Role of Antidepressants in cancer therapeutics:

A review of Julian Lieb's study titled "The multifaceted value of antidepressants in cancer therapeutics"

By Kottapurath Kunjumoideen MD

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Recently I have seen an interesting article by Julian Lieb titled "The multifaceted value of antidepressants in cancer therapeutics" and I saw some very interesting concepts in this article. In this review I am trying to look in to some of the theories and findings presented by Dr. Julian Lieb in this article (Ref 1).

Julian Lieb, M.D is a retired, Yale medical school psychiatry professor. His major interest is immunopharmacology of infectious disorders and cancer in which he is a recognized authority. Dr. Julian Lieb has authored or coauthored forty- five articles and nine books.

It has been shown that depression can predispose a person to infections, cancer, osteoporosis and degenerative diseases of the nervous system (Ref 2, 3). In a patient with depression excessive amounts of prostaglandin is produced which is responsible for this increased vulnerability of patients with depression to other disorders mentioned above (Ref 2, 3). Prostaglandins are believed to have regulatory influence on every component of the cellular microenvironment (Ref 4, 5).

Carcinogenesis is a complex mechanism and include among factors an up-regulation of cyclooxygenase, oncogene synthesis and expression, viral activation, signal disruption, accelerated cell replication, failed apoptosis, tumor initiation and promotion, angiogenesis, metastasis, immunosuppression and autoimmunity (Ref 1). These are intimately connected with prostaglandins and enzymes involved in their metabolism (Ref 6, 7, 8, 9, 10)

It has been shown that drugs used to treat depression like lithium have potent anti-prostaglandin, immunostimulating effects (Ref 11, 12). In addition lithium have antiviral, antibacterial, antiparasitic and fungicidal properties. Antidepressants have a paradoxical ability to reverse autoimmunity (Ref 2, 3).

Chronically depressed people over the age of 70 years are 88% more likely to develop cancer than their comparable peer without depression (Ref 13). Based on this theory Dr. Lieb theorizes that antidepressants may have a potential role in cancer treatment (Ref 1). Many in vitro studies have shown that antidepressants may have anti-cancer properties (ref 14, 15, 16, 17).

Antidepressants may have other uses in cancer patients. Antidepressants have been used to treat hot flashes associated with chemotherapy. A word of caution goes here with regard to treatment of hot flashes related to tamoxifen treatment for breast cancer. Studies have shown that use of antidepressants may interfere with the beneficial effects of tamoxifen . Hence use of antidepressants for the treatment of tamoxifen induced hot flashes needs further evaluation (Ref 18, 19). Venlafaxine (Effexor) can remit acute neurosensory symptoms secondary to oxaliplatin chemotherapy (Ref 20).

It remains to be determined whether antidepressants alone can reverse malignancies, and whether or when they need to be combined with chemotherapy or radiation (Ref 1).

Dr. Lieb's article is thought provoking. And his theories should be tested in phase I and phase II clinical trial.

References

1. Lieb, J. The multifaceted value of antidepressants in cancer therapeutics.: Eur J Cancer 44 (2008) 172-174
2. Lieb, J.”Remission of rheumatoid arthritis and other disorders of immunity in patients taking with monoamine oxidase inhibitors.” Int J Immunopharmac. (1983); 3 (4).353-357
3. Lieb, J. The immunostimulating and antimicrobial properties of lithium and antidepressants. J Infection (2004) 49(2) 88-93
4. Fitzpatrick FA. Cyclooxygenase enzymes: regulation and function. Curr Pharm Des. 2004;10(6):577–588.
5. Horrobin DF, Manku MS. Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anesthetic, anti-arrhythmic, anti-malarial, tricyclic anti-depressant and methyl xanthine compounds. Effects on membranes and on nucleic acid function. Med Hypotheses. 1977;3(2):71–86.
6. Lieb J. Antidepressants, prostaglandins and the prevention and treatment of cancer. Med Hypotheses. 2007;69:684–689. Abstract | Full Text | Full-Text PDF (120 KB) | CrossRef
7. Lieb J. Antidepressants, eicosanoids and the prevention and treatment of cancer. Plefa. 2001;65(5–6):233–239.
8. Williams ED, Karim SMM, Sandler M. Prostaglandin secretion by medullary carcinoma of the thyroid. Lancet. 1968;1:22–23.
9. Goodwin JS, Murphy S, Bankhurst AD, et al. Prostaglandin-producing suppressor cells in Hodgkin’s disease. New Engl J Med. 1977;297:963–968.
10. Pace E, Siena L, Ferraro M, et al. Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis. Eur J Cancer. 2006;42(14):236–239
11. Ballin A, Gershon V, Brener J, Weizman A, Meytes D. The antidepressant fluvoxamine increases natural killer cell counts in cancer patients. Isr J Med Sci. 1997;33(11):720–723.
12. Frank M, Hendricks S, Johnson D, et al. Antidepressants augments natural killer cell activity: in vivo and in vitro. Neuropsychobiology. 1999;39(1):18–24. CrossRef
13. Penninx BW, Guralnik JM, Pahor M, et al. Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst. 1998;90(24):1888–1893
14. Levkovitz Y, Gil-Ad I, Zeidich E, et al. Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for p-c-Jun, cytochrome c, and caspase-3 involvement. J Mol Neurosci. 2005;27(1):29–42.
15. Arimochi H, Morita K. Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells. Eur J Pharmacol. 2006;541(1-2):17–23.
16. Volpe DA, Ellison CD, Parchment RE, Grieshaber CK, Faustino PJ. Effects of amitriptyline and fluoxetine upon the in vitro proliferation of tumor cell lines. J Exp Ther Oncol. 2003;3(4):169–184.
17. Peer D, Margalit R. Fluoxetine and reversal of multidrug resistance. Cancer Lett. 2006;237(2):180–187.
18. Vered et al. Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine. JNCI 2003 95(23):1758-1764
19. Goetz et al. A Hot Flash on Tamoxifen Metabolism: JNCI 2003 95(23):1734-1735
20. Durand JP, Brezault C, Goldwasser F. Protection against oxaliplatin acute neurosensory toxicity by venlafaxine. Anticancer Drugs. 2003;i14(6):423–425.