Hypobaric hypoxia exposure in rats differentially alters antidepressant efficacy of the selective serotonin reuptake inhibitors fluoxetine, paroxetine, escitalopram and sertraline
Pharmacology Biochemistry and Behavior. 2018-07-01; 170: 25-35
DOI: 10.1016/j.pbb.2018.05.002
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Kanekar S(1), Sheth CS(2), Ombach HJ(2), Olson PR(3), Bogdanova OV(3), Petersen M(2), Renshaw CE(2), Sung YH(2), D’Anci KE(4), Renshaw PF(5).
Author information:
(1)Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt
Lake City, UT, United States; VISN19 MIRECC, 500 Foothill Drive, Salt Lake City,
UT 84148, United States; The Brain Institute, University of Utah, 383 Colorow
Drive, Salt Lake City, UT 84108, United States. Electronic address:
.
(2)Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt
Lake City, UT, United States.
(3)The Brain Institute, University of Utah, 383 Colorow Drive, Salt Lake City, UT
84108, United States.
(4)ECRI Institute, Plymouth, Meeting, PA 19462, United States.
(5)Diagnostic Neuroimaging, Department of Psychiatry, University of Utah, Salt
Lake City, UT, United States; VISN19 MIRECC, 500 Foothill Drive, Salt Lake City,
UT 84148, United States; The Brain Institute, University of Utah, 383 Colorow
Drive, Salt Lake City, UT 84108, United States; Veterans Affairs Salt Lake City
Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148, United States.
Treatment-resistant depression, a chronic condition that affects 30% of depressed
patients on antidepressants, is highly linked to suicidal behavior. Chronic
hypoxia exposure via living at altitude (hypobaric hypoxia) or with chronic
hypoxic diseases is demographically linked to increased risk for depression and
suicide. We previously demonstrated that housing rats at altitude for a week
incrementally increases depression-like behavior in the forced swim test (FST) in
females, but not males. In animal models, high altitude exposure reduces brain
serotonin, and selective serotonin reuptake inhibitors (SSRIs) can lose efficacy
when brain serotonin levels are low. To address whether residence at moderate
altitude is detrimental to SSRI function, we examined SSRI efficacy in the FST
after a week of housing rats at altitudes of 4500 ft. or 10,000 ft. as compared
to at sea level. In females, the tricyclic antidepressant desipramine (positive
control) functioned well in all groups, increasing latency to immobility and
decreasing immobility, by increasing climbing. However, the SSRIs fluoxetine,
paroxetine and escitalopram were ineffective in females in all groups: only
paroxetine improved swimming in the FST as expected of a SSRI, while all three
unexpectedly reduced climbing. Fluoxetine was also ineffective in male rats.
Sertraline was the only SSRI with antidepressant efficacy at altitude in both
females and males, increasing swimming, climbing and latency to immobility, and
reducing immobility. Hypobaric hypoxia thus appears to be detrimental to efficacy
of the SSRIs fluoxetine, paroxetine and escitalopram, but not of sertraline.
Unlike the other SSRIs, sertraline can improve both serotonergic and dopaminergic
transmission, and may be less impacted by a hypoxia-induced serotonin deficit. A
targeted approach may thus be necessary for successful antidepressant treatment
in patients with depression who live at altitude or with chronic hypoxic
diseases, and that sertraline may be the SSRI of choice for prescription for this
population.
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