Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5-hydroxyindoleacetic acid ratios in depressed patients: relationship to suicidal behavior and dexamethasone nonsuppression

Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.     

Cerebrospinal fluid monoamine metabolites and suicide

Prospective studies of the serotonergic system and suicide report that low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and a history of attempted suicide predict suicide risk. Low CSF homovanillic acid (HVA) is reported to be associated with past and future lethality of suicide attempts but not with suicide. The interrelationships between monoamine metabolites, violent method, suicide intent and lethality of suicidal behaviour are complex. We hypothesized that CSF 5-HIAA and HVA levels are related to suicide intent, violence and lethality of suicidal behaviour. Fifteen male suicide attempters admitted to a psychiatric ward at the Karolinska University Hospital and eight healthy male volunteers were submitted to lumbar puncture and CSF 5-HIAA and HVA were assayed. Suicide intent with the Beck Suicide Intent Scale (SIS), lethality and violence of suicidal behaviour were assessed. All patients were followed up for causes of death. Six suicides and one fatal accident were identified with death certificates. Mean CSF 5-HIAA but not CSF HVA differed between suicides and survivors. Violent suicides had higher suicide intent and CSF 5-HIAA than non-violent suicides. In violent suicides, CSF 5-HIAA levels were negatively correlated with SIS. Greater suicide intent may be associated with greater aggressive intent and predicts a violent suicide method.     

CSF 5-HIAA and DST non-suppression — Orthogonal biologic risk factors for suicide in male mood disorder inpatients

Two biomarkers of suicide risk; non-suppression in the dexamethasone suppression test (DST) and low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) have been reported to be predictors of suicide in mood disorders. The interrelation of the two systems seems to be different in suicide attempters compared with depressed inpatients who have not made a suicide attempt, indicating that the two biomarkers may be seen as independent. This investigation examined the interrelation of low CSF 5-HIAA and DST non-suppression in suicide victims with mood disorder. Fifty-eight mood disorder inpatients not receiving any treatment with antidepressants underwent lumbar puncture and the DST. Plasma cortisol levels at 8:00 a.m., 4:00 p.m. and 11:00 p.m. were analysed in relation to CSF 5-HIAA. All patients were followed up for causes of death and suicides were verified with death certificates. During follow-up (mean 21 years), 11 (19%) patients had committed suicide. In male suicide victims (n = 6), the serum cortisol level at 4:00 p.m. showed a significant positive correlation with CSF 5-HIAA. Low CSF 5-HIAA predicted all early suicides (within 1 year), whereas all males who committed suicide after 1 year were DST non-suppressors. In female suicide victims (n = 5), the post-DST serum cortisol did not correlate with CSF 5-HIAA. Low CSF 5-HIAA and DST non-suppression are orthogonal biologic risk factors for suicide in male mood disorder inpatients. CSF 5-HIAA is associated with short-term suicide risk; dysregulation of the hypothalamic-pituitary-adrenal axis seems to be a long-term suicide predictor.     

CSF 5-HIAA levels are lower in impulsive as compared to nonimpulsive violent suicide attempters and control subjects.

BACKGROUND: We studied CSF 5-HIAA and HVA concentrations in violent suicide attempters and examined their relationship with depression, anxiety, and impulsivity. METHODS: CSF 5-HIAA and HVA concentrations were determined very shortly after hospital admission and compared to those of a matched control population. Clinical evaluation was performed concomitantly; the level impulsivity was evaluated by the Impulsivity Rating Scale (IRS). RESULTS: Twenty-three patients and 23 control subjects were included. According to the IRS, 14 patients were classified as impulsive, including all patients suffering from personality disorders, and 9 as nonimpulsive, with a main DSM-IIIR diagnosis of melancholia. CSF 5-HIAA concentrations in the suicide group were significantly lower than in control subjects. This difference was entirely due to the impulsive suicide attempters. There was an inverse correlation between the IRS score and CSF 5-HIAA (r = -.47, p = .02) and only a trend for HVA (r = -.41, p = .078) levels in the suicide group. CONCLUSIONS: This study of a group of violent suicide attempters distinguished a subgroup of patients diagnosed with personality disorder with high impulsivity scores and a subgroup of patients with the main diagnosis of severe depression. CSF 5-HIAA was significantly lower in impulsive violent attempters than in nonimpulsive violent attempters, therefore desintangling violence from impulsivity and linking this biologic abnormality to impulsivity.     

A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder

Objectives:  Bipolar disorder is a severe illness that is associated with suicidal behavior. A biological predictor of highly lethal suicide attempts in patients with bipolar disorder would be valuable. We hypothesized that cerebrospinal fluid (CSF) monoamine metabolite levels are related to lethality of suicide attempts in bipolar patients and examined the relation between CSF 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and maximum lethality of suicide attempts at baseline and during a 2-year follow up.
Methods:  Twenty-seven bipolar depressed patients participated in the study. Demographic and clinical parameters were examined and recorded. Lumbar punctures were performed and CSF 5-HIAA, HVA, and MHPG were assayed by high-performance liquid chromatography with electrochemical detection. Following discharge, patients were evaluated after 3 months, 1 year, and 2 years. Each follow-up interview included an in-depth assessment of suicidal behavior during the intervening time period.
Results:  Six subjects made suicide attempts during the 2-year follow-up. Bipolar patients who attempted suicide during the follow-up period had higher aggression and hostility scale scores compared to bipolar subjects who did not make a suicide attempt during the follow-up period. CSF 5-HIAA, HVA, and MHPG levels were negatively correlated with the maximum lethality of suicide attempts during the 2-year follow-up period.
Conclusions:  Our finding is the first observation that CSF monoamine metabolite levels may be predictors of lethality of suicide attempts in patients with bipolar disorder. Further studies are necessary to answer the question whether CSF monoamine metabolite levels are clinically useful biochemical predictors of highly lethal suicide attempts or completed suicides.     

Skin conductance habituation and cerebrospinal fluid 5-hydroxyindoleacetic acid in suicidal patients

The concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and psychophysiologic variables, such as habituation of the skin conductance response, were measured in 35 drug-free, suicidal inpatients. Twenty-four patients were hospitalized after a suicide attempt, and another 11 had suicidal ideation. The suicide attempters were classified into nonviolent (drug overdoses taken orally, or a single wrist cut) and violent (all other methods). As in previous studies, the suicide attempters had significantly lower CSF concentrations of 5-HIAA compared with healthy, matched controls. The distribution of habituation rate was bimodal (slow and fast habituators). All violent attempters were fast habituators, as were all four patients who in a one-year follow-up were found to have completed a suicide (all by violent methods). The lowest frequency of fast habituators was found in the group of patients with suicidal ideation. There was no correlation between CSF 5-HIAA and habituation rate. A combination of these two variables yielded a highly significant correlation with type of suicide behavior, both retrospectively and prospectively.     

Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts

Magnesium and calcium concentrations were measured in the cerebrospinal fluid (CSF) of 15 neurological controls and 41 psychiatric patients suffering from major depression (n = 16), schizophrenic disorder (n = 15), or adjustment disorder (n = 10). All subjects were women 19-67 years of age and free from drugs at the time of the study. CSF was evaluated for 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol (CS) levels, and all patients received a dexamethasone suppression test (DST) following lumbar puncture. CSF calcium levels did not differ among groups, although we found a trend toward higher mean levels in both depression and schizophrenia. By contrast, CSF magnesium was found to be significantly lower in both depression and adjustment disorder; if, however, patients who had made suicide attempts were excluded, the difference became insignificant. Patients who had made suicide attempts (by using either violent or nonviolent means) had significantly lower mean CSF magnesium level irrespective of the diagnosis. CSF calcium did not correlate with magnesium, 5-HIAA, HVA, CS, global severity, therapeutic response, or DST, but CSF magnesium correlated significantly with CSF 5-HIAA, especially after correcting for age and body height. Both variables seemed to be primarily related to recorded suicide attempts, but decreased magnesium was not limited to violent cases.     

Amine metabolites, neuroendocrine findings, and personality dimensions as correlates of suicidal behavior

Levels of 5-hydroxyindoleactic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid (CSF) of 62 female inpatients with major depression (n = 19), schizophrenic disorder (n = 18), alcohol dependence (n = 13), and other disorders (n = 12). Nineteen patients had attempted suicide immediately before admission, and six had used violent methods. Fifty-three patients received a dexamethasone suppression test (DST) following lumbar puncture and all completed the Marke-Nyman Temperament Scale (Hungarian version) within 10 days. CSF 5-HIAA was significantly lower in patients who had made violent suicide attempts, but did not differ between suicide attempters who had taken drug overdoses and nonattempters. CSF HVA showed no significant differences. Dexamethasone nonsuppression occurred more frequently among attempters, but this difference did not reach statistical significance. Among the three personality dimensions of the Marke-Nyman Scale, validity was lower and stability higher in suicidal patients; both findings were more pronounced in the violent subgroup. CSF 5-HIAA and Marke-Nyman validity were inversely correlated to each other in all three subgroups, and violent attempters could be separated from the other two groups by their simultaneously low CSF 5-HIAA values and Marke-Nyman validity scores.     

Rorschach ratings in depressed and suicidal patients with low levels of 5-hydroxyindoleacetic acid in cerebrospinal fluid

In order to explore the psychodynamics of a previously observed association between a low concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and an increased tendency to suicidal behavior, blind ratings of Rorschach variables were compared between depressed and/or suicidal patients with low (<80 nanomoles/1) and normal (&#62;80 nanomoles/1) CSF 5-HIAA. In 14 patient pairs matched for sex, age, body height, and interview-based ratings of severity of depression, the low 5-HIAA subjects had significantly more anxiety and more hostility in the Rorschach ratings. Their anxiety tolerance was lower, and they were significantly less efficient in their handling of conflict. The results support the hypothesis that biochemical variables may be of importance for certain psychodynamic mechanisms suggested to be relevant for psychopathology, including suicidal behavior.     

Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels.

BACKGROUND: We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. METHODS: Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. RESULTS: Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. CONCLUSIONS: Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study.     

Association of aggressive behavior with altered serotonergic function in patients who are not suicidal

OBJECTIVE: The purpose of this study was to determine whether aggression and serotonergic dysfunction are related in the absence of a history of suicidal behavior. Although serotonergic dysfunction has been implicated in aggressive and impulsive behavior, most studies of such behavior have included individuals with a history of suicide attempts. Low concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) have been consistently associated with suicidal behavior, presenting a potential confound in the link between aggression and serotonergic dysfunction. METHOD: The authors examined the association between aggression and CSF 5-HIAA concentrations in a group of 64 patients who had different DSM-III-R axis I diagnoses and no past suicidal behavior. Aggressive (N=35) and nonaggressive (N=29) groups were defined by a median split on a six-item history of adulthood aggressive behavior. RESULTS: The aggressive group had significantly lower CSF 5-HIAA concentrations than the nonaggressive group. Aggressive individuals also scored significantly higher on self-report measures of hostility, impulsiveness, and sensation seeking. CSF 5-HIAA concentrations, however, did not correlate with self-reported hostility and impulsivity. CONCLUSIONS: There is an association between aggressive behavior and serotonergic dysfunction independent of suicidal behavior in patients with axis I disorders who exhibit relatively milder forms of aggressive behavior. Analogous to findings with suicidal behavior, a low concentration of CSF 5-HIAA is related to aggressive behavior but does not show the same relationship to the continuum of aggressive feelings and thoughts.     

CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters

OBJECTIVE: To study the predictive value of the Beck Suicide Intent Scale (SIS), the Beck Hopelessness Scale (BHS) and of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid for future early suicide in a group of high-risk male suicide attempters. METHOD: Fifteen consecutive male suicide attempters admitted to a psychiatric ward at the Karolinska Hospital, who were not receiving any treatment with antidepressants were diagnosed according to DSM-III, assessed with SIS and BHS and submitted to lumbar puncture. All patients were followed up for cause of death. RESULTS: Five early suicides (within 2 years) were identified. Mean cerebrospinal fluid (CSF) 5-HIAA differed between suicides and survivors. Low CSF 5-HIAA was identified in those who committed early suicide. Neither the Suicide Intent Score nor the Hopelessness Score distinguished suicides from survivors. CONCLUSION: In high suicide risk hospitalized male psychiatric patients CSF 5-HIAA may be a better predictor of early suicide after attempted suicide than SIS or BHS.     

The relationship between CSF HVA/5-HIAA ratio and suicide intent in suicide attempters.

There is a need to find stable biomarkers for suicidal behavior and suicide prediction. Reduced homovanillic acid/5-hydroxyindolacetic acid (HVA/5-HIAA) ratios in cerebrospinal fluid (CSF) in depressed suicide attempters have been reported. Suicide intent is a predictor of repetition of attempts and suicide. In the present study we investigated the relationship of HVA/5-HIAA ratio to the scales rating suicide intent and depressive symptoms. Fifteen consecutive medication-free male suicide attempters admitted to a psychiatric ward at the Karolinska Hospital and eight healthy male volunteers underwent lumbar puncture and had the CSF monoamine metabolite levels assayed. Patients were assessed with the Beck Suicide Intent Scale (SIS), the Montgomery Asberg Depression rating Scale (MADRS) and the Chapman Scale of Anhedonia. Within the suicide attempter group, HVA/5-HIAA ratio was significantly associated with the Suicide Intent Scale (SIS), but not with the MADRS scale or the Chapman Scale of Anhedonia indicating that the HVA/5-HIAA ratio may be a biomarker of suicide intent.     

Natural killer cell activity and csf monoamine metabolites in suicide attempters

Abstract

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD 16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.     

The dexamethasone suppression test and CSF-5-HIAA in relation to suicidality and depression in suicide attempters.

This study tested suicidality in relation to cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and the dexamethasone suppression test. Patients with nonsuppression of cortisol had the highest scores of the Suicide Assessment Scale (SUAS) and the Montgomery Asberg Depression Rating Scale (MADRS), respectively (P < 0.05; P < 0.01). The results persisted when analysed for covariance with CSF-5-HIAA. We have previously noted an elevated suicide risk in suicide attempters with high SUAS-scores, why a large part of nonsuppressors may be at high risk for future suicide.     

Monoamine oxidase (MAO), 5-hydroxyindole acetic acid (5 HIAA) and homovanillic acid (HVA.) in motor neuron disease

Thrombocyte monoamine oxidase (MAO) activity and concentrations of 5-hydroxyindole acetic acid (5-HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid (CSF) were studied in patients with motor neuron disease (MND) and healthy controls. The MAO activity in MND (n = 32) did not differ from age and sex-matched controls (n = 27) or from healthy relatives (n = 9) and no difference was found between advanced and mild cases. In an attempt to explain divergent results from other studies, the effect of storage time on analysis of platelet concentration was studied in three healthy subjects and in three patients with MND. No difference was observed between the groups. No differences were found between the MND group (n = 28) and healthy controls (n = 18) with regard to CSF levels of 5-HIAA and HVA, except for an increase of 5-HIAA among males with MND. The results of this study do not confirm earlier studies that have reported extensive changes in the variables analyzed in patients with MND.     

Natural killer cell activity and CSF monoamine metabolites in suicide attempters

The aim of this study was to investigate markers of serotonin and immune function in suicidal patients. Cytotoxic activity of natural killer cells (NK) and CD16 lymphocytes were studied in 28 suicide attempters and 26 healthy controls, and related in patients to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF). Patients with CSF 5-HIAA below the median had significantly lower NK cell activity than other patients. CD16 cell frequency was significantly lower in patients than in controls, and patients also tended to have lower NK cell cytotoxicity than healthy controls. There were no statistically significant correlations between 4-hydroxy-3methoxyphenyl glycol (HMPG), homovanillic acid (HVA), CSF cortisol and NK cell activity. The results support the hypothesis of compromised immune function in suicidal patients with evidence of disordered serotonin function.     

CSF metabolites in borderline personality disorder compared with normal controls.

Cerebrospinal metabolites were measured in 17 patients with borderline personality disorder and 17 normal controls. There were no significant differences between the two groups in levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylglycol (MHPG). Within the borderline group, lower levels of CSF 5-HIAA were significantly associated with a history of genuine suicide attempts, but were not associated with violence, self-mutilation, or with the presence of major depression. Thus, CSF 5-HIAA levels are not distinctively low in a diagnostic group characterized by impulsivity and suicidal behavior, but within that group may be associated with genuine suicide attempts.     

Low brain serotonin turnover rate (low CSF 5-HIAA) and impulsive violence.

The findings of a series of studies by the authors support the idea that most impulsive offenders who have a tendency to behave aggressively while intoxicated have a low brain serotonin turnover rate. The impulsive violent offenders with the lowest CSF 5-HIAA concentrations have diurnal activity rhythm disturbances, and are also prone to hypoglycemia after an oral glucose challenge. Low CSF 5-HIAA combined with hyoglycemic tendency also predicts future violence under the influence of alcohol. Sons of alcoholic fathers, who have committed violent crimes, have very low CSF 5-HIAA concentrations. Vagal tone does not correlate significantly with CSF 5-HIAA but correlates with enhanced insulin secretion, which is most prominent in subjects with intermittent explosive disorder. A polymorphism of tryptophan hydroxylase (TPH) gene is associated with low CSF 5-HIAA and a history of suicide attempts.     

CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression.

Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.