Hormones and menopausal status as predictors of depression in women in transition to menopause

BACKGROUND: Associations between depressed mood and hormonal changes during transition to menopause are controversial. To our knowledge, there has been no prospective study of these associations in women commencing when they are premenopausal. OBJECTIVE: To longitudinally study the associations among reproductive hormones, menopausal status, and other predictors of depressed mood in midlife women. DESIGN: Cohort study with 6 assessment periods during a 4-year interval. Blood samples were collected 12 times during the follicular phase (days 2-6). SETTING: Philadelphia County, Pennsylvania. PARTICIPANTS: A randomly identified, population-based, stratified sample of African American (n = 218) and white (n = 218) women aged 35 to 47 years with regular menstrual cycles, no hormonal or psychotropic medication use, and no serious physical or mental health problems at enrollment. MAIN OUTCOME MEASURES: Center for Epidemiologic Studies Depression Scale score and history of depression via the Primary Care Evaluation of Mental Disorders. RESULTS: There was an increased likelihood of depressive symptoms during transition to menopause and a decreased likelihood after menopause after adjustment for other predictors of depression, including history of depression, severe premenstrual syndrome, poor sleep, age, race, and employment status (P =.03). The likelihood of depressive symptoms decreased for individuals with a rapidly increasing follicle-stimulating hormone profile (P< or =.001) and also decreased with age compared with premenopausal women (P =.02). Participant aggregate profiles with increasing estradiol levels were significantly associated with depressive symptoms in bivariate analysis (P =.053). CONCLUSIONS: Depressive symptoms as assessed herein increased during transition to menopause and decreased in postmenopausal women. Hormone associations provided corroborating evidence that the changing hormonal milieu contributes to dysphoric mood during transition to menopause.     

Symptoms at the menopausal and premenopausal years: Their relationship with insulin, glucose, cortisol, FSH, prolactin, obesity and attitudes towards sexuality

The symptoms of 81 premenopausal and 70 menopausal women were studied to determine the association with obesity, attitudes towards sexuality (ATS), and diverse hormone values: fasting and postprandial glucose (FG, PG) and insulin (Fl, PI), cortisol, prolactin, follicle-stimulating hormone (FSH). The mean age of the women studied was 49.1 years. The frequency of symptoms was 35.4% for depression, 34.3% for nonspecific symptoms of depression (NSSD), 38.6% for empty nest syndrome (ENS), and 42.3% for anxiety. NSSD, ENS, FSH and cortisol levels all possessed higher values at late-menopausal stage. A multiple regression analysis revealed the following results; NSSD was associated to ATS (negative); sleep alterations were correlated to prolactin, FSH, PI/PG, FI/FG and waist/hip ratio; FSH was associated with both a decreased sexual interest and depression. In the study of hormone levels it was found that cortisol, insulin and FI/FG were associated with ATS; PI, cortisol, FI/FG and PI/PG were associated with body mass index (BMI) and FSH; prolactin and FI/FG were associated with age. We concluded that: (1) data indicative of insulin resistance correlated to both depression and sleep alterations; (2) overweight is related to NSSD, sleep alterations, and hormonal changes.     

Associations of hormones and menopausal status with depressed mood in women with no history of depression

CONTEXT: Whether depressed mood reported in the transition to menopause by women with no history of depression is associated with menopausal status and changes in reproductive hormones is controversial and lacks scientific information. OBJECTIVES: To identify new onset of depressive symptoms and diagnosed depressive disorders in the menopausal transition and to determine the associations of menopausal status, reproductive hormones, and other risk factors with these cases. DESIGN: A within-woman, longitudinal (8-year) study to identify risk factors of depressed mood. SETTING: A subset of a randomly identified, population-based cohort. PARTICIPANTS: Premenopausal women with no history of depression at cohort enrollment. MAIN OUTCOME MEASURES: The Center for Epidemiological Studies of Depression scale (CES-D) was used to assess depressive symptoms, and the Primary Care Evaluation of Mental Disorders (PRIME-MD) was used to identify clinical diagnoses of depressive disorders. RESULTS: High CES-D scores (> or=16) were more than 4 times more likely to occur during a woman's menopausal transition compared with when she was premenopausal (odds ratio, 4.29; 95% confidence interval, 2.39-7.72; P<.001). Within-woman change in menopausal status, increased levels of follicle-stimulating hormone and luteinizing hormone, and increased variability of estradiol, follicle-stimulating hormone, and luteinizing hormone around the woman's own mean levels were each significantly associated with high CES-D scores after adjusting for smoking, body mass index, premenstrual syndrome, hot flashes, poor sleep, health status, employment, and marital status. A diagnosis of depressive disorder was 2(1/2) times more likely to occur in the menopausal transition compared with when the woman was premenopausal (odds ratio, 2.50; 95% confidence interval, 1.25-5.02; P=.01); the hormone measures were also significantly associated with this outcome. CONCLUSION: Transition to menopause and its changing hormonal milieu are strongly associated with new onset of depressed mood among women with no history of depression.     

Neuroendocrine regulation in depressed postmenopausal women and healthy subjects

Results from prior studies utilizing gonadotropin-releasing hormone (GnRH) in affective illness have been contradictory. There have been no systematic investigations of multiple pituitary hormonal responses to GnRH infusion in either depressed or healthy postmenopausal women. Potential abnormalities in the hypothalamic-pituitary-gonadal (HPG) axis may be limited to postmenopausal women who lack the estradiol feedback influence at the pituitary level. We therefore studied 18 depressed and nine healthy postmenopausal women with the GnRH infusion test and measured LH, FSH, prolactin, growth hormone, and thyrotropin responses. Our findings confirmed earlier reports of a lower basal LH concentration in postmenopausal depressed subjects. GnRH stimulated release of LH, FSH, and prolactin in both patients and controls; however, there were no differences in the mean peak hormone values between groups.     

Sleep, rhythms and women's mood. Part II. Menopause

This review summarizes studies of sleep and other biological rhythms in menopausal women with major depression compared with healthy control subjects. Where feasible, we focused on studies in women who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for a major depressive episode (MDE) compared with matched normal control subjects and the Staging System for Reproductive Aging in Women (STRAW) criteria. The aim was to review supporting evidence for the hypothesis that a disruption of the normal temporal relationship between sleep and other biological rhythms, such as melatonin, cortisol, thyroid stimulating hormone (TSH) or prolactin, occur during the menopausal transition. As a result, depressive disorders occur in predisposed women. Treatment strategies, designed to correct these altered phase (timing) or amplitude abnormalities, thereby improve mood. Although there may be some common features to menopausal depression compared with other depressive disorders related to the reproductive cycle (e.g. premenstrual dysphoric disorder or postpartum major depression), such as increased morning melatonin secretion, a specific profile of sleep and biological rhythms may distinguish healthy from depressed women during menopause. Further work is needed to characterize more fully the particular abnormalities associated with well-defined menopausal depression in order to develop treatment strategies targeted more specifically to pathogenesis.     

The citalopram challenge test in patients with major depression and in healthy controls

Neuroendocrine challenge tests in depressed patients have revealed a blunted hormonal reaction to serotonergic stimuli. In the present study, citalopram was chosen as the serotonergic agent for neuroendocrine stimulation. Compared to earlier challenge agents, citalopram has the advantage of serotonergic selectivity, its application is well tolerated and the possibility of intravenous application reduces pharmacokinetic interference. Sixteen patients suffering from an acute episode of major depression and 16 healthy controls underwent the stimulation procedure with 20 mg of citalopram and placebo. Whereas significant differences in the secretion of prolactin and cortisol between citalopram and placebo challenge were observed in the control group, no differences were found in the group of depressed patients. Comparison of depressed patients and controls showed a significantly blunted prolactin secretion in patients. Differences in cortisol secretion following serotonergic stimulation with citalopram did not become significant. The stimulation procedure was well tolerated in all subjects, although a higher number of side effects was observed in the control group. The amount of side effects did not correlate with the hormone responses. These results are in line with the hypothesis of serotonergic hypofunction in depressed patients. In conclusion, the 20-mg citalopram challenge test is thought to be a promising tool for further investigation of serotonergic function in psychiatric illness.     

Prolactin response to D-fenfluramine and suicidal behavior in depressed patients

Previous studies of the prolactin response to D-fenfluramine in depressed patients have yielded inconsistent results. This may be because they did not address the question of suicidality. We carried out this study to test the hypothesis that lower prolactin response to D-fenfluramine is more closely associated with suicidal behavior than with depression itself. A D-fenfluramine test was performed in a sample of 18 healthy control subjects and in 85 drug-free inpatients with a DSM-III-R diagnosis of major depressive episode (49 with a history of suicide attempt, 36 without). Depressed inpatients with a history of suicide attempt showed a significantly lower prolactin response to D-fenfluramine compared to depressed inpatients without such a history and compared to control subjects. Healthy control subjects and depressed inpatients without a history of suicide attempt showed comparable levels of prolactin after D-fenfluramine. Time elapsed since suicide attempt did not influence prolactin level (baseline or post-stimulation). Results show that in our depressed drug-free inpatient sample, prolactin response to D-fenfluramine seems to be a marker of suicidality, but not of depression itself. We suggest that it is a trait marker of suicidality.     

HPA-Axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors.

2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed.

3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist.

4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), B endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values.

5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.     

Prolactin hyperresponsiveness to D-fenfluramine in drug-free schizophrenic patients: a placebo-controlled study.

BACKGROUND: Functional alterations in the central serotonergic system have been reported in schizophrenia but no conclusive data have been provided. In the present study, we investigated the prolactin (PRL) response to the selective serotonin (5-HT) releasing agent D-fenfluramine in both patients with schizophrenia and matched healthy subjects. METHODS: Sixteen drug-free schizophrenics and 16 healthy subjects were randomized in a double-blind neuroendocrine test to D-fenfluramine (30 mg p.o.) or placebo. Blood PRL and cortisol concentrations were determined by radioimmunoassay, while plasma levels of D-fenfluramine were measured by mass spectrometry. RESULTS: In schizophrenic patients, baseline plasma PRL levels were not different from controls, whereas plasma cortisol concentrations were significantly increased (p < .03). The PRL response to D-fenfluramine was significantly enhanced in patients as compared to matched control subjects (p < .005). Schizophrenics meeting Kane's criteria for previous nonresponse to typical neuroleptics exhibited a PRL response to D-fenfluramine significantly higher than non-drug-resistant patients (p < .04). No significant difference in plasma D-fenfluramine concentrations was observed between schizophrenic and healthy subjects. CONCLUSIONS: These findings suggest a serotonergic hypersensitivity in chronic schizophrenia. This alteration seems to be peculiar to those patients refractory to typical neuroleptics.     

Hormone responses to fenfluramine and placebo challenge in endogenous depression.

Plasma prolactin and cortisol levels after oral administration of d-l fenfluramine hydrochloride (60 mg) and placebo were examined in 24 endogenously depressed patients and 21 age- and sex-matched normal control subjects in a randomized, double-blind study. Prolactin levels were significantly increased by fenfluramine in both groups, but the response was significantly blunted in the depressed patients compared with the controls. This effect was partially dependent upon elevated baseline cortisol levels in the depressed group and was also influenced by a history of weight loss. Plasma cortisol levels were not increased by fenfluramine in either group. These findings confirm previous reports and suggest that patients with endogenous major depression are characterized by central serotonergic hyporesponsivity. The need to account for baseline effects on hormonal responses to putative serotonergic agents is supported by the findings; however, these effects appear to be less striking when endogenicity is a prominent clinical feature of the depressive syndrome. The apparently complex influence of weight loss on prolactin response to serotonergic challenge remains to be clarified as well as the role played by the bioavailability of the challenge drug and its metabolite.     

The associations between menopausal syndrome and depression during pre-, peri-, and postmenopausal period among Taiwanese female aborigines

Aim:  The aim of the study was to evaluate the association between physiological menopausal symptoms and depression during the pre-, peri-, and postmenopausal period among female Taiwanese aborigines.
Methods:  A total of 672 Taiwanese aboriginal women, aged 40–60 years, were recruited in the interviewing study and classified as pre-, peri-, and postmenopausal according to menstrual bleeding patterns in the previous 12 months. Then, the postmenopausal symptoms, depression, self-perceived health, family support, and associated demographic variables were assessed by questionnaire based on the results of interviewing by research assistants.
Results:  The results revealed that perimenopausal statuses are associated with depression and women with a perimenopausal status had a higher prevalence of depression than those with a premenopausal status. A higher score on physiological postmenopausal symptoms was found to be significantly associated with depression. Furthermore, somatic symptoms were associated with depression for pre-, peri-, and postmenopausal statuses. Moreover, sexual dysfunction and vasomotor symptoms were associated with depression only in the premenopausal status and postmenopausal status, respectively.
Conclusion:  Depression should be routinely evaluated for female Taiwanese aborigines consulting with physicians for menopause symptoms, especially for somatic symptoms. Furthermore, attention should be provided to premenopausal women with sexual dysfunction and postmenopausal women with vasomotor symptoms for depression.     

Assessment and treatment of hot flushes and menopausal mood disturbance.

More than 1 million women are expected to reach menopause each year, many of whom will experience hot flushes and other neuropsychological symptoms that may diminish their quality of life. Hot flushes are the core symptoms that reflect the brain's response to the changing hormonal milieu of the menopause transition, particularly to the rapidly fluctuating and falling levels of estradiol. The physical symptoms of hot flushes and the associated changes in sleep, mood, and cognition will lead many women to seek medical care. It is critical to understand the interrelationship of hot flushes and other neuropsychological symptoms of the menopause transition so that treatment priorities can be established. For example, if sleep disruption explains most daytime neuropsychological problems in women with hot flushes, treating insomnia should be considered a priority. Alternatively, mood, cognition, and quality of life may be disturbed independent of sleep problems. In such a situation, each symptom should be evaluated separately from any assessment of sleep. As recent data from the WHI establish the risks of long-term HRT use, concern about using HRT, even as a short-term intervention, has increased substantially. Although HRT remains the first-line treatment for hot flushes, the WHI findings have drawn attention to nonhormonal treatments of hot flushes and other menopausal symptoms. Growing evidence to support the efficacy of serotonergic antidepressants and other psychoactive medications in the treatment for hot flushes suggests that nonhormonal interventions will prove important alternatives to HRT. As further evidence of the benefits of psychoactive medications for menopausal symptoms is established, the choice between using hormonal and nonhormonal therapies for management of menopausal symptoms will continue to evolve.     

Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles

CONTEXT: Transition to menopause has long been considered a period of increased risk for depressive symptoms. However, it is unclear whether this period is one of increased risk for major depressive disorder, particularly for women who have not had a previous episode of depression. OBJECTIVE: To examine the association between the menopausal transition and onset of first lifetime episode of depression among women with no history of mood disturbance. DESIGN: Longitudinal, prospective cohort study. SETTING: A population-based cross-sectional sample. PARTICIPANTS: Premenopausal women, 36 to 45 years of age, with no lifetime diagnosis of major depression (N = 460), residing in 7 Boston, Mass, metropolitan area communities.Main Outcome Measure Incidence of new onset of depression based on structured clinical interviews, Center for Epidemiologic Studies Depression Scale scores, and an operational construct for depression. RESULTS: Premenopausal women with no lifetime history of major depression who entered the perimenopause were twice as likely to develop significant depressive symptoms as women who remained premenopausal, after adjustment for age at study enrollment and history of negative life events. The increased risk for depression was somewhat greater in women with self-reported vasomotor symptoms. CONCLUSIONS: The current study suggests that within a similarly aged population of women with no lifetime history of depression, those who enter the menopausal transition earlier have a significant risk for first onset of depression. Further studies are needed to determine more definitively whether other factors, such as the presence of vasomotor symptoms, use of hormone therapy, and the occurrence of adverse life events, independently modify this risk. Physical symptoms associated with the menopausal transition and mood changes seen during this period may affect many women as they age and may lead to a significant burden of illness.     

Investigating the effects of estradiol or estradiol/progesterone treatment on mood, depressive symptoms, menopausal symptoms and subjective sleep quality in older healthy hysterectomized women: a questionnaire study

Clinical studies have documented that estrogen treatment often ameliorates mood disturbances and depressive symptoms occurring during the menopausal transition. The relevance of gonadal hormones for mood and well-being in healthy older nondepressed women is less well understood. Fifty-one healthy hysterectomized women (mean age 64) participated in a placebo-controlled double-blind study on the effects of gonadal hormones on cognition. They received either estradiol (2 mg estradiol valerate), estradiol plus progesterone (100 mg micronized progesterone) or placebo. Mood, well being, menopausal symptoms, depressive symptoms and subjective sleep quality were measured at baseline and after 4 and 24 weeks of treatment using three questionnaires. Thirty-five women could be included into the final analysis. Strong increases in estradiol and progesterone levels occurred in response to the treatment. The two hormones, however, had no effects on mood, well-being, menopausal symptoms, sleep quality and depressive symptoms. The current small study suggests that older healthy nondepressed hysterectomized women do not react with positive or negative mood changes to estradiol or estradiol/progesterone treatment.     

Prolactin response to fenfluramine administration in patients with unipolar and bipolar depression and healthy controls

The hormonal response to the serotonin releasing agent/uptake inhibitor fenfluramine has been used as an indicator of central serotonin system function. The serotonergic system plays an important role in the etiology and pathogenesis of mood disorders. We compared the prolactin response to fenfluramine administration in unipolar depressed patients (major depressive disorder), depressed patients with bipolar disorder, and healthy controls. We found a trend towards a blunted prolactin response in depressed patients compared to healthy controls, after controlling for sex, family history, family history-by-gender interaction, and baseline levels. There was no significant difference between unipolar and bipolar patients in the baseline prolactin levels or the response to the fenfluramine administration. We also found a negative correlation between aggression and impulsivity scores and prolactin responses in subgroup with unipolar but not bipolar depression. Female patients with unipolar depression who had first-degree relatives with unipolar depression and normal controls had significantly higher prolactin responses than female patients with unipolar depression who did not have first-degree relatives with unipolar depression. The lack of difference in the response to fenfluramine administration between unipolar and bipolar depressed patients may indicate that overall serotonergic function in unipolar and bipolar depressed patients is similarly impaired.     

Effects of Menopause on Seizures in Women with Epilepsy

Summary: Purpose: Although important associations between epilepsy and women's hormonal phases are described, the relation of menopause to epilepsy has received little attention. Methods: By using a structured interview, we studied menopausal women with epilepsy seen at the University of Maryland Epilepsy Center over a 1-year period from 1994 to 1995. We analyzed the characteristics and temporal relation of the seizures to menopause and compared the frequency and severity of the seizures with those in a similar group of premenopausal women. Results: We identified 61 menopausal women (46 who were postmenopausal and 15 perimenopausal) and compared them with 46 premenopausal women. No statistically significant differences were noted in either the frequency or the severity of seizures comparing all menopausal or only postmenopausal with premenopausal women. However, 12 (20%) of the 61 menopausal women noted that their seizures first began during or after menopause, with eight having no proven cause for their seizures. Many individual women described changes in their seizures with menopause. Among the 61 menopausal women, 49 had established epilepsy before the onset of menopause, and 20 (41%) reported worsening of their seizures with menopause, 13 (27%) noted improvement, and 16 (33%) described no changes. These observations were similar for peri- and post-menopausal women. Of the 15 menopausal women taking hormone replacement therapy, the six taking progestin were significantly less likely to report worsening of their seizures. Conclusions: These findings support the view that hormonal influences are important in women with seizures. Although, in aggregate, menopausal (combined perimenopausal and post-menopausal) and postmenopausal women's seizures were similar in frequency and severity to those of other women, menopause was associated with changes in seizures for some women. Moreover, menopause may be a previously unrecognized factor for some new-onset seizures. The relations between menopause and epilepsy deserve to be more fully investigated.     

Serotonin dysregulation in adolescents with major depression: hormone response to meta-chlorophenylpiperazine (mCPP) infusion

This study examined central serotonin disturbance, as reflected by neuroendocrine hormones, among adolescents with major depression. Prolactin, cortisol, and growth hormone were measured following the infusion of a serotonin agonist, meta-chlorophenylpiperazine (mCPP). Twelve (M=6, F=6) medication-free adolescents with major depression (MDD) were compared with 12 (M=6, F=6) matched normal control subjects, ranging in age from 13 to 17 years. Baseline evaluations and a battery of laboratory tests were completed. mCPP, 0.1 mg/kg i. v., was administered in a placebo-controlled design. Analyses of the neuroendocrine hormones revealed that the depressed group had a higher baseline prolactin level and an augmented prolactin response to mCPP challenge than did the control group. The depressed group experienced a sharper baseline-cortisol decline between 08.00 and 11.00 h, and compared to control subjects they displayed an augmented response to the challenge. The depressed group reported more side effects than the control group during saline infusion, but not during mCPP infusion. Findings suggest that depressed adolescents have an elevated baseline prolactin level, and also experience enhanced prolactin and cortisol responses to the serotonergic challenge. These preliminary findings will be confirmed during our ongoing study.     

Growth hormone and other hormonal responses to clonidine in melancholic and nonmelancholic depressed subjects and controls.

To study putative differences in central neurotransmitter function in depressive subtypes, growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin responses to the alpha 2-noradrenergic receptor agonist clonidine (1.3 micrograms/kg i.v.) were examined in 26 subjects with major depression, 13 of whom had melancholia. The responses of 10 of these endogenous/melancholic subjects were compared with those of 10 controls who were matched to the patients on age, sex, and menopausal status. In 15 of the depressed subjects, prolactin and cortisol responses to the putative serotonergic agonist fenfluramine were also examined to test for associations between these challenges. There were no significant differences in any of the responses between melancholic and nonmelancholic depressive subgroups after controlling for age and sex. With the exception of a greater reduction in ACTH in the endogenous/melancholic subjects, there were also no significant differences in hormonal responses between these patients and controls. There was, however, a significantly greater reduction in systolic blood pressure in the control subjects. There were no significant correlations between the responses to clonidine and fenfluramine. The findings suggest that clonidine at a dosage of 1.3 micrograms/kg is neither able to differentiate reliably between depressive subtypes nor to differentiate reliably between depressed and control subjects.     

Effect of age, gender, menopausal status, and ovarian hormonal level on rTMS in treatment-resistant depression

This study examines how gender and menopausal status contribute to age effect on the antidepressant efficacy of repetitive transcranial stimulation (rTMS). Thirty-one women (17 premenopausal, 14 postmenopausal), and 16 men with treatment-refractory bipolar/major depression underwent 10 consecutive sessions of rTMS. Mood symptoms and female hormones were measured. ANOVA-R revealed a significant gender (p<0.05) and time effect (p<0.001) on the Hamilton Depression Rating Scale (HAM-D) score. Percentage reduction of the rating correlated negatively with age in women (p<0.001). While no difference in the rTMS response was observed between male and premenopausal female patients (68.8% and 70.6%, respectively), postmenopausal women responded least (0%). We also found that greater improvement of depression score was associated with a higher estradiol/progesterone ratio in premenopausal women (p<0.05), suggesting an important role of female hormones in the therapeutic response. Regression analysis revealed that menopausal status and ovarian steroid levels, but not age, were the main determinants of antidepressant efficacy of rTMS in females. This is the first study to specifically investigate the effect of female hormones on rTMS therapeutic effect. Our data support changes in menopausal status and ovarian steroid levels as effectors of mood and the CNS neural substrate response to rTMS in refractory depression. However, the restricted number of patients and the shorter duration of rTMS treatment and follow-up might influence its generalization. Further study examining the interactions between mood, ovarian hormones, and rTMS treatment is warranted.     

Neurohormonal responses to D-fenfluramine in healthy elderly subjects. A placebo-controlled study

Considering age-related changes in serotonin (5HT) function, we examined normative data of prolactin (PRL) and cortisol (CORT) responses to D-fenfluramine (D-FEN) in healthy elderly subjects. Twenty-three healthy male and female volunteers aged 60-86 participated in a single-blind, placebo-controlled, fixed-order, crossover-design challenge test. Two baseline PRL and CORT values and the responses of these hormones to 30 mg of oral D-FEN and placebo over a 4 h period were measured on two separate sessions. PRL and CORT responses were significantly greater following D-FEN than after placebo. Peak PRL responses (maximum change from baseline following D-FEN) were relatively robust compared to peak CORT responses. Peak PRL concentration was positively correlated with plasma D-nor-FEN concentration. Gender and aging had no effect on hormonal responses in the elderly. Although the weight adjusted dose used in this study was higher than the therapeutic dose of D-FEN, PRL responses were modest and only two participants experienced side effects. D-FEN is a safe serotonergic probe and PRL responsivity to D-FEN is a reliable index of central 5HT function in the elderly. An age-related decline in serotonergic function must be considered in determining the dose requirement for maximal hormonal responses to D-FEN challenge tests in the elderly.