Abstract
Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001).Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications.
Highlights
Depression is common in ovarian cancer patients, with a recent study reporting that 55% of newly diagnosed patients suffer from clinical or subclinical depression. [1] Management of depression is important in oncology patients as it may negatively impact quality of life, [2, 3] adherence to medical regimens, [4] decision making [5] and cancer outcomes. [6, 7] Antidepressants are commonly prescribed to treat depression in cancer patients
selective serotonin-reuptake inhibitors (SSRIs) were analyzed separately due to small sample size for other classes of antidepressants
Key findings of this study are that SSRIs are associated with a decreased time to disease progression after adjusting for significant covariates, they are not associated with overall survival
Summary
Depression is common in ovarian cancer patients, with a recent study reporting that 55% of newly diagnosed patients suffer from clinical or subclinical depression. [1] Management of depression is important in oncology patients as it may negatively impact quality of life, [2, 3] adherence to medical regimens, [4] decision making [5] and cancer outcomes. [6, 7] Antidepressants are commonly prescribed to treat depression in cancer patients. [8] It is unclear how best to manage depression in cancer populations since there have been reports that antidepressants, SSRIs and TCAs, may promote tumor growth in preclinical experimental models for various cancers. Animal experiments have demonstrated inhibition of lymphocyte proliferation and growth-promoting effects of SSRIs on mammary tumors, melanoma, and fibrosarcoma. [12] The potential for antidepressants to promote tumor growth has led to various epidemiologic studies examining the risk of developing cancer among antidepressant users. [30] Selectiveserotonin reuptake inhibitors (SSRIs) are designed to increase 5-HT levels in the synaptic cleft by inhibiting SERT reuptake of 5-HT. Outside of their designed function, SSRIs decrease reuptake of 5-HT by platelets through binding of SERT. Outside of their designed function, SSRIs decrease reuptake of 5-HT by platelets through binding of SERT. [30, 31] Consequences of changes to peripheral 5-HT regulation are poorly understood and have important implications regarding tumor growth in cancer patients
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