Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type

The possibility of disturbed dopamine and serotonin metabolism in senile dementia of Alzheimer type was studied. The basal concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were studied in 28 patients with senile dementia of Alzheimer type and in 13 controls of similar age with no neurological disease. The concentrations of HVA were significantly reduced in the dementia patients compared to the concentrations of the controls. The values of HVA were also significantly reduced in the most severely demented patients compared to the less severely demented ones. There was a slight but statistically significant decrease in the 5-HIAA levels in the dementia patients compared to the levels of the controls. The 5-HIAA levels were reduced in the most severely demented patients compared to the controls but not when compared with the less severely demented patients.
It is concluded that in severe forms of senile dementia of Alzheimer type, there is a decrease in the levels of HVA and 5-HIAA in CSF which may reflect a decreased turnover of dopamine and serotonin. Patients diagnosed as senile dementia of Alzheimer type, but with less severe symptoms, had levels of HVA and 5-HIAA similar to controls.     

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.     

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.     

5-HIAA in cerebrospinal fluid of patients with status epilepticus

Cerebrospinal fluid concentration of 5-hydroxyindolacetic acid (5-HIAA) was determined in 15 patients soon after recovery from status epilepticus. Similarly, patients with generalised epilepsy and persons without epilepsy, serving as controls, were also studied. The level of 5-HIAA was significantly reduced in all epileptic patients with or without status epilepticus, as compared with the nonepileptic control group. However, there was no statistical difference between patients with status epilepticus and those with generalised epilepsy. Among patients with epilepsy, low 5-HIAA levels in CSF could not be correlated with frequency or severity of seizures, or with antiepileptic drugs. A link between CSF 5-HIAA and susceptibility of humans to epilepsy may indicate a possible future therapeutic approach.     

Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression.

(1) A radioimmunoassay of thyrotropin releasing hormone (TRH) in cerebrospinal fluid (CSF) has been developed. The lower detection limit was 2.0 pg/ml. (2) The concentration of TRH in lumbar fluid from 20 patients with various neurological diseases averaged 5.4 pg/ml (1.9–10.7). In 2 patients the concentration was below detection limit. (3) The TRH concentration was not related to sex or age. (4) In 15 patients with endogenous depression the concentration was elevated (p<0.01), before electroconvulsive treatment (24.2 pg/ml, range: 6.9–187) as well as after such therapy (14.4 pg/ml, range 6.0–31.0). The values before and after treatment were not significantly different. (5) The concentration of TRH was not correlated to the serum thyrotropin (TSH) response to 200 μg TRH i.v. (6) Changes in TRH concentration were also unrelated to changes in the TSH response to TRH and to the clinical outcome after 6 months of observation.     

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.     

5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of children with febrile convulsions.

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by high-performance liquid chromatography (HPLC) in lumbar cerebrospinal fluid (CSF) obtained from febrile children subdivided according to the presence or absence of convulsions. Lumbar puncture was made either early (mean time 2 h) or late (3-6 days) after the febrile convulsion. The level of 5-HIAA was significantly decreased in children early and late after the febrile convulsion as compared with the convulsion-free group, but the HVA level was reduced only early after the febrile convulsion. These results support the hypothesis that a decrease in CSF 5-HIAA may be a biologic marker of susceptibility to convulsions and indicate that the transient decrease in HVA is a secondary phenomenon related to occurrence of convulsions.     

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.     

Monoamine metabolites in successive samples of spinal fluid

Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were measured in the cerebrospinal fluid from patients with multiple sclerosis and from healthy volunteers. The fluid was withdrawn with the persons in the lateral recumbent position. In the controls and in 4 of the patients 10 successive samples of 2 ml each were analyzed. In the remaining patients the first 2 ml and last 2 ml of a total 20 ml were analysed. The highest values were obtained in the last portion. Patients with multiple sclerosis had significantly lower levels of 5-HIAA than controls in both the first and last CSF samples. Patients with a progressive course or prominent residual symptoms had a lower concentration of 5-HIAA and HVA than those with a relapsing course and little residual symptoms. The difference was significant for 5-HIAA.     

Uncoupling of serotonergic and noradrenergic systems in depression: Preliminary evidence from continuous cerebrospinal fluid sampling

We used the technique of continuous cerebrospinal fluid (CSF) sampling to test the following hypotheses regarding CNS monoaminergic systems in depression:(1) absolute concentrations of the informational substances tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) are altered in the CNS of depressed patients (2) abnormal rhythms of tryptophan and/or 5-HIAA, or defective conversion of tryptophan to serotonin (5HT), exist in the CNS of depressed patients, and (3) the relationship between the CNS 5HT and norepinephrine (NE) systems is disrupted in depressed patients. We obtained 6-h concentration time series of tryptophan, 5-HIAA, NE, and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF of 10 patients with major depression and in 10 normal volunteers. No significant differences in CSF tryptophan, 5-HIAA, NE, or MHPG concentrations or rhythms were observed between normal volunteers and depressed patients. Neither were there differences in the mean tryptophan-to-serotonin ratio. However, a negative linear relationship was observed between mean concentrations of 5-HIAA and NE in the CSF of the normal volunteers (r = 0.916 [r2 = 0.839], df = 9, P < 0.001) while, in contrast, depressed patients showed no such relationship (r = +0.094 [r2 = 0.00877], df = 9, n.s.). Furthermore, the correlation coefficients expressing the relationship between CSF MHPG and CSF 5-HIAA within the normal and depressed groups were significantly different. These data support the hypothesis that a disturbance in the interaction between the serotonergic and noradrenergic systems can exist in depressive illness in the absence of any simple 5HT or NE deficit or surplus. Depression and Anxiety 6:89–94, 1997.© 1997 Wiley-Liss, Inc.     

Measurement of 5-HIAA levels in ventricular CSF (by LCEC) and in striatum (byin vivo voltammetry) during pharmacological modifications of serotonin metabolism in the rat

Summary The relationship between the concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF and in the striatum has been evaluated in the rat by measuring the levels of this metabolite in ventricular CSF (by liquid chromatography coupled with electrochemical detection) and in the striatal extracellular fluid (byin vivo voltammetry) after administration of inhibitors of serotonin synthesis or degradation. Pargyline, NSD 1015 and-propyldopacetamide all caused an exponential decline of 5-HIAA in both CSF and striatum. For a given drug, the rate constants for 5-HIAA disappearance were identical in the CSF and in the striatal extracellular fluid. These results confirm the view that CSF 5-HIAA may serve as a good index of brain serotonin turnover.     

Antidepressant treatment is associated with a reduction in suicidal ideation and suicide attempts

Objective: To measure changes in suicidal behaviours during 6 months of treatment with antidepressants. Method: A group of depressed patients (n = 195) were assessed for suicidal behaviours in the 6 months prior to treatment. They were prospectively assessed for suicidal behaviours during 6 months of treatment with antidepressants. Results: Patients who made suicide attempts fell from 39 in the 6 months prior to treatment to 20 during treatment. Significant suicidal ideation reduced from 47% at baseline to 14% at 3 weeks remaining below this during the rest of the treatment. Twenty patients had emergent suicidal ideation; five of them had not experienced some level of suicidal behaviour in the 6 months prior to treatment. Conclusion: Suicide behaviours are common in depressed out‐patients. Antidepressant treatment is associated with a rapid and significant reduction in suicidal behaviours. The rate of emergent suicidal behaviour was low and the risk benefit ratio for antidepressants appears to favour their use.     

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene

Summary Psychotic women with schizophrenic symptoms were treated with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34) using a double-blind procedure. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.A preliminary report of the present study was presented at the VI International Congress of Pharmacology, Helsinki, 1975Financial support was provided by the Swedish Medical Research Council (14X-03560), National Institutes of Mental Health, (MH 27254-01), Bethesda, Maryland, USA, F. Hoffmann-La Roche & Co., Basle, Switzerland, Svenska Sällskapet för Medicinsk Forskning, Karolinska Institutet, AB Ferrosan, Sweden, and Pfizer-Roerig, Sweden.     

Biogenic amine metabolites in cerebrospinal fluid of patients with affective disorders

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in lumbar CSF from 33 patients with affective illnes and from 23 neurological controls. The group of patients with affective illness comprised 29 depressed and four manic patients. During illness, the concentration of HVA was higher in the depressed patients (P >0.001) than in the controls. Both unipolar and bipolar depressed patients had increased HVA levels (P >0.001 and P >0.05, respectively). The concentration of MHPG was greater than control values in the unipolar (P < 0.001) and bipolar (P < 0.002) subgroups but did not differ from control values in the depressed group as a whole. The concentration of 5-HIAA in the depressed patients as a whole and in the unipolar and bipolar subgroups did not differ from control concentrations. During illness the manic patients had increased levels of HVA (P >0.01) and normal levels of 5-HIAA and MHPG. Sixteen of the 29 depressed patients had a second lumbar puncture after they had recovered. Compared with the pre-recovery values, the concentration of HVA was reduced in the unipolar depressives (P < 0.01) and the concentration of 5-HIAA lowered in the depressed group as a whole (P >0.02). The present findings suggest involvement of catecholamines in affective disorders.     

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.     

Retrospective analysis of psychomotor agitation, hypomanic symptoms, and suicidal ideation in unipolar depression

In bipolar depression, psychomotor agitation is relatively common and often is associated with other noneuphoric hypomanic symptoms and suicidal ideation. Our goal in this retrospective study was to ascertain the co-occurrence of agitation, bipolar features, and suicidal ideation in unipolar disorder. We retrospectively evaluated 314 inpatients with DSM-IV major depressive disorder (MDD) and no other Axis I diagnosis with the National Institutes of Mental Health (NIMH) Life Chart Method and the Operational Criteria for Psychotic Illness (OPCRIT) checklist to ascertain their symptom profiles across all episodes. Univariate and multivariate comparisons were performed between the subgroups with and without psychomotor agitation (OPCRIT item 23> or =1). Agitated depression (AD, a major depressive episode with psychomotor agitation) was present in 19% of the sample. Compared to nonagitated counterparts, patients with AD were older and had lower educational levels and more dysphoria, insomnia, positive thought disorder, and psychotic manifestations. Hypomanic symptoms other than agitation were relatively uncommon (<10%) and more represented in subjects with AD. No significant differences emerged between AD and control groups with respect to most bipolar validators (gender, familiarity, recurrence). Patients with AD had higher levels of suicidal ideation than non-AD controls; however, such a difference was no longer significant after controlling for psychotic features. Excessive self-reproach, early awakening, diurnal changes, poor appetite, and hypomanic symptoms were independently associated with suicidal thoughts in nonpsychotic MDD. Incomplete information on drug treatment, exclusion of patients with Axis I comorbidity, and tertiary care setting were the most important limitations of the study. Although we failed to support the bipolar nature of MDD-AD by common validators, probably because we used a more heterogeneous definition of agitation compared to similar studies, our data confirm the association of agitation with hypomanic symptoms and suicidal thoughts in major depression, and emphasize the complex phenomenology of AD in an inpatient setting.