Evaluating the role of serotonin in hot flashes after breast cancer using acute tryptophan depletion

Abstract

Objective: Among women with breast cancer, hot flashes are frequent, severe, and bothersome symptoms that can negatively impact quality of life and compromise compliance with life-saving medications (eg, tamoxifen and aromatase inhibitors). Clinicians' abilities to treat hot flashes are limited due to inadequate understanding of physiological mechanisms involved in hot flashes. Using an acute tryptophan depletion paradigm, we tested whether alterations in central serotonin levels were involved in the induction of hot flashes in women with breast cancer.

Methods: This was a within-participant, double-blind, controlled, balanced, crossover study. Twenty-seven women completed two 9-hour test days. On one test day, women ingested a concentrated amino acid drink and encapsulated amino acids (no tryptophan) according to published procedures that have been shown to have specific effects on serotonin within 4.5 to 7 hours. On the other test day, women ingested a control drink. Serial venous blood sampling and objective hot flash monitoring were used to evaluate response to each condition.

Results: Response to acute tryptophan depletion was variable and unexplained by use of selective serotonin reuptake inhibitors, antiestrogens, breast cancer disease and treatment variables, or genetic polymorphisms in serotonin receptor and transporter genes. Contrary to our hypothesis, hot flashes were not worsened with acute tryptophan depletion.

Conclusions: Physiologically documented and self-reported hot flashes were not exacerbated by tryptophan depletion. Additional mechanistic research is needed to better understand the etiology of hot flashes.

Figure 1. Study Accrual and Retention

Legend: This figure shows the participant flow with attrition throughout the study. The Ham-D phone interview refers to the study psychologist verifying eligibility as non-depressed using the Hamilton Rating Scale-Depression (score ≤ 18) .

Figure 2. Safety Monitoring During Acute Tryptophan Depletion (ATD) and Control Arm

(2a) Hamilton Rating Scale-Depression Scores Legend: This figure denotes the mean Hamilton Rating Scale-Depression score at each time point for the study sample (n=27): initial screening to verify eligibility (as assessed by the study psychologist), at discharge from the study visit (as assessed by the study psychologist), and the following day (as assessed by a trained nurse). The solid square refers to the active amino acid drink and the open square to the control drink. Scores remained below 18 (cutoff for depression) at all time points and for both study arms. (2b) Profile of Mood States Total Mood Disturbance Scores Legend: This figure denotes the Profile of Mood Disturbance Total Mood Disturbance Score at each time point for the study sample (n=27). The solid square refers to the active amino acid drink and the open square to the control drink. Hours 0 to 7 were during the test day for each condition. Total mood disturbance scores were not significantly different over time (p > .20). (c) Number and Severity of Side Effects Legend: This figure denotes the number and mean severity of side effects over time for each condition. Subjects (n=27) indicated if they were having symptoms using a checklist and the number they endorsed was summed to calculate the total number of symptoms. For each symptom that they endorsed, subjects rated severity from 0 (not at all) to 4 (extremely) severe. Mean severity for all symptoms endorsed was calculated (total severity/total number of symptoms). The closed triangle and circle refer to the active amino acid drink and the open triangle and circle to the control drink. Hours 0 to 7 were during the test day for each condition. Number and severity of symptoms were not significantly different between study arms over time (p > .20).

Figure 2. Safety Monitoring During Acute Tryptophan Depletion (ATD) and Control Arm

(2a) Hamilton Rating Scale-Depression Scores Legend: This figure denotes the mean Hamilton Rating Scale-Depression score at each time point for the study sample (n=27): initial screening to verify eligibility (as assessed by the study psychologist), at discharge from the study visit (as assessed by the study psychologist), and the following day (as assessed by a trained nurse). The solid square refers to the active amino acid drink and the open square to the control drink. Scores remained below 18 (cutoff for depression) at all time points and for both study arms. (2b) Profile of Mood States Total Mood Disturbance Scores Legend: This figure denotes the Profile of Mood Disturbance Total Mood Disturbance Score at each time point for the study sample (n=27). The solid square refers to the active amino acid drink and the open square to the control drink. Hours 0 to 7 were during the test day for each condition. Total mood disturbance scores were not significantly different over time (p > .20). (c) Number and Severity of Side Effects Legend: This figure denotes the number and mean severity of side effects over time for each condition. Subjects (n=27) indicated if they were having symptoms using a checklist and the number they endorsed was summed to calculate the total number of symptoms. For each symptom that they endorsed, subjects rated severity from 0 (not at all) to 4 (extremely) severe. Mean severity for all symptoms endorsed was calculated (total severity/total number of symptoms). The closed triangle and circle refer to the active amino acid drink and the open triangle and circle to the control drink. Hours 0 to 7 were during the test day for each condition. Number and severity of symptoms were not significantly different between study arms over time (p > .20).

Figure 2. Safety Monitoring During Acute Tryptophan Depletion (ATD) and Control Arm

(2a) Hamilton Rating Scale-Depression Scores Legend: This figure denotes the mean Hamilton Rating Scale-Depression score at each time point for the study sample (n=27): initial screening to verify eligibility (as assessed by the study psychologist), at discharge from the study visit (as assessed by the study psychologist), and the following day (as assessed by a trained nurse). The solid square refers to the active amino acid drink and the open square to the control drink. Scores remained below 18 (cutoff for depression) at all time points and for both study arms. (2b) Profile of Mood States Total Mood Disturbance Scores Legend: This figure denotes the Profile of Mood Disturbance Total Mood Disturbance Score at each time point for the study sample (n=27). The solid square refers to the active amino acid drink and the open square to the control drink. Hours 0 to 7 were during the test day for each condition. Total mood disturbance scores were not significantly different over time (p > .20). (c) Number and Severity of Side Effects Legend: This figure denotes the number and mean severity of side effects over time for each condition. Subjects (n=27) indicated if they were having symptoms using a checklist and the number they endorsed was summed to calculate the total number of symptoms. For each symptom that they endorsed, subjects rated severity from 0 (not at all) to 4 (extremely) severe. Mean severity for all symptoms endorsed was calculated (total severity/total number of symptoms). The closed triangle and circle refer to the active amino acid drink and the open triangle and circle to the control drink. Hours 0 to 7 were during the test day for each condition. Number and severity of symptoms were not significantly different between study arms over time (p > .20).

Figure 3. Percentage Change in Serum Tryptophan Over Time During Acute Tryptophan Depletion (ATD) Versus Control Arms

Legend: This figure denotes the percentage change in tryptophan from baseline over time for each study arm (n=27). Times 0 to 8 refer to hourly blood draws during each test day. The solid square refers to the active amino acid drink and the open square to the control drink. Repeated measures analysis indicated that tryptophan values were not significantly different (p=.46) between randomized groups at hours 0, 1, or 2 but were significantly lower in the acute tryptophan depletion group compared to control group at hour 3 (p < .01) and hours 4, 5, 6, 7, and 8 (p < .001). Significant differences are shown with an asterisk next to the time point (i.e. hours 3 through 8).