C, Rao KV. The effect of topical isoprenaline on psoriatic skin. Br J Dermatol 1978; 99(2): 197-200. PubMed
10. Editorial. Stress and the skin. Arch Dermatol 2001; 137: 78-82. PubMed
11. Oberbeck R, Van Griensven M, Nickel E, Tschernig T, Wittwer T, Tape HC. Influence of beta-adrenoceptor antagonists on hemorrhage-induced cellular immune suppression. Shock 2002; 18(4): 331-5. PubMed
12. Harvima IT, Viinamaki H, Naukkarinen A, Paukkonen K, Nei Haanmaki H, Harvima RJ, et al. Association of cutaneous mast cells and sensory nerves with psychic stress in psoriasis. Psychother Psychosom 1993; 60(3-4): 168-16. PubMed
13. Alanko J, Riutta A, Vapaatalo H. Effects of catecholamines on eicosanoid synthesis with special reference to prostanoid/leukotiene ratio. Free Radic Biol Med 1992; 13(6): 677—88. PubMed
14. Ricci A, Amenta F, Bronzetti E, Mannino F, Mariotta S, Tayebati SK. Expression of peripheral blood lymphocyte muscarinic cholinergic receptor subtypes in airway hyperresponsiveness. J Neuroimmunol 2002; 129: 178-85. PubMed
15. Okuma Y, Nomura Y. Roles of muscarinic acetylcholine receptors in interleukin-2 synthesis in lymphocytes. Jpn J Pharmacol 2001; 85(1): 16-9. PubMed
16. Snijdewint FGM, Kalinski P, Wierenga EA, Bos JD, kapsenberg ML. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J Immunol 1993; 150: 5321-9. PubMed
17. Prynce AE, Arzt E, Fernandez Castelo S, Finkielman S, Nahmod V. The inhibitory effect of the muscarinic agonist pilocarpine on lymphocyte activation involves the IL-2 pathway and the increase in suppressor cell function. Int J Neurosci 1992; 62(3-4): 277-85. PubMed
18. Borda ES, Sterin-Borda LJ, Pascual JO, Gorelik G, Felix JC, Von Kreuter BF, et al. Trypanosoma cruzi attachment to lymphocyte muscarinic cholinergic and beta adrenergic receptors modulate intracellular signal transduction. Mol Biochem Parasitol 1991; 47(1): 91-100. PubMed
© 2008 Dermatology Online Journal