P. Anne McBride

Increased anterior cingulate and caudate activity in bipolar mania

BACKGROUND Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. METHODS We utilized a high-sensitivity H(2)(15)0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. RESULTS The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. CONCLUSIONS The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical-subcortical neural system that includes the anterior cingulate and caudate.

Effects of age and gender on CNS serotonergic responsivity in normal adults

The effects of age and gender on central nervous system (CNS) serotonergic responsivity were assessed with a neuroendocrine challenge test in 30 normal adults. Subjects greater than or equal to 30 years of age, compared with younger subjects, exhibited decreased prolactin secretion in response to a 60-mg oral dose of dl-fenfluramine hydrochloride, an indirect serotonin agonist. Furthermore, women had greater prolactin responses than men. As prolactin secretory capacity appears to be stable through midlife, the age-associated decrease in fenfluramine-induced prolactin release suggests a decline in CNS serotonergic responsivity. In contrast, the finding of greater prolactin release in women than in men probably reflects the effects of nonserotonergic modulatory influences at the level of the lactotroph. Age and gender effects must be considered in studies of the CNS serotonergic system.

Platelet and whole blood serotonin content in depressed inpatients: Correlations with acute and life-time psychopathology

Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +/- 27.3 versus 77.6 +/- 41.7 ng/10(8) platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +/- 41.5 ng/10(8) platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +/- 31.1 ng/10(8) platelets) and 27% greater than healthy controls (62.4 +/- 19.8 ng/10(8) platelets). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD). Nevertheless, BPD attempters had lower serotonin levels than BPD nonattempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r = 0.44, p = 0.04 and r = 0.41, p = 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.

Blunted Serotonergic Responsivity in Depressed Inpatients

We found a 38% lower maximal prolactin response to an oral challenge dose of 60 mg of dl-fenfluramine relative to placebo in younger (<30 years) depressed inpatients compared with the response in age-matched healthy controls (p <. 03). Severity of depression did not correlate with prolactin response. Prolactin responses in older depressed patients (⩾30 years) did not differ from older controls. Younger depressed patients differed from older depressed patients in terms of earlier age of onset of first lifetime episode of major depression, greater degree of suicidal intent during a recent suicide attempt, double the level of hopelessness on admission to hospital, and a higher rate of comorbid borderline personality disorder. A blunted prolactin response to fenfluramine may be interpreted as evidence for reduced serotonergic function in younger depressed patients and may underlie their observed greater suicidality and hopelessness.

Effects of Diagnosis, Race, and Puberty on Platelet Serotonin Levels in Autism and Mental Retardation

OBJECTIVE To reevaluate platelet serotonin (5-HT) levels in autism, measuring and controlling for effects of race and puberty. The specificity of hyperserotonemia for autism versus cognitive impairment is also assessed. METHOD Platelet 5-HT levels were measured in 77 individuals, aged 2 through 37 years, with autistic disorder; 65 normal controls; and 22 mentally retarded or otherwise cognitively impaired (MR/CI) prepubertal children. Effects of diagnosis, race, and pubertal status were evaluated by analysis of variance in separate pre- and postpubertal groups. 5-HT levels were expressed as ng/mL blood and ng/microL platelet volume. RESULTS Among prepubertal children, significant effects of diagnosis (ng/mL; F2,109 = 5.9, p = .004) and race (F2,109 = 14.7, p < .0005) were found. Autistic youngsters had significantly higher 5-HT concentrations than controls, although the elevation (25%) was less than typically reported; MR/CI children had levels very similar to those of controls. White children had significantly lower 5-HT levels than black or Latino youngsters, regardless of diagnosis. Diagnosis and race effects were nonsignificant in the postpubertal group. Postpubertal subjects had lower 5-HT concentrations than prepubertal subjects (ng/mL; F1,114 = 28.5, p < .0005). CONCLUSIONS The data underscore the importance of matching for race and pubertal status in neuropsychiatric research and suggest that the prevalence of hyperserotonemia in autistic individuals may have been overestimated because of a failure to control for both variables. Hyperserotonemia was not found in MR/CI youngsters without autistic features.

The relationship of platelet 5-HT2 receptor indices to major depressive disorder, personality traits, and suicidal behavior.

Previous research has suggested that major depression and suicidal behavior may be associated with altered serotonin receptor function. In this study, platelet serotonin2 (5-HT2) receptor binding indices were measured in conjunction with serotonin-amplified platelet aggregation, a response mediated by the platelet 5-HT2 receptor complex, in depressed patients and normal controls. The magnitude of serotonin-amplified platelet aggregation was positively correlated with the number of platelet 5-HT2 receptor sites in both groups. Mean values for the receptor binding indices and the receptor-mediated response did not differ significantly between patients and controls, although patients exhibited a wider range of values for each parameter compared with controls. Exploratory analyses were undertaken to determine clinical variables that might contribute to the increased variance in depressed individuals. These analyses failed to reveal a statistically significant relationship between any of the platelet 5-HT2 receptor measures and the subtype or severity of depressive illness, or the presence of comorbid borderline personality disorder. Although the mean number of receptor sites did not differ between patients who had recently attempted suicide and those who had never attempted suicide, a strong positive correlation (p = 0.002) was found between receptor number and the degree of medical damage resulting from the suicidal act. Furthermore, the ratio of the serotonin-amplified platelet aggregation response to platelet 5-HT2 receptor number, an index of the mean responsivity of an individual receptor complex, was lower in suicide attempters versus nonattempters (p = 0.06) and normal controls (p = 0.01). Exploratory analyses also suggested that recent exposure to psychotropic medication may result in a significant increase in platelet 5-HT2 receptor number (p = 0.03). Thus, although the study did not show a consistent alteration in platelet 5-HT2 receptor indices in major depression, the data suggest that specific factors such as suicidality and drug exposure may explain some of the variance in depressed patients.

Peripheral serotonin measures in prepubertal psychiatric inpatients and normal children: associations with suicidal behavior and its risk factors

BACKGROUND This study reports relationships between suicidal behavior and its risk factors in prepubertal children and whole blood and platelet serotonin-related measures. METHODS Seventy-five prepubertal psychiatric inpatients including 23 (30.7%) nonsuicidal, 32 (42.7%) with suicidal ideation, and 20 (26.6%) with a suicide attempt were compared to 35 normal prepubertal controls with regard to platelet serotonin content, serotonin-amplified platelet aggregation, and whole blood tryptophan. RESULTS Mean whole blood tryptophan content was significantly lower among inpatient children with a recent suicide attempt than among normal controls or inpatients with suicidal ideation (F = 3.94, df = 3.54, p < or = .01). Inpatient children with a mood disorder had significantly higher platelet serotonin content than inpatients without a mood disorder (F = 3.86, df = 2.80, p < or = .03). Racial/ethnic differences were also observed for inpatients and normal controls, with whites having significantly lower levels of platelet serotonin (expressed as ng/mL blood or ng/10(9) platelets) than blacks or Latinos. Blacks had significantly higher levels of whole blood tryptophan than other racial/ethnic groups. CONCLUSIONS The results suggest that whole blood tryptophan and platelet serotonin content should be studied for their predictive validity as risk factors for suicidal behavior in youth while controlling for racial/ethnic differences.

Characterization of serotonin binding sites on human platelets

A high affinity, saturable 3H-spiroperidol binding site was identified for the first time on the intact human platelet, with drug affinities comparable to the serotonin-2 (S-2) receptor in human frontal cortex. The site was characterized by a KD of 2.7 +/- 0.3nM and a Bmax of 1.4 +/- 0.2 pmoles/10(8) platelets. A 3H-serotonin binding site was also found, with a KD of 42 +/- 8 nM, which appeared to represent the serotonin uptake site. No 3H-serotonin binding site with features of the serotonin-1 (S-1) receptor in brain was found on the platelet. Assay of 3H-spiroperidol binding to platelets may serve as an easily applied model for studying S-2 receptor function in man, and its relationship to age, hormonal, drug, and disease effects.

Inhibition of serotonin-amplified human platelet aggregation by ketanserin, ritanserin, and the ergoline 5HT2 receptor antagonists - LY53857, sergolexole, and LY237733

Human platelets are known to possess 5HT2 receptors which, when activated, amplify the aggregation response produced by other aggregating agents. Several 5HT2 receptor antagonists, including ketanserin and ritanserin, are known to antagonize serotonin-mediated aggregation of human platelets. In the present study, we document the ability of three ergoline 5HT2 receptor antagonists, LY53857, sergolexole, and LY237733, to antagonize the serotonergic component of the human platelet aggregation response. Potencies of the ergoline esters (LY53857 and sergolexole) and the ergoline amide (LY237733) to inhibit serotonin-amplified platelet aggregation responses were similar to the potencies of ketanserin and ritanserin under the conditions of our study. Furthermore, all five 5HT2 receptor antagonists were capable of fully inhibiting the serotonergic component of the platelet aggregation response. In contrast to these potent ergoline esters and amides, 1-isopropyl dihydrolysergic acid (up to 10(-5)M), a putative metabolite of the ergoline esters, was ineffective under these in vitro conditions. These data are consistent with the high potency of these ergolines as antagonists of 5HT2 receptors and further support the involvement of 5HT2 receptors on human platelets in the amplifying response to serotonin.

Serotonin-mediated responses in autism

372 young adult controls (27 -+ 2 years). The following metabolic alterations were observed in the dorsal prefrontal cortex of the autistic patients. (1) Decreased levels of phosphomonoesters (p = .Ol), (2) increased levels of phosphodiesters (p = .004), and (3) decreased levels of UDP-sugars (p = .004). The PCr levels were non-significantly decreased (p = .08) and the levels of ATP and intracellular pH were normal. These findings suggest (1) decreased synthesis and increased breakdown of membrane phospholipids, (2) decreased glycosylation of membrane gangliosides, and (3) normal or slightly increase utilization of PCr. The membrane phospholipid alterations are similar to those demonstrated in never-medicated first episode schizophrenics, but the PCr changes are in the opposite direction from those demonstrated in schizophrenics.