Gene expression associated with suicide attempts in US veterans.

According to a recent report from the Office of Suicide Prevention in the US Department of Veterans Affairs, veterans represent 8.5% of the US population, but account for 18% of all deaths from suicide. The aim of this study of psychiatric patients (n=39; 87% male) was to compare blood gene expression data from veterans with a history of one or more suicide attempts to veterans who had never attempted suicide. The attempter and non-attempter groups were matched for age and race/ethnicity, and both groups included veterans with a diverse psychiatric history that included posttraumatic stress disorder (PTSD) and substance-use disorders. Veterans were interviewed for lifetime psychiatric history, including a detailed assessment of prior suicide attempts and provided a blood sample. Results of Ingenuity Pathway Analysis (IPA) identified several pathways associated with suicide attempts, including the mammalian target of rapamycin (mTOR) and WNT signaling pathways. These pathways are of particular interest, given their role in explaining pharmacological treatments for suicidal behavior, including the use of ketamine and lithium. These results suggest that findings observed in civilians are also relevant for veterans and provide a context for interpreting results observed in post-mortem samples. In conclusion, an emerging body of work that shows consistency in findings across blood and brain samples suggests that it might be possible to identify molecular predictors of suicide attempts.

Influence of estrogen replacement therapy on cardiovascular responses to stress of healthy postmenopausal women.

Two experiments were conducted to understand the influence of estrogen exposure on cardiovascular responses to acute stress measured by impedance cardiography. Study I compared stress responses of 29 postmenopausal women who used postmenopausal hormone replacement therapy (HRT) and 29 who did not use HRT. Women who did not use HRT had higher systolic blood pressure and pulse pressure responses to the tasks relative to HRT users. Study 2 compared stress responses of 38 healthy postmenopausal women not initially on HRT who were randomly assigned to transdermal estradiol or placebo treatment for 6-8 weeks. HRT assignment did not influence substantially women's cardiovascular responses to stress. Characteristics correlated with HRT use, not HRT itself, or differences in type, duration, and dosage may account for the discrepancy in results.

Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults.

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age-at-onset occurring earlier in individuals having at least one APOE epsilon 4 allele, relative to the APOE epsilon 3 or APOE epsilon 2 isoforms. Moreover, nondemented older adults with the APOE epsilon 4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE epsilon 4 allele and cognitive performance to healthy, middle-aged adults. A community sample of 220 non-Hispanic Caucasian men and women, aged 24-60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e. g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE epsilon 4 allele, relative to adults with APOE epsilon 2 and epsilon 3 genotypes (P <.01). Attention span did not differ by genotype. These findings, the first in a sample of middle-aged adults, suggest that the APOE polymorphism is a marker for age-related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707-711, 2000.

Effects of behavioural family management on family communication and patient outcomes in schizophrenia.

BACKGROUND: Family interventions for schizophrenia have proved to be highly effective in preventing relapse, but it is not clear how they work or how they should be structured. AIMS: To examine the effects of a behavioural family intervention and a family support programme on communication, problem solving and outcome in order to determine the impact of structured communication training. METHOD: Patients and family members participating in the Treatment Strategies in Schizophrenia study were videotaped engaging in 10-minute problem-solving conversations at baseline and after the conclusion of the family intervention. Tapes were subsequently evaluated for changes in communication patterns. RESULTS: The intensive behavioural intervention did not produce differential improvement in communication, and change in communication was unrelated to patient outcomes. CONCLUSIONS: The data suggest that intensive behavioural family interventions may not be cost efficient, and that change in family communication patterns may only be important for a subset of families.

A regulatory polymorphism of the monoamine oxidase-A gene may be associated with variability in aggression, impulsivity, and central nervous system serotonergic responsivity.

This study presents preliminary evidence of an association between polymorphic variation in the gene for monoamine oxidase-A (MAOA) and interindividual variability in aggressiveness, impulsivity and central nervous system (CNS) serotonergic responsivity. An apparently functional 30-bp VNTR in the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR), as well as a dinucleotide repeat in intron 2 (MAOA-CAn), was genotyped in a community sample of 110 men. All participants had completed standard interview and questionnaire measures of impulsivity, hostility and lifetime aggression history; in a majority of subjects (n=75), central serotonergic activity was also assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). The four repeat variants of the MAOA-uVNTR polymorphism were grouped for analysis (alleles '1+ 4' vs. '2+3') based on prior evidence of enhanced transcriptional activity in MAOA promoter constructs with alleles 2 and 3 (repeats of intermediate length). Men in the 1/4 allele group scored significantly lower on a composite measure of dispositional aggressiveness and impulsivity (P<0.015) and showed more pronounced CNS serotonergic responsivity (P<0.02) than men in the 2/3 allele group. These associations were also significant on comparison of the more prevalent one and three alleles alone (encompassing 93% of subjects). Although in linkage disequilibrium with the MAOA-uVNTR polymorphism, MAOA-CAn repeat length variation did not vary significantly with respect to behavior or fenflluramine challenge in this sample. We conclude that the MAOA-uVNTR regulatory polymorphism may contribute, in part, to individual differences in both CNS serotonergic responsivity and personality traits germane to impulse control and antagonistic behavior.

Do the daily experiences of healthy men and women vary according to occupational prestige and work strain?

OBJECTIVE: This study evaluated the influence of occupational prestige and work strain on mood, the occurrence of interpersonal conflict, and ambulatory blood pressure and heart rate. METHODS: Participants were 50 men and 50 women matched for occupational prestige who were healthy and middle-aged and who completed measures of mood and conflict simultaneously with measures of ambulatory blood pressure and heart rate recorded every 30 minutes during waking hours of two workdays and one nonworkday; at the end of each day, overall ratings were made. Work strain was assessed by the Work Section of the Self-Evaluation and Social Support Interview Schedule. Multiple level random regression coefficients analyses were conducted. RESULTS: Men and women with low-prestige occupations experienced more interpersonal conflict, b = -0.03, p = .04, and higher ambulatory heart rate, b = -4.83, p = .004, throughout the three days of the study. Relative to those with low work strain, those reporting high work strain experienced negative emotion, b = -0.41, p < .0001, and boredom, b = -0.17, p < .0004. End of the day ratings of negative mood were more influenced by work strain among men than among women. No effects of occupational prestige or work strain were obtained for ambulatory blood pressure readings after adjustment for physical activity, posture, and location. CONCLUSIONS: Individuals in low-prestige occupations experience greater exposure to interpersonal conflict and arousal as indexed by heart rate, which might increase risk for stress-related illnesses often associated with social class. Individuals who report work strain experience negative mood and boredom, both at work and at home. The absence of work effects on ambulatory blood pressure may be due to the participants being healthy.

Effects of lovastatin on cognitive function and psychological well-being.

PURPOSE: Animal research and cross-sectional studies suggest that serum lipid concentrations may influence cognitive function, mood, and behavior, but few clinical trials have studied these effects. SUBJECTS AND METHODS: In this double-blind investigation, 209 generally healthy adults with a serum low-density-lipoprotein (LDL) cholesterol level of 160 mg/dL or higher were randomly assigned to 6-month treatment with lovastatin (20 mg) or placebo. Assessments of neuropsychological performance, depression, hostility, and quality of life were conducted at baseline and at the end of the treatment period. Summary effect sizes were estimated as z scores on a standard deviation (SD) scale. RESULTS: Placebo-treated subjects improved between baseline and posttreatment periods on neuropsychological tests in all five performance domains, consistent with the effects of practice on test performance (all P <0.04), whereas those treated with lovastatin improved only on tests of memory recall (P = 0.03). Comparisons of the changes in performance between placebo- and lovastatin-treated subjects revealed small, but statistically significant, differences for tests of attention (z score = 0.18; 95% confidence interval (CI), 0.06 to 0.31; P = 0.005) and psychomotor speed (z score = 0.17; 95% CI, 0.05 to 0.28; P = 0. 004) that were consistent with greater improvement in the placebo group. Psychological well-being, as measured several ways, was not affected by lovastatin. CONCLUSION: Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function. Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed, the clinical importance of which is uncertain.

Does socioeconomic status relate to central serotonergic responsivity in healthy adults?

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.

Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism.

A deletion/insertion polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) was reported to be associated with dimensional measures of neuroticism, although subsequent replication attempts have failed. These replication attempts, however, have been dissimilar to the initial study in sample size, distribution of allelic frequency and/or assessment of neuroticism. The current study was conducted in a further attempt to replicate the initial finding using: (a) a sample that was more comparable to each of the individual samples in the initial report; and (b) identical psychometric methodology to assess neuroticism. Two hundred and twenty-five Caucasian adults were genotyped for the 5-HTTLPR polymorphism and completed the NEO Personality Inventory. Results did not replicate the association between the 5-HTTLPR polymorphism and neuroticism; individuals with the short form of this variant did not report higher NEO Neuroticism. Indeed, men with the short form reported lower Anxiety, a finding that is directionally opposite to the initial results. These findings, combined with other failures to replicate, indicate that the reproducibility of the association between the 5-HTTLPR polymorphism and neuroticism must be regarded as questionable. The contradictory findings suggest the need for a replication attempt in a large, normative sample that is stratified by ethnicity and sex.

Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene.

BACKGROUND: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. METHODS: Locally recruited men and women (n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). RESULTS: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. CONCLUSIONS: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

Effects of optimism, pessimism, and trait anxiety on ambulatory blood pressure and mood during everyday life.

This study tested whether dispositional measures of optimism, pessimism, and anxiety affected ambulatory blood pressure (BP) and mood and whether any cardiovascular effects of dispositions were moderated by mood. Pessimistic and anxious adults had higher BP levels and felt more negative and less positive than did optimists or low anxious adults throughout the monitoring. The few times that optimists did feel negative were associated with levels of BP as high as those observed among pessimists or anxious individuals, regardless of their mood. To the extent that trait anxiety measures neuroticism, these findings suggest that neuroticism is directly related to health indicators rather than simply to illness behavior. Furthermore, the results suggest that pessimism has broad physiological and psychological consequences.

Effects of hostility on ambulatory blood pressure and mood during daily living in healthy adults.

This study (a) tested the effects of hostile attributes on ambulatory blood pressure (BP), heart rate, and mood monitored repeatedly over 3 days in 100 healthy men and women and (b) determined whether the cardiovascular effects of trait hostility were moderated by mood. Multilevel random-coefficients regression analyses showed that hostile individuals exhibited higher systolic and diastolic BP and rated their current moods as more negative and less positive throughout the monitoring. Individuals low in hostility exhibited high BP only during the few occasions when they experienced negative mood. However, these patterns were true only when participants were classified by Potential for Hostility ratings from the Structured Interview (R. H. Rosenman, 1978), not by the Cynical Hostile Attitudes score derived from the Cook-Medley scale. Results provide convergent and ecological validity of interview rating of hostility and illuminate one possible dynamic mechanism by which overt hostile behaviors might contribute to the rates of increased cardiovascular morbidity and mortality.

Inverse relationship between fenfluramine-induced prolactin release and blood pressure in humans.

Although substantial evidence from experimental animals suggests that augmentation and reduction in serotonergic neurotransmission both affect arterial blood pressure (BP), it is unknown whether "tonic" central serotonergic activity is related to resting BP variability in humans. We tested this hypothesis in a community sample by evaluating the relationship between resting BP and a neuropharmacologic index of brain serotonergic activity (the fenfluramine challenge test). Subjects were 270 generally healthy men and women aged 25 to 60 years who were not receiving prescribed antihypertensive or psychotropic medications. The sample included 216 non-Hispanic whites and 47 blacks. Resting systolic BP ranged from 85 to 161 mm Hg and diastolic from 58 to 98 mm Hg. Each subject received 0.55 to 0.65 mg/kg D,L-fenfluramine hydrochloride, and the plasma prolactin concentration was measured over 3.5 hours. Analyses revealed a linear, inverse relationship between the maximum fenfluramine-induced prolactin rise and systolic and diastolic BP in whites: r=-0.36 and r=-0.29, respectively (P<0.001 for both). These relationships were not observed in the black participants. In whites, the prolactin response to fenfluramine remained a significant predictor of systolic and diastolic BPs in multivariate models including age, gender, body mass index, physical activity, smoking, and alcohol consumption (P135/85 mm Hg. These data reveal that in white but not black adults, fenfluramine-induced prolactin release correlates inversely with BP and may indicate a role of central serotonergic activity in the pathogenesis of hypertension.

Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample.

To test the hypothesis that traits of aggression and impulsivity correlate negatively with central serotonergic system function in a nonpatient population, a standard fenfluramine challenge (for assessment of serotonergic responsivity) and behavioral measurements germane to aggression/impulsivity were administered to a community-derived sample of 119 men and women. In men, peak prolactin responses to fenfluramine correlated significantly with an interview-assessed life history of aggression (r = -.40, p < .002), the Barratt Impulsiveness Scale (r = -.30, p < .03), and traits of Conscientiousness (r = +.30, p < .03), Neuroticism (r = -.31, p < .02) and Angry Hostility (r = -.35, p < .01) on the NEO-Personality Inventory. No significant relationships were observed across all women, although subanalyses restricted to postmenopausal subjects (in whom ovarian influences on prolactin secretion may be mitigated because of diminished estrogen) showed a pattern of behavioral associations somewhat similar to that seen in men. By extending documented relationships between an index of central serotonergic system function and traits of aggression and impulsivity to a more normative range of population variability than is represented in prior literature, this study supports speculation that these associations reflect a basic neurobehavioral dimension of individual differences.

Effects of short-term suppression of ovarian hormones on cardiovascular and neuroendocrine reactivity to stress in women.

The present study reduced the levels of ovarian hormones to early postmenopausal levels by a GnRH agonist and evaluated the effects of a temporary suppression of ovarian hormones on premenopausal women's cardiovascular and neuroendocrine responses to laboratory challenges. The stress responses of 24 healthy young women were evaluated during three tasks during the early follicular phase and then after three monthly injections of Lupron, which suppressed their levels of estradiol, FSH, and LH. Thereafter, half the group resumed menstrual cycles (labeled Cycle), and half continued having Lupron injections in combination with transdermal estradiol (labeled Patch) and all were reevaluated a third time. A third group (labeled Control) of 12 women had four monthly injections of Lupron first and then were evaluated the first time. After their cycles resumed, they were reevaluated twice 3 months apart. Results showed that the magnitude of the blood pressure and catecholamine changes declined over the three evaluations, suggesting that the women's stress responses habituated. Although the suppression of ovarian hormone levels led to alterations in ovarian hormones for several months, which were accompanied by typical menopausal symptoms, cardiovascular and neuroendocrine responses to stress did not vary. This study did not test the effects of current estrogen exposure or of long term suppression of ovarian hormones upon cardiovascular and neuroendocrine responses.

Recovery from major depression is not associated with normalization of serotonergic function.

BACKGROUND: Plasma prolactin response to fenfluramine, a serotonergic agent, is typically blunted in moderately to severely depressed adults when compared to healthy controls. It is not clear, however, whether this dysregulation represents an acute change during symptomatic depression or a chronic disturbance. METHODS: In the current study, the prolactin responses to D,L-fenfluramine (weight-adjusted oral dose) of 29 adults who had a history of at least one major depressive episode (DSM-III-R criteria), but not during the past year, were compared to the prolactin responses of 58 age-, sex-, and socioeconomic status-matched adults without a lifetime history of major depression. RESULTS: Individuals with a positive history of major depression had significantly lower peak prolactin responses than controls. This finding was not attributable to weight, fenfluramine bioavailability, or baseline prolactin levels. CONCLUSIONS: This is the first investigation to compare men and women with a history of depression but not depressed at the time of the fenfluramine challenge to a similar group of healthy controls. The results are consistent with the hypothesis that central serotonergic activity is persistently disturbed in adults who experience depressive episodes.

Effects of lovastatin on the immune system.

Laboratory investigations have demonstrated that blockade of HMG-CoA reductase in vitro reduces lymphocyte proliferation in response to mitogens as well as other facets of the immune system, such as natural killer cell cytotoxicity. However, in this randomized and double-blind clinical investigation, treatment with 20-mg lovastatin for 6 months did not significantly alter several enumerative and functional characteristics of circulating immune cells.

Immune system differences in men with hypo- or hypercholesterolemia.

Substantial epidemiologic evidence indicates that relative hypocholesterolemia in apparently healthy individuals is associated with increased subsequent mortality from cancer and other nonatherosclerotic causes of death. To test a hypothesis potentially underlying these unexplained associations, we evaluated whether individuals with hypo- and hypercholesterolemia differ in various enumerative and functional indices of the immune system. Nineteen healthy adult men with a mean age of 46 years and a mean total cholesterol concentration of 151 mg/dl constituted a low cholesterol group and were compared with 39 men of a similar age whose total cholesterol averaged 261 mg/dl. Relative to the high cholesterol group, hypocholesterolemic men had significantly fewer circulating lymphocytes, fewer total T cells, and fewer CD8+ cells (P's < 0.05). Trends toward fewer CD4+ cells and less IL-2 release in response to PHA were also noted in the low, compared to the high, cholesterol group. The low and high cholesterol groups did not differ in number of B lymphocytes, level of PHA-induced proliferation, number of natural killer (NK) cells, or degree of NK cytotoxicity. These data provide preliminary evidence of immune system differences in healthy individuals with hypo- and hypercholesterolemia.

Sympathetic reactivity to acute stress and immune response in women.

We evaluated if the effects of acute stress on immune parameters were apparent in only the women who showed concomitant and substantial sympathetic nervous system activation and after statistical adjustment for changes in plasma volume. Nineteen women in the follicular stage of their menstrual cycles were assessed for immunological responsiveness to a series of three 3-minute psychological tasks, which reliably elicit cardiovascular and neuroendocrine stress responses. Women were classified as high or low sympathetic reactors based on their cardiovascular and neuroendocrine responses to one of the three tasks, a public speaking task. The stress-induced decreases in CD4+ percentage and increases in natural killer cell number and cytolytic activity were only apparent among the high reactors. Further analysis adjusting for alterations in plasma volume changes showed that the increase in NK cell number remained. Stress-induced proliferative responses to pokeweed mitogen and phytohemagglutinin were not more apparent among high reactors. These results are consistent with the hypothesis that the sympathetic nervous system plays a direct role in modulating the short term response to stress of some indices of the immune system in women.