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Psychosomatic Medicine 62:231-237 (2000)
© 2000 American Psychosomatic Society

ORIGINAL ARTICLES

Does Socioeconomic Status Relate to Central Serotonergic Responsivity in Healthy Adults?

Karen A. Matthews, PhD, Janine D. Flory, PhD, Matthew F. Muldoon, MD and Stephen B. Manuck, PhD

From the Department of Psychiatry (K.A.M.), Center for Clinical Pharmacology (M.F.M.), and Department of Medicine (M.F.M.), University of Pittsburgh School of Medicine, Pittsburgh, PA; and Department of Psychology (J.D.F., S.B.M.), University of Pittsburgh, Pittsburgh, PA.

Address reprint requests to: Karen A. Matthews, PhD, Department of Psychiatry, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213. Email: matthewska{at}msx.upmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: We tested whether low SES was associated with reduced central serotonergic responsivity in a community sample of adult men and women and the extent to which standardized measures of aggression and impulsivity mediate the association.

METHODS: A total of 270 adults who were enrolled in a clinical trial on the neurobehavioral effects of lipid lowering were given a neuropharmacologic challenge (plasma prolactin response to orally administered fenfluramine) to measure serotonergic responsivity. Measures of family income and educational attainment were standardized and summed to derive an overall index of SES. Scores from the Brown-Goodwin Life History of Aggression interview, the Barratt Impulsiveness Scale, and the Angry Hostility subscale from the NEO Personality Inventory were also standardized and summed to form an aggression/impulsivity score.

RESULTS: Low SES was correlated with low prolactin responses to the fenfluramine challenge in the full sample (r = .15) as well as in whites, men, and women evaluated separately. Although the standardized SES score was correlated inversely with aggression/impulsivity measure (r = -.19, p < .01), the association between SES and prolactin responses remained significant when statistical adjustments were made for age, gender, body mass index, and aggression/impulsivity scores.

CONCLUSIONS: Blunted serotonergic responsivity is associated with low social class as measured by annual family income and educational attainment.

Key Words: socioeconomic status • serotonin • aggression • impulsivity • hostility

Abbreviations: SES = socioeconomic status; 5-HIAA = 5-hydroxyindoleacetic acid; 5-HT = 5-hydroxytryptamine, serotonin; PRL = prolactin; LHA = Life History of Aggression.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Low SES is a powerful predictor of premature mortality and morbidity in the US and in other developed countries (eg, Refs. 1 and 2; see Refs. 3 and 4 for reviews). This relationship does not seem to simply be due to poverty. Rather, with each increment in status, there is an accompanying increase in longevity and well being (3). Access to medical care also does not completely account for the relationships between socioeconomic status and health because countries having universal health care also exhibit the gradient, although less steeply (5–8).

One specific factor that is likely to be important to understanding the SES-health gradient is exposure to a stressful social environment. Indeed, available data show that low SES individuals report more stressful life events than do high SES individuals (9). Low SES individuals are exposed to more episodes of physical and psychological violence and are more often victims of violence than are high SES individuals, even as children (10, 11).

Animal studies show that a stressful social environment can have long-lasting behavioral effects and, furthermore, that these behavioral effects are associated with alterations in brain serotonergic systems. Rats deprived of maternal attention during the first 7 days of life later show larger physiological responses to stress and more signs of fearfulness than rats not deprived of maternal attention. These greater responses are associated with decreased serotonin turnover in the hippocampus (12–14). Similarly, rhesus monkeys without normal maternal care in the first 6 months of life later have reduced brain serotonin turnover as well as increased reactivity to stress, increased alcohol preference, increased aggression, and decreased affiliative behaviors (15–17). In female rhesus monkeys, variability of the cerebrospinal fluid concentration of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), correlates positively with social rank (18). Additionally, cynomolgus monkeys exposed to past social perturbation (recurrent reorganization of group housing membership) had lower concentrations of serotonin (5-HT) and 5-HIAA in the prefrontal cortex than monkeys exposed to stable conditions of housing or recent group reorganization. No differences were found in dopamine, norepinephrine, or their metabolites (19). These data suggest that chronic social stress may induce long-term changes in brain serotonergic activity in nonhuman primates. If applicable to humans, these findings suggest that low SES, by virtue of exposure to chronic stress, may also be associated with reduced central serotonergic function.

Individual differences in aggression and impulsivity are associated with variability in central serotonergic function in a variety of clinical and forensic populations (20–24). We recently reported that reduced serotonergic responsivity indexed by neuropharmacologic challenge (plasma prolactin response to orally administered fenfluramine) was associated with high scores on trait measures of aggression and impulsivity in a sample of healthy adults, without any current or past history of DSM-III-R Axis I pathology (25). In other samples, low SES individuals have been more hostile, aggressive, and depressed relative to their high SES counterparts (26). These characteristics themselves are associated with coronary heart disease morbidity and all cause mortality (27–29). Indeed, Williams (30) has hypothesized that reduced central serotonergic function may account for the clustering of hostility, aggressiveness, and depressive symptoms and may aid in understanding why low SES is linked to poor health.

The primary purpose of the present investigation is to assess the association between indicators of social class and central serotonergic responsivity in a community sample of adult men and women. We previously reported an association between central serotonergic responsivity and traits of aggression and impulsivity in a subset of the participants without DSM-III-R Axis I pathology (25). We also evaluated the association of the traits of aggression and impulsivity with SES indicators, and then tested whether any obtained associations of SES and serotonergic function were mediated by these traits.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
All subjects were enrolled in the University of Pittsburgh Cholesterol and Risk Evaluation project, a study of neurobehavioral correlates of variability in plasma lipids. Participants were recruited through media advertisements and local distribution of brochures and posters. Exclusion criteria included medical diagnoses of schizophrenia or delusional disorder, cancer, stroke, insulin-dependent diabetes, chronic kidney or liver disease, uncontrolled thyroid disease, migraines, and use of psychotropic, glucocorticoid, hypolipidemic medication, or other cardiovascular medications, including antihypertensive medications. Those with controlled thyroid disease (ie, receiving treatment and having normal TSH levels) were not excluded. Pregnant or lactating women were also excluded. The study protocol was approved by the University of Pittsburgh Institutional Review Board for Biomedical Research, and participants gave informed consent to participate.

Subjects attended three laboratory appointments for the measurement of fasting plasma lipids, blood pressure, and other cardiovascular disease risk factors; demographic characteristics; aspects of mood, personality, and health-related quality of life; neuropsychological (cognitive) functioning; and plasma prolactin responses to an orally administered fenfluramine challenge. Several subjects were excluded because of hyperprolactinemia at baseline (>25 ng/ml) or missing prolactin values because of technical difficulties. In the early phase of the project, the dose of fenfluramine was not adjusted for participant weight; only those participants whose dose was weight adjusted are included in the present analysis. These 270 subjects included 145 men and 125 women ranging in age from 24 to 60 years (mean age = 44.7 ± 8.0 years). Eighty percent of subjects were white, 62% were married, and 79% were employed full- or part-time. Six subjects did not know their annual income or refused to report income. Income and educational attainment varied substantially in the sample and are reported in Table 1.


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  		Table 1. Educational Attainment and Annual Income in Full Sample
 
Fenfluramine Challenge
Fenfluramine, in both its D,L- and D- stereoisomers, induces presynaptic release of serotonin stores, inhibits the reuptake of synaptic serotonin, and by possible direct activation of postsynaptic serotonergic receptors, enhances serotonin neurotransmission (31–33). Stimulation of serotonergic receptors in the hypothalamus promotes pituitary release of prolactin into the circulation. The resulting change in plasma PRL concentration provides an index of overall serotonergic responsivity in the hypothalamic-pituitary axis, an interpretation that is supported by the inhibition of PRL responses by central 5-HT (in particular, 5-HT2) receptor blockade (34–37).

Participants reported to the laboratory between 8 AM and 10 AM after a 12-hour fast, were seated in a comfortable chair, and a 20-gauge, heparin-locked catheter was inserted aseptically into a vein in the antecubital fossa. After a 30-minute adaptation period, a blood sample for determination of baseline PRL concentration was obtained and the drug was administered as a single dose from 30 to 60 mg orally to achieve a dose in the range of 0.55 to 0.65 mg/kg body weight (<60 kg, 30 mg; 60–73 kg, 40 mg; 74–91 kg, 50 mg, >91, 60 mg) (38). Subsequent blood samples were drawn 1, 2, 2.5, 3, and 3.5 hours later. Additional samples were taken at 2.5 and 3.5 hours for measurement of fenfluramine and norfenfluramine (the principal active metabolite of fenfluramine) concentrations. All blood samples were centrifuged immediately, separated, and frozen at -70°C until analysis.

Plasma PRL levels were determined in duplicate using Immunocorp’s (Montreal, Canada) solid phase, two-site immunoradiometric method. The lower limit of sensitivity of the PRL assay is 0.5 ng/ml, and the interassay coefficient of variation is 6% to 9%. Plasma levels of fenfluramine and norfenfluramine were measured to examine individual differences in bioavailability. These samples were collected in borosiliate acid-washed glass tubes with balanced ammonium-potassium oxylate crystals. A gas chromatograph fitted with a nitrogen detection system was used, and the internal standard was isopropyl fenfluramine. The lower detection limit was 2 ng/ml, and the coefficient of variation was 5.2% at 5 ng/ml.

Behavioral Assessments
Among the behavioral measurements obtained in the parent project, three measures were selected: an interview-derived LHA (20); the Barratt Impulsiveness Scale (39); and the Angry Hostility subscale from the NEO Personality Inventory (40). These were selected because a) scores on similar or the same scales correlated inversely with indices of central serotonergic function in psychiatric samples; b) they correlated with central serotonergic function in a previous analysis of the subset of individuals in the present study who did not have a current or past history of DSM-III-R Axis I psychopathology, including alcohol or substance abuse (25); and c) along with the Conscientiousness score from the NEO, they formed a single principal component factor.

The LHA interview assesses diverse aspects of aggressive behavior, including aggression expressed toward others (by verbal and physical assault) or toward inanimate objects (destruction of property), temper tantrums, antisocial behaviors involving disciplinary actions and illicit acts, and injury to self. This semistructured instrument was administered by one of two experienced interviewers. Items were scored for frequency of occurrence on a four-point scale (never, rarely, occasionally, and often), referenced separately to subjects’ experiences in childhood, adolescence, and adulthood. Excellent interrater reliability was observed between the two interviewers in this investigation ({kappa} coefficients = 1.0, 0.92, and 0.86 for the childhood, adolescent, and adult codes, respectively). For the present study, the LHA aggression score was calculated by summing the highest code obtained in the adolescent or adult age periods, as described by Coccaro et al. (41). Note that no self-injurious behavioral acts were recorded, and the interviewers were not blind to other information reported on questionnaires.

The Barratt Impulsiveness Scale contains 30 questions regarding subjects’ control of thoughts and behavior (eg, acts without thinking, decides "on the spur of the moment," and does not plan ahead), each was scored on a four-point Likert scale (39, 42). The Barratt Impulsiveness Scale has high internal consistency ({alpha} coefficients = 0.79–0.83) (43) and was highly reproducible over 6 months (reliability coefficient = 0.88) among a subsample of 64 participants.

The NEO Personality Inventory measures five broad domains of personality variability commonly observed in factor-analytic studies of lexically-derived trait ratings (40). Respondents indicate on a four-point scale the degree to which each of 240 items is descriptive of their own behavior, attitudes, and feelings. The subscale score from the Neuroticism domain, Angry Hostility, was included in the present analysis. The three scores were initially standardized and then summed to yield an overall aggression/impulsivity score.

Statistical Analysis
To index the PRL response to fenfluramine [fen], a peak PRL change ({Delta}) was calculated for each subject as the arithmetic difference between the highest PRL value obtained after drug administration and PRL concentration at baseline. The resulting distributions of {Delta}PRL[fen] scores were skewed positively and, therefore, were normalized by logarithmic transformation (log10({Delta}PRL[fen] + c), where c is the smallest constant yielding a minimum score greater than 1 (44)). The {Delta}PRL[fen] scores were adjusted for covariation with initial values, yielding a baseline-free index of PRL response to fenfluramine. Although prolactin levels were not collected after administration of placebo in this study, prior research has shown that peak prolactin response to fenfluramine is correlated very highly with both placebo-adjusted prolactin responses and the calculated area under the curve, r > 0.88 (45, 46).

Income (continuous) and educational attainment (high school degree or less, some college, four-year degree, and advanced degree) were standardized within each of the following groups: the entire sample, men only, women only, whites only, and African Americans only. Then the standardized income and educational attainment scores were added to create an overall SES ranking for the entire sample and for each group, such that higher scores reflected greater income and more education. (The separate standardization scores in each group were calculated because of group differences in income and education.) Adjusting for age and weight, partial correlation coefficients were calculated between {Delta}PRL[fen] scores and income, educational attainment, and their sum, and the aggregate aggression/impulsivity score. Multiple linear regression analyses were conducted regressing age, gender, ethnicity (white vs. others), and body mass index on the {Delta}PRL[fen] scores in the first step, total aggression/impulsivity scores at the second step, and the SES indicators at the third step to evaluate the independent influence of behavioral traits and SES. Body mass index was included even though prolactin dose was administered according to weight categories because the weight cutoffs were necessarily crude and body mass index is correlated with SES. Because in our previous analysis in a subset of participants, we found stronger associations between the {Delta}PRL[fen] scores and behavioral traits in men than in women, we also tested for interactions between gender and behavioral traits. Because these comparisons were nonsignificant in relation to the influence of SES, they are not reported below.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
In the full sample and in the subgroups, there were inverse associations between SES and the {Delta}PRL[fen] scores (Table 2). In all groups but African Americans, the lower the combined income and educational attainment score, the lower the {Delta}PRL[fen] scores. In African Americans, the correlation was similar in magnitude and direction to the correlations obtained in other subgroups but was nonsignificant due to the small sample size. The partial correlations for women, also adjusting for use of hormone replacement therapy or oral contraceptives, showed nearly identical associations. To illustrate the findings with respect to SES, Figure 1 shows the mean (unadjusted) prolactin response to fenfluramine challenge according to quintiles of the distribution of income in the full sample.


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  		Table 2. Partial Correlation Coefficientsa Between Sociodemographic Characteristics and Fenfluramine-Induced Prolactin Responses
 


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  		Fig. 1. Association between standardized family income scores categorized into quintiles based on the distribution of sample scores and unadjusted mean fenfluramine-induced prolactin responses (1 SEM).

 
In the full sample and in all subgroups except African Americans, the lower the income the higher the scores on the aggression/impulsivity scale (Table 3). Multiple regression analyses showed that the combined income and education score still was significantly related to {Delta}PRL[fen] scores (unstandardized b = 0.112, SE = 0.04, p = .003), after adjustment for age, gender, ethnicity, body mass index, and aggression/impulsivity scale score. Similarly, income (b = 0.145, SE = 0.06, p = .02) and educational attainment (b = 0.139, SE = 0.06, p = .02) were independently related after adjustment for the aggression/impulsivity score and other covariates. The aggression/impulsivity score was inversely related to the {Delta}PRL[fen] scores in the final model for educational attainment (p < .05), whereas it tended to be inversely related for the combined income and education score (p < .11) and income only (p < .08).


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  		Table 3. Correlation Coefficients Between Sociodemographic Characteristics and the Aggression/Impulsivity Index
 
We also conducted additional regression analyses, adding as covariates in the model, lifetime history of alcohol or substance abuse, lifetime or current history of major depression (N = 54, DSM-III-R criteria, assessed by the Structured Clinical Interview of DSM-III-R: Nonpatient edition (47)), and mean plasma concentrations of fenfluramine and norfenfluramine at 2.5 and 3.5 hours after the fenfluramine administration as a marker of bioavailability. These covariates did not alter the above pattern of results. Lifetime or current history of depression was unrelated to {Delta}PRL[fen] scores in the combined education and income score in the full model, p = .34, or to education, income, or the combined score in the full sample.1


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
The present study evaluated the association between socioeconomic status and serotonergic responsivity in a community sample of adult men and women. Individuals who reported low family income and little education showed a blunted prolactin response to a fenfluramine challenge compared with persons with higher family income and more education. Although the association was small, it was consistently obtained in subgroup analyses of men, women, whites, and African Americans (education only) taken separately, and when statistical adjustments were introduced for age, body mass index, use of hormone replacement therapy or oral contraceptives, bioavailability of fenfluramine, and history of alcohol or substance abuse or depression.

It should be noted that the specificity of the racemic (D,L-) fenfluramine for central serotonergic neurons is not perfect, and in rodents, actions of the L-isomer on catecholaminergic neurons have been described. However, in humans, prolactin responses to the serotonin-selective D-fenfluramine isomer correlate highly with responses to the racemic mixture (48). Also, the topographical pattern of neuronal activation on positron-emission tomography induced by racemic fenfluramine is also similar to that observed after administration of D-fenfluramine (49, 50).

Why might such an association between socioeconomic status and serotonergic responsivity exist? We had reasoned that the stressful environments to which individuals from low socioeconomic status are exposed leads to blunted serotonergic function. Although we could not directly test this explanation in our data set, it is attractive because of its consistency with results from primate studies. A second, but not incompatible possibility that could be evaluated in our study was that socioeconomic status is related to aggression and impulsivity, which, in turn, is related to reduced serotonergic responsivity. Our analyses indicated that, even when adjusting for participants’ scores on standardized measures of aggression and impulsivity, a more blunted serotonergic response was obtained among those with lower income and less education. It should be noted that the aggression-impulsivity measure was still associated with reduced serotonergic responsivity in the multivariate model testing the association of education and serotonergic responsivity. This suggests that serotonergic responsivity is correlated with both education attainment and individual differences in aggression and impulsivity.

Although speculative, it is worthwhile considering the role that reduced serotonergic function might have in mediating the well-documented relationship between socioeconomic status and health. There is some evidence that central nervous system 5-HT depletion increases food intake, body weight, and adiposity (51, 52) and the reinforcing properties of nicotine (53); and serotonergic-enhancing drugs reduce alcohol intake (54). Similarly, we recently reported central serotonergic activity to be inversely correlated with resting blood pressure (55). Central adiposity, obesity, smoking, excessive alcohol intake, and hypertension are all associated with socioeconomic status and health (3). Reduced serotonergic function is associated with increased sympathetic and reduced parasympathetic activation (see Ref. 56 for a review). For example, postsynaptic 5-HT1A receptors apparently mediate the central inhibition of cardiovascular responses because at least some drugs that activate serotonergic receptors inhibit cardiovascular responses and depress heart rate and blood pressure. Increased sympathetic activation in response to frequent environmental stressors is thought to lead to the development of hypertension and atherosclerosis. Although almost no data on the association of sympathetic activation and social class exist (cf. Ref. 57), if environmental stressors are indeed more prevalent among the lower social class, then there should be more stimulus conditions for eliciting sympathetic responses among the lower class.

In sum, among healthy middle-aged men and women, blunted serotonergic responsivity is associated with low social class as measured by annual family income and educational attainment. This is the first study to evaluate the association in humans, and it seems to be confirmed consistently among the subgroups of men, women, whites, and African Americans. The association is not due primarily to personality factors of aggression and impulsivity.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
This research was supported by National Institutes of Health Grant HL46328.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
We previously reported that in a sample overlapping with, but not identical to, the present, cases with a history of depression (but not current depression) had lower prolactin responses to the fenfluramine challenge than controls matched for race, sex, age, and socioeconomic status (58). Back

Received for publication February 5, 1999.

Revision received September 17, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 

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