Evaluating the role of serotonin on neuropsychological function after breast cancer using acute tryptophan depletion

Abstract

Although cognitive dysfunction is a prevalent and disruptive problem for many breast cancer survivors (BCSs), little research has examined its etiology. One potential mechanism that remains to be explored is serotonin. Serotonin has been implicated in normal and dysfunctional cognitive processes, and serotonin levels are significantly affected by estrogen withdrawal, a common side effect of breast cancer treatment. However, no study has evaluated serotonin's role on cognitive dysfunction in BCSs. The purpose of this study was to examine the role of serotonin in cognitive dysfunction in survivors by lowering central serotonin concentrations via acute tryptophan depletion (ATD). Based on previous research in noncancer populations, we hypothesized that alterations in central serotonin levels would induce cognitive dysfunction in these women controlling for confounding characteristics such as fluctuating mood and glucose levels. Secondarily, we explored whether genetic variations in serotonin genes would partly explain ATD. Participants included 20 female BCSs, posttreatment for nonmetastatic breast cancer, who received ATD or control in a double-blind, crossover design. Cognitive performance was measured at the 5-hr tryptophan/serotonin nadir on each test day using standardized neuropsychological tests. Specific impairment was noted in episodic memory (delayed recall) and motor speed during ATD versus control. ATD did not alter new learning (immediate recall), working memory, verbal fluency, or information processing speed. Findings suggest that serotonin may play a critical role in memory consolidation and motor functioning in BCSs.

Figure 1

Study accrual and retention. This figure details the study accrual, retention, and attrition from the time patients were approached in the clinic, screened for eligibility, expressed interest and consented, and then completed both weeks of study. Data were dropped for one subject due to environmental issues that interfered with the cognitive testing.

Figure 2

Percentage change in serum tryptophan over time during acute tryptophan depletion (ATD) versus control arms. This figure denotes the mean percentage change in tryptophan with standard deviation bars from baseline over time for ATD (solid line with diamonds) compared to control condition (dashed line with squares) for subjects (n = 20). Times 0 to 8 refer to hourly blood draws during each test day. Tryptophan values were not significantly different (p = .46) between randomized groups at baseline, but at the 5-hr nadir when cognitive testing occurred, they had decreased significantly in both conditions and were significantly lower in the ATD condition than in the control condition.

Figure 3

(A) Rey AVLT-delayed recall (memory; top graph) and (B) psychomotor ability (motor speed) for dominant and nondominant hand (bottom graph) by group interaction.

Figure 4

Mean score total mood disturbance and mean glucose level. This figure denotes (A) the mean percentage change in mood disturbance and (B) glucose levels from baseline over time for acute tryptophan depletion (solid line with diamonds) compared to control condition (dashed line with squares) for subjects (n = 20). Mood disturbance was graphed for times 0, 3, 5, and 7 hr and the next day. Blood glucose levels were measured every hr from times 0 to 8 during each test day. Mood disturbance and blood glucose level did not significantly differ between ADT and control conditions (p = .21 and .93, respectively).