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.     

Anxiety in major depression: relationship to suicide attempts

OBJECTIVE: This study was an examination of the relationship of lifetime panic disorder and anxiety symptoms at index hospitalization to a history of a suicide attempt in patients with a major depressive episode. METHOD: A total of 272 inpatients with at least one major depressive episode, with or without a history of a suicide attempt, were entered into the study. They were given structured diagnostic interviews for axis I and axis II disorders. Suicide attempt history, current psychopathology, and traits of aggression and impulsivity were also assessed. RESULTS: The rates of panic disorder did not differ in the suicide attempters and nonattempters. Agitation, psychic anxiety, and hypochondriasis were more severe in the nonattempter group. A multivariate analysis confirmed that this effect was independent of aggression and impulsivity. CONCLUSIONS: Comorbid panic disorder in patients with major depression does not seem to increase the risk for lifetime suicide attempt. The presence of greater anxiety in the nonattempters warrants further investigation.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Comparison of cerebrospinal fluid monoamine metabolite levels in dominant-aggressive and non-aggressive dogs

Aggression has been shown to be related to reduced serotonergic activity in humans and non-human primates, and in rodents. We now studied the relationship between cerebrospinal fluid (CSF) monoamine metabolites and canine aggression in 21 dominant-aggressive dogs (Canis familiaris) and 19 controls. The diagnosis of dominance-related aggression was based upon a history of biting family members in contexts associated with dominance challenges. Post-mortem CSF 5-HIAA, MHPG and HVA were measured by high-performance liquid chromatography using electrochemical detection. Concentrations of CSF 5-HIAA (P = 0.01) and HVA (P < 0.001) were lower in the aggressive group (median values: 5-HIAA 202.0 pmol/ml; HVA 318.0 pmol/ml) than in controls (5-HIAA 298.0 pmol/ml; HVA 552.0 pmol/ml). No differences were noted in CSF MHPG levels. Differences in 5-HIAA were maintained after controlling for breed and age of dogs, but HVA differences may have been breed-dependent. Lower levels of 5-HIAA (P = 0.02) and HVA (P = 0.04) were found in the subgroup of aggressive dogs with a history of biting without warning (5-HIAA 196.0 pmol/ml; HVA 302.0 pmol/ml) compared to dogs that warned (5-HIAA 244.0 pmol/ml; HVA 400.0 pmol/ml). This study suggests that reduced serotonergic function is associated with aggressive behavior and impaired impulse control in dogs, a finding that is consistent with observations in primates, and suggests that serotonin modulates aggressive behavior throughout mammals.     

Cerebrospinal fluid monoamine and monoamine metabolite levels and the dexamethasone suppression test in depression. Relationship to life events

The cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 23 patients meeting DSM-III criteria for major depressive episode, 15 of whom also met criteria for melancholia. Life events during the six-month period before the onset of depression were recorded using Paykel's method. There was no difference in Hamilton depression ratings between patients with life events and those without. However, depressed patients who did not have a life event in the six months before the onset of depression had significantly lower levels of the dopamine metabolite homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid than those with life events. The incidence of nonsuppression on the dexamethasone suppression test was also greater in patients with a major depressive episode who did not have an undesirable life event than in those who did. Thus, the presence or absence of life events led to a separation into biologically distinct groups.     

Acetylcholinesterase activities and monoamine metabolite levels in the cerebrospinal fluid of patients with Alzheimer's disease.

We measured cholinesterase (ChE) activity and monoamine metabolite levels in the cerebrospinal fluid (CSF) of 22 patients with early-onset Alzheimer type dementia (Alzheimer's disease; AD) and of 32 controls. Acetylcholinesterase (AChE) activity, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were significantly lower in AD patients than in controls. However, there was an overlap in values of each CSF parameter. The measurement of various CSF parameters rather than one alone was more useful as a diagnostic aid. CSF ChE activities correlated with scores on the GBS rating scale, Hasegawa dementia scale, and Wechsler Adult Intelligence Scale, but the monoamine metabolite levels did not. Although cholinergic and monoaminergic deficits may coexist in AD patients, cholinergic deficits tend to be more often associated with cognitive decline than the monoaminergic deficits.     

Reproducibility of monoamine metabolite measurements in human cerebrospinal fluid

The levels of homovanillic acid (HVA), 5-hydroxy indoleacetic acid (5HIAA), and 3-methoxy-4-hydroxy phenylglycol (MHPG) were determined in the cerebrospinal fluid (CSF) of 28 patients with cognitive disorders on Day 1 and Days 8 or 15. During that period all patients were kept hospitalized under strict standard conditions, did not develop any acute CNS lesion, had no changes in their treatment and no acute systemic disease. The mean levels found in the first and second determinations were almost identical for the 3 metabolites; respectively 37.8 ng/ml and 36.3 ng/ml for HVA, 27.8 ng/ml and 27.9 ng/ml for 5HIAA, and 12.9 ng/ml and 12.3 ng/ml for MHPG. Thus, the mean values of these metabolites in CSF are reproducible at least during a 15-day hospitalization. However statistically significant individual changes in metabolite levels were found between the two samples in 82% of patients for HVA, 32% for HIAA and 48% for MHPG. The number of patients required to detect a significant change in the mean levels of each monoamine metabolite has been calculated taking into account the extent of intraindividual variations.     

Effect of chlorpromazine treatment on monoamine metabolite levels in cerebrospinal fluid of psychotic patients

Levels of HVA, MOPEG and 5-HIAA in cerebrospinal fluid (CSF) from psychotic men and women with a schizophrenic symptomatology were measured by mass fragmentography. Measurements were made before, 2 and 4 weeks after treatment with chlorpromazine (CPZ) which was given randomly in doses of 200, 400 or 600 mg per day. Before treatment there were positive correlations between the levels of HVA and 5-HIAA in both sexes. During CPZ treatment HVA was significantly elevated, whereas MOPEG and 5-HIAA were reduced. There was a tendency towards tolerance to CPZs effect on HVA during treatment but a significant effect persisted after 4 weeks. No indication of tolerance to the effects on MOPEG or 5-HIAA was found. There were the same tendencies for the elevations of the HVA/MOPEG and HVN5-HIAA ratios. The changes in HVA, MOPEG, 5-HIAA, HVA/MOPEG and HVA/5-HIAA were related to dose of CPZ in men but not in women. The bidirectional change of the different metabolites in CSF during CPZ treatment excludes a general and non-specific mechanism for the metabolite changes. The HVA elevations is in accordance with previous results in animals and man, and is pesumably related to blockade of central dopamine receptors. Possible mechanisms for the effects on MOPEG and 5-HIAA are discussed.     

抑郁症患者脑脊液生长抑素及单胺代谢产物的测定

目的 探讨抑郁症可能的生化病理机制,方法 采用放射免疫测定法及高效液相色谱法,分别测定２７例抑郁症患者和２７例对照者脑脊液（ＣＳＦ）生长抑素（ＳＳ）及单胺代谢产物水平。结果抑郁症组ＧＳＦ中ＳＳ水平和３－甲氧－４羟苯乙二醇（ＭＨＰＧ）水平（Ｐ〈０．０５）和５－羟吲哚乙酸水平（Ｐ〈０．０１）,均低于对照组,而抑制症组ＣＳＦ中高香草酸含量与对照组间的差异无显著性（Ｐ〉０．０５）;抑郁症组ＣＳＦ中ＳＳ与Ｍ     

Diurnal rhythms of plasma cortisol, beta-endorphin and prolactin, and cerebrospinal fluid amine metabolite levels before suicide. Case report

There are indications to suggest a relationship between low levels of 5-hydroxy-indoleacetic acid (5HIAA) in the cerebrospinal fluid and suicidal behavior. Many depressed patients show an elevated cortisol secretion. As beta-endorphin is derived from the same precursor as ACTH, it is expected that plasma beta-endorphin levels will also rise in depressed patients. We report here a case of severe depression with diurnal variation who showed low CSF 5HIAA prior to his suicide. In contrast, his catecholamine metabolites were 50% above the mean values of other depressed patients. Hormonal measurements, however, showed low cortisol, prolactin and beta-endorphin levels.     

Cerebrospinal fluid monoamine metabolite levels in male arsonists

Cerebrospinal fluid (CSF) monoamine metabolite levels were studied in 20 arsonists, 20 habitually violent offenders, and ten healthy inpatient volunteers. The arsonists and violent offenders had been in prison an average of six months before the study. Both the raw data and data adjusted by analysis of covariance for group differences in age, height, sex, and season of the lumbar puncture showed significantly lower concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in the arsonists than in the other groups. The finding remained the same when arsonists with violent suicide attempts were excluded from the analysis. Although CSF concentrations of MHPG or 5-HIAA did not correlate with the severity of repeated fire-setting behavior, low blood glucose nadir in the oral glucose tolerance test (a measure of the tendency toward hypoglycemia) did. These results support the hypothesis that poor impulse control in criminal offenders is associated with low levels of certain CSF monoamine metabolites and with a hypoglycemic tendency.     

Intravenous probenecid loading. Effects on plasma and cerebrospinal fluid probenecid levels and on monoamine metabolites in cerebrospinal fluid.

Probenecid blocks the active transport from cerebrospinal fluid to blood of homovanillic acid and 5-hydroxyindoleacetic acid, thus increasing cerebrospinal fluid levels of these products of central monoamine metabolism. The half-life in plasma of probenecid given as a single intravenous infusion (40 mg per kilogram of body weight) to patients with either Huntington's chorea or Parkinson's disease averaged about 6.6 hours. In cerebrospinal fluid, peak values for homovanillic acid and 5-hydroxyindoleactic acid occurred in samples collected 8 hours after the 1-hour probenecid infusion was started. Even after 4 hours, however, levels of both monoamine metabolites were significantly increased. There was a positive correlation between cerebrospinal fluid levels of probenecid and the increase in 5-hydroxyindoleacetic acid but not homovanillic acid. Compared with the oral administration of probenecid, the intravenous infusion technique produced more consistent elevations in plasma and cerebrospinal fluid probenecid levels, greater increases in cerebrospinal fluid homovanillic acid values, and fewer gastrointestinal side effects.     

Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts

OBJECTIVE: To determine if there is a relation to low serum cholesterol, lipoprotein, serotonin or tryptophan levels in patients with depression who have recently attempted suicide. DESIGN: Biochemical and behavioural study. SETTING: Inpatient and outpatient treatment at the Instituto Mexicano de Psiquiatría. PARTICIPANTS: Thirty-three patients with a diagnosis of major depressive episode. Eighteen of these patients had attempted suicide in the month before the start of the study; 15 patients had never attempted suicide. OUTCOME MEASURES: Serum levels of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, serotonin (5-HT) and tryptophan. Scores on Hamilton Depression Rating Scale, Carroll Depression Rating Scale, Beck Hopelessness Scale and Beck Suicide Attempt Severity Scale. RESULTS: There were no significant differences between patients who had attempted suicide and those who had not in terms of serum cholesterol, HDL, LDL and triglyceride levels. Serum levels of 5-HT and tryptophan were significantly lower in patients with depression who had a recent suicide attempt than in those patients who had never attempted suicide. A comparison of patients not taking antidepressant medication found serum 5-HT levels to be more than 3 times lower in those patients with a recent suicide attempt than in patients with no history of suicide attempt. CONCLUSIONS: The study found no difference in lipid profiles between patients who had attempted suicide and those who had not. Low serum levels of 5-HT may increase the risk of suicide attempt in patients who are depressed.     

Serum lipid levels and suicide attempts

OBJECTIVE: To determine whether a correlation exists between lower serum lipid concentrations and increased suicide risk. METHOD: Serum lipid profiles were pair-matched for 60 patients who had recently experienced failed attempts at suicide and equal numbers of non-suicidal psychiatric patients, and normal controls. Suicide attempt severity was scored using Weisman and Worden's risk-rescue rating scale. RESULTS: (a). Total serum cholesterol and low density lipoprotein levels were found to be lower in the parasuicidal population at statistically significant levels (P < 0.01 and <0.05, respectively); (b). triglyceride concentrations were lower in suicide attempters with major depression compared with non-suicidal depressed patients; and (c). risk-rescue rating scores were negatively correlated with total serum cholesterol levels (r = -0.347, P = 0.007). CONCLUSION: Low lipid metabolism may be a potential biological marker in the assessment of suicide risk. Further investigations are necessary to elucidate the biological mechanisms of these findings.     

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.     

The relationship between cerebrospinal fluid biomarkers and depression in elderly women.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers including the 42 amino-acid form of beta-amyloid (Abeta42), total tau protein (T-tau), and the CSF/serum albumin ratio are markers of brain pathology and metabolism. Abeta42 and T-tau are sometimes used to discriminate geriatric depression from mild forms of Alzheimer disease (AD) in clinical studies. However, studies focusing on the relationship between these CSF biomarkers and geriatric depression are lacking. METHODS: This was a cross-sectional study with a population-based sample of 84 nondemented elderly women in Sweden. Measurements included neuropsychiatric, physical, and lumbar puncture examinations, with Diagnostic and Statistical Manual of Mental Disorders, Third Revision-based depression diagnoses and measurement of CSF levels of Abeta42, T-tau, albumin, and serum albumin. RESULTS: Fourteen women (mean age: 72.6 years) had any depression (11 with major depressive disorder [MDD]). Compared to women without depression, women with MDD had higher levels of Abeta42 and the CSF/serum albumin ratio. The CSF/serum albumin ratio was also higher in women with any depression. No differences in T-tau were observed; however, T-tau increased with age. CONCLUSION: Higher levels of CSF Abeta42 were observed among elderly depressed women, in contrast to lower levels usually observed in AD, indicating potential neuropathological differences between the two disorders. Higher CSF/serum albumin ratios observed in depressed women point to potential vascular processes.     

Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia

Cerebrospinal fluid levels of norepinephrine and six monoamine metabolites were measured in 28 medication-free depressed patients. Patients with a major depressive episode with melancholia (n = 15) had significantly lower levels of the three dopamine metabolites: homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), and conjugated dihydroxyphenylacetic (CONJDOPAC), when compared with a combined group of patients with a major depressive episode or dysthymic disorder (n = 13). In patients with major depressive episode with melancholia, levels of HVA and of the serotonin metabolite 5-hydroxyindoleacetic acid significantly correlated with the severity of depression. In the total group of 28 depressed patients, cerebrospinal fluid (CSF) levels of norepinephrine significantly correlated with symptoms of anxiety. In both patients with major depressive episode and major depressive episode with melancholia, those who were non-suppressors on the dexamethasone suppression test had significantly higher CSF levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol compared to those who were suppressors.