CSF 5-HIAA Research Articles

Excessive mortality in free-ranging male primates with low CSF 5-HIAA

Excessive mortality in free-ranging male primates with low CSF 5-HIAA

The concentration of neurotransmitter metabolites in the cerebrospinal fluid of suicidal individuals: a meta-analysis.

A review of 27 research reports on the cerebrospinal fluid levels of neurotransmitter metabolites involving 1202 psychiatric patients found strong evidence for the involvement of the serotonin system in suicidal behavior. Attempted suicides, especially those using violent methods, had lower levels of CSF 5-HIAA as compared to psychiatric controls, and those making subsequent suicidal actions also had lower levels of CSF 5-HIAA. The meta-analysis permitted more reliable conclusions to be drawn than did each individual study alone.

Suicide as an indicium of biologically-based brain disease

Abstract Neurobiological evidence indicates that more than mood disorders, impulsive self-directed and other-directed violence and associated behaviors resistent to impulse control are biologically based and associated with alterations in serotonin metabolism. Serotonergic mechanisms are involved with sexual drive, affect, and fight or flight behavior (Linnoila et al., 1983; Traskman-Bendz et al., 1990) which at times may manifest itself as impulsive and be self-destructive. Serotonergic aberrations have been reported with assaults, rape, and eating disorders, in addition to suicides and homicides (Cohen et al., 1988). Schizophrenia, obsessive-compulsive disorder and panic disorder, is also reported associated with serotonergic dysfunction (Vander Kar, 1990). Many healthy people without evidence of psychiatric disorder show a decrease in CSF-5–HIAA (Asberg et al., 1990). supporting a multifactorial concept of suicide. In addition to the biogenetic vulnerably evinced in indoleamine metabolism, situational (e.g., stress, life events, lack of social support, severe illness, reversal of fortune), existential (e.g., angst), and psychological (e.g., early loss, hopelessness), play roles in compelling a person to take his or her own life (Asberg et al., 1990). The reduction of suicidal and impulsive behaviors, such as homicide and rape, requires a coordinated treatment plan involving psychopharmacotherapy, psychotherapy, and socio-therapy (Slaby, 1993). It is the challenge of researchers in suicide to identify which interventions are critical for managing patients with these disorders.

The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression

Prolonged hypothalamic-pituitary-adrenocortical (HPA) axis overactivity occurs at all levels of this axis during stress in normals and some depressed patients. This can induce enlargement of the pituitary and adrenals. Various reports showed that cortisol can affect mood and behavior, and disrupt memory and recall. The integrity of the hippocampus is essential for memory function and, via the high density of its cortisol receptors, cortisol induced inhibitory feedback to the HPA axis. Animal data suggest that over time aging and stress can permanently downregulate hippocampal cell receptors, produce chronic hippocampal inflammation (astroglial), and kill cells. Cushing's syndrome patients (high cortisol) show diminished hippocampal size and verbal recall inversely related to cortisol levels. All the above is consistent with the ‘cascade hypothesis’ of cortisol induced hippocampal damage with resultant diminished inhibition to HPA hyperactivity in a circular manner. High cortisol is associated with altered neurotransmitter function, e.g., diminished brain serotonin synthesis, low CSF 5HIAA, and increased noradrenergic activity.

MEASUREMENT OF AGGRESSION IN CHILDREN WITH DISRUPTIVE BEHAVIOR DISORDERS

The definition of aggression, acknowledged as an important parameter of childhood psychopathology, is poorly and inconsistently operationalized. This study examined the convergence of six measures of aggression in a group of 43 children and adolescents with Disruptive Behavior Disorders and assessed whether severity physical aggression toward humans and/or animals was related to these other measures. Patients with severe physical aggression were oversampled to examine these questions. Physical aggression directed toward people and animals had been associated with CSF 5-HIAA both at baseline and upon follow-up of children under the age of 12. Two frequently utilized factor analysis derived measures, the parent-rated Child Bellanor Checklist (CBCL) aggressive factor and the teacher-rated Iowa Conners aggression factor did not correlate with severity of physical aggression. Teacher ratings from two different school settings were not significantly correlated with other measures from other sources. The results...

Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates.

The purpose of this study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control. During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period. CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with "escalated" aggression, i.e., a measure of more intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence of physical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations. Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy.

CSF concentration gradients of monoamine metabolites in patients with hydrocephalus.

Concentration gradients of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), were assessed in 762 successive CSF fractions (2 ml lumbar CSF) from 15 patients with the adult hydrocephalus syndrome (AHS) and 11 patients with hydrocephalus of other causes (mixed group). A mean volume of 49.6 (SD 11.8) ml CSF was removed in the AHS group and 56.4 (10.2) ml in the mixed group. The CSF was collected with a specially designed carousel fraction collector and the corresponding CSF dynamics were continuously registered by a constant pressure CSF infusion method. Pronounced gradients in CSF HVA and CSF 5-HIAA were seen in both patient groups in the first 25 ml of CSF removed. The concentration curves levelled off, despite the removal of larger amounts of CSF and stabilised at about twice the initial concentrations. This phenomenon has not been described before. Concentrations of HVA and 5-HIAA in the first CSF fraction correlated strongly with concentrations in fractions up to about 40 ml. A positive correlation between the first fraction of CSF HVA and CSF 5-HIAA concentrations and CSF outflow conductance was found in the AHS group. There was no gradient in MHPG. It is suggested that the rostrocaudal gradients in CSF HVA and 5-HIAA may be explained by a downward flow of CSF along the spinal cord with absorption of metabolites occurring during passage. Mixing of CSF from different CSF compartments, extraventricular production sites of CSF, clearance of metabolites to venous blood or extracellular fluid, and CSF outflow conductance are probably important determinants of the plateau phase in patients with hydrocephalus. It is concluded that lumbar CSF does not exclusively reflect the concentrations of HVA, 5-HIAA, or MHPG in the ventricles. It should be noted that these results obtained in patients with hydrocephalus may not be applicable to other groups of patients or normal subjects.

A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) was determined for elderly delirious patients during the acute stage and after a 1-year follow-up period, and the 5-HIAA levels were compared with age-equivalent controls. As compared with the controls, the 5-HIAA levels were significantly higher at the beginning of the index admission in patients with multi-infarct dementia and patients with no apparent CNS disease. The 5-HIAA levels were also higher in the latter subgroup in the 1-year sampling, but no other differences between delirious patients and controls were observed. The one-way procedure showed no differences between the subgroup means of delirious patients when divided according to the severity of cognitive decline or type of delirium in any of the samples. The 5-HIAA levels measured during the index admission correlated with the length of life after delirium suggesting that serotonergic dysfunction may have prognostic significance in delirious patients.

Cholesterol and serotonin: Seeking a possible link between blood cholesterol and CSF 5-HIAA

The parallel findings relating impulsive/violent behavior to decreases in plasma cholesterol and CNS serotonin led us to perform two retrospective analyses of a possible 5-HIAA-cholesterol relationship in partially overlapping samples of men who were psychiatric inpatients and community volunteers

Gender and reproductive effects on cognitive function

creases in symptom scores during high dose MT administration of negative mood (irritability, mood swings, violent feelings, hostility), positive mood (euphoria. energy, sexual arousal), and cognitive impairment (distractibility, forgetfulness, confusion). MT significantly decreased CSF MHPG and significantly increased CSF 5-HIAA. Cognitive impairment was associated with relatively blunted suppression of the pituitary gonadal and pituitary adrenal axes by MT. Changes in plasma dehydroepiandrosterone (DHEA) and CSF HVA accounted for approximately 50% of the variance of MT induced symptoms on stepwise regression analysis. The different biochemical and behavioral profiles exhibited in response to MT suggest that in humans, as in animals, the biological and behavioral response to androgens is context dependent. tion from cell surface receptors to various effectors. They are especially important in the CNS, where they play a major role in the amplification and integration of signals, thereby affecting the functional balance between neurotransmitter systems, and have recently been shown to be modulated by sex steroids, most notably ! 7[~-Estradiol. Although a variety of biochemical effects may contribute to the CNS manifestations of (physiological or pathophysiological) alterations in gonadal steroids, modification of G protein function or content (with the inherent amplification of receptor responses) represents an attractive mechanisms. We are presently conducting a study designed to elucidate biochemical and physiological targets of gonadal in humans. Data will be presented on the effects of these key neuromodulatory hormones on the levels and function of various G protein subtypes.

Plasma 5‐Hydroxyindoleacetic Acid as an Indicator of Monoamine Oxidase‐A Inhibition in Rat Brain and Peripheral Tissues

We have examined the changes induced by the monoamine oxidase (MAO; EC 1.4.3.4) inhibitors tranylcypromine, clorgyline, and deprenyl on MAO activity and 5-hydroxytryptamine (serotonin, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content in rat brain and blood (plasma and whole blood). The decreases of MAO-A activity observed in the liver and lungs after different doses of clorgyline or tranylcypromine correlated significantly (r > 0.80 in all cases) with the decline of plasma 5-HIAA. This was unaffected by 0.25 and 5 mg kg-1 of deprenyl, indicating that 5-HT was deaminated exclusively in the periphery by MAO-A. It is interesting that very potent and significant correlations (r > 0.75) were found between plasma 5-HIAA and MAO-A activity, 5-HIAA and 5-HT content in brain tissue. These results suggest that plasma 5-HIAA can be used confidently as a peripheral indicator of the inhibition of MAO-A in brain. This may represent a favorable alternative to the analysis of 5-HIAA in CSF in psychiatric patients undergoing antidepressant treatment with nonspecific MAO inhibitors or with the new selective MAO-A inhibitors.

Brain serotonin, type II alcoholism and impulsive violence.

There is ample evidence that low CSF 5-HIAA concentration is associated with a tendency to exhibit impulsive violent behavior under the influence of alcohol. This is especially true for subjects who fulfill criteria for psychiatric diagnoses often associated with early onset alcoholism such as antisocial personality disorder and intermittent explosive disorder. Brain serotonin turnover as indicated by CSF 5-HIAA concentration does not correlate with CSF free testosterone concentration. The latter is more strongly associated with outward-directed aggressiveness and lack of socialization than impulsiveness. CSF ACTH concentration on the other hand correlates positively with socialization.

The concentrations of GABA, 5-HIAA and HVA in the cerebrospinal fluid of children with infantile spasms and the effects of ACTH treatment

Children with infantile spasms (IS) are generally treated with ACTH although little is known of the biochemical basis of the symptoms and the mechanism of this therapy. We have measured the concentrations of gamma-aminobutyric acid (GABA), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF of IS children, followed the effect of ACTH treatment on these parameters and correlated CSF GABA values with the cause of IS, cranial CT findings and antiepileptic treatment. While significant differences in GABA concentrations were found between the children with IS and those with febrile seizures or nonconvulsive symptoms, these could be accounted for by age, not the disease present. The CSF GABA level was highest in the IS children with normal CT, cryptogenic cause and no antiepileptic treatment, and lowest in those with abnormal CT, symptomatic cause and antiepileptic treatment. The basal level of CSF 5-HIAA in the IS children was higher than that in the nonconvulsive children, but HVA levels did not differ. ACTH therapy did not change the CSF levels of GABA, 5-HIAA and HVA significantly.

Simultaneous effects of p-chloroamphetamine, d-fenfluramine, and reserpine on free and stored 5-hydroxytryptamine in brain and blood.

The effects of acute treatment with p-chloramphetamine, d-fenfluramine, and reserpine on intracellular (brain tissue and whole blood) and extracellular (CSF and platelet-free plasma) compartments of 5-hydroxytryptamine (5-HT) in the brain and blood of the same rats have been examined. These treatments affected 5-HT in brain tissue and whole blood similarly (r = 0.823). Reserpine significantly reduced both intracellular pools at 2 and 24 h. p-Chloroamphetamine and d-fenfluramine were more effective on brain tissue 5-HT. The concentration of 5-HT in CSF was significantly increased by all treatments. p-Chloroamphetamine induced a dramatic 70-fold increase of CSF 5-HT, paralleling a 42% decrease in brain tissue. d-Fenfluramine significantly increased CSF 5-HT to 212% of controls and reduced whole brain 5-HT (-23%). The effects of p-chloroamphetamine and d-fenfluramine on 5-HIAA in brain, CSF, and plasma were nonsignificant. Individual values of 5-hydroxyindoleacetic acid (5-HIAA) in CSF and brain were highly correlated (r = 0.855), indicating that CSF 5-HIAA reflects well the concentration of 5-HIAA in brain tissue. Yet the intra- and extracellular concentrations of 5-HIAA were unrelated to the 5-HT changes. This indicates that CSF 5-HIAA does not reflect the active (extracellular) compartment of 5-HT in brain.

CSF neurotransmitter metabolites and short-term outcome of patients in coma after head injury

The main metabolites of the neurotransmitters noradrenaline, dopamine, and serotonin, methoxy-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) respectively, were estimated by HPLC with electrochemical detection in CSF samples from 24 patients in coma after head injury, 1 to 12 (mean 3.0) days from accident, and from 24 age- and sex-matched subjects undergoing myelography for possible herniated disk. Analysis of variance with age as covariate, revealed significantly elevated levels of all three metabolites in the patients group. The concentrations of 5HIAA were negatively correlated to the score in the Glasgow Coma Scale. Fourteen patients who recovered with no or minor neurological deficits, had significantly lower CSF 5HIAA levels compared to the ten patients who had a bad outcome (death), while there were no differences regarding HVA or MHPG concentrations. The possibility of a connection of the high neurotransmitter turnover during coma to the development of post-traumatic depression is discussed.

Suicide risk and serotonin.

The accumulating research evidence for the psychobiological reconceptualization of suicidal behaviour is briefly reviewed, particularly regarding the serotonin hypothesis of suicide risk. The first suggestion of a link between suicide and serotonin came with the biochemical results from postmortem brain studies of suicide victims. Currently available research data suggest decreased brain stem levels of serotonin and 5-HIAA, altered distribution of presynaptic binding of the ligand 3H-imipramine to serotonin neurons and a region-specific increase in the number of postsynaptic 5HT2 receptors in the prefrontal cortex in suicide victims. Early CSF studies have indicated decreased CSF 5-HIAA in patients recently attempting suicide and follow-up studies of large samples of mood-disorder patients confirm the original hypothesis that low CSF 5-HIAA predicts suicide risk after attempted suicide. However, the clinical utility of these compelling biological correlates of suicide in the management of suicide risk in psychiatric patients will depend on the results of psychopharmacological treatment research targeting suicidal behaviour.

HPA-related CSF neuropeptides in suicide attempters

Corticotropin-releasing hormone (CRH), somatostatin (SOM), delta-sleep-inducing peptide (DSIP), neuropeptide Y (NPY), beta-endorphin (beta-END), and vasopressin (AVP), which are regarded as being involved in the HPA-regulation were investigated in lumbar CSF of 44 suicide attempters. The patients were diagnosed according to the DSM-III-R, and rated with the MADRS. The neuropeptides were compared with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF and with post-dexamethasone plasma cortisol. We found strong correlations between CRH and the peptides SOM and beta-END. The latter also correlated positively with SOM. There were no differences between men and women. Patients with major depressive disorders had significantly lower SOM, CRH, and DSIP than other patients. Both SOM and beta-END correlated negatively with post dexamethasone plasma cortisol in all patients. We found no significant relationships between neuropeptides and CSF 5-HIAA. Patients who had made previous suicide attempts had significantly lower CRH than those who had not. No other significant associations between neuropeptides and suicidal subgroups of patients appeared, and there was no indication of specific neuropeptide patterns in patients who later completed suicide. Intercorrelations of some neuropeptides and low SOM and DSIP in major depressed patients are findings in line with those by others.

Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin

Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.

Self-mutilation in personality disorders: psychological and biological correlates

The goal of this study was to determine whether self-mutilators with personality disorders differ from nonmutilators with personality disorders in impulsivity, aggression, and other psychopathology and whether serotonergic dysfunction contributes to self-mutilation. Twenty-six self-mutilators with personality disorders were matched to 26 control subjects with personality disorders for gender, age, education, axis I diagnosis of affective disorder, and axis II diagnosis of personality disorder. Numerous indexes of psychopathology as well as CSF 5-hydroxyindoleacetic acid (5-HIAA) levels and platelet imipramine binding sites (Bmax) and affinity (Kd) were determined. Self-mutilators had significantly more severe character pathology, had greater lifetime aggression, and were more antisocial than the control subjects. The self-mutilators scored higher on the Hamilton Rating Scale for Depression but not on the Beck Depression Inventory or the Beck Hopelessness Scale. The two groups did not differ on the Buss-Durkee Hostility and Guilt Inventory or on the Sensation Seeking Scale. The degree of self-mutilation was significantly correlated with impulsivity, chronic anger, and somatic anxiety. Both self-mutilation and impulsivity showed significant negative correlations with Bmax, although the two groups did not differ in CSF 5-HIAA levels or in platelet imipramine binding. The results demonstrate the contribution of severe character pathology, aggression, impulsivity, anxiety, and anger to self-mutilation and provide preliminary support for the hypothesis of underlying serotonergic dysfunction facilitating self-mutilation.

Lateral ventricle-brain ratio and balance between CSF HVA and 5-HIAA in schizophrenia

Lateral ventricle enlargement in schizophrenia has been positively correlated with poor premorbid competence, negative symptoms, and poor treatment response and negatively correlated with concentrations of homovanillic acid (HVA), a dopaminergic metabolite. The authors provide further evidence of a reciprocal relationship between lateral ventricle size and dopaminergic activity in schizophrenia. They assessed the relationship between lateral ventricle enlargement (ventricle-brain ratio, VBR) and CSF neurotransmitter metabolite concentrations (HVA and 5-hydroxyindoleacetic acid [5-HIAA]) in 45 patients with schizophrenia, 28 with affective disorders (19 patients with major depression and nine with bipolar disorder), and 91 normal comparison subjects. No group mean differences were significant. Although individual correlations of VBR with HVA and 5-HIAA were not statistically significant, the ratio of HVA to 5-HIAA was significantly correlated with VBR in the patients with schizophrenia, a finding consistent with dopaminergic-serotonergic balance hypotheses. These data suggest that it is the balance between HVA and 5-HIAA rather than their absolute levels which is associated with brain morphology and that this relationship between brain chemistry and morphology may be characteristic of the normal range of functioning for these systems. In other words, independent of whether brain morphology and chemistry differentiate psychopathological from nonpsychopathological states, there may be an orderly relationship between lateral ventricle size and the balance between HVA and 5-HIAA balance that is especially prominent in schizophrenia.