Depression and parkinson's disease: possible role of serotonergic mechanisms

Summary Depression is frequently encountered in Parkinson's disease and was seen to occur in 14 of 26 patients studied. The levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin (5-HT), in CSF samples of the patients were significantly lower than in those of controls. However, within the group of patients the levels of 5-HIAA in CSF samples were significantly lower in the depressive subgroup compared with the non-depressive patients. Moreover, no correlation was recorded between motor disability and depression. The results indicate that disturbed 5-HT metabolism may possibly play a role in Parkinson's disease as a predisposing factor in the development of depression.     

Concentrations of indoleamine metabolic intermediates in the ventricular cerebrospinal fluid of advanced Parkinson's patients with severe postural instability and gait disorders

Summary Postural instability and gait disorders (PIGD) are the primary causes of disability in many but not all advanced Parkinson's disease (PD) patients. We have measured the concentrations of serotonin, 5-hydroxytryptophan (5-HTP), 5-hydroxy-3-indoleacetic acid (5-HIAA), and homovanillic acid (HVA) in samples of ventricular cerebrospinal fluid from ten PD patients with severe disability from PIGD and from ten PD patients with tremor and levodopa induced dyskinesia as their predominant motor dysfunction. The two groups were prospectively matched for duration of disease and age. No significant differences between the two groups were found in the concentration (mean ± SD in ng/ml, PIGD dominant vs. tremordyskinesia dominant) of 5-HIAA (106 ± 50 vs. 99 ± 34) or HVA (1,068 ± 595 vs. 881 ± 469). Serotonin concentration was significantly lower (0.7 ± 0.5 vs. 1.5 ± 0.9) and 5-HTP concentration was substantially higher (684 ± 1,054 vs. 6 ± 5) in the patient group with PIGD as their predominant symptoms. Thus, the distinguishing feature of patients with severe PIGD appears to be a derangement in indoleamine metabolism at the reaction step catalyzed by aromatic amino acid decarboxylase (AADC). These findings suggest that aggravation of PIGD in advanced Parkinson's may be related in part to impaired serotonergic transmission secondary to inhibition or down regulation of AADC.     

Study of tryptophan metabolism via serotonin in cerebrospinal fluid of patients with noncommunicating hydrocephalus using a new endoscopic technique

By a recent minimally invasive neuroendoscopic technique, the cerebral ventricles have been reached in a quick, reliable, and harmless way, making possible the study of cerebrospinal fluid (CSF) of the lateral ventricles and, above all, the CSF adjacent to the walls of the third ventricle. Tryptophan, 5-hydroxytryptophan, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured in CSF by HPLC equipment. Twenty-six patients affected with noncommunicating hydrocephalus were enrolled in the study and, as controls, 28 subjects not suffering from any neurological disease. The concentrations of tryptophan were higher in right ventricular CSF than in lumbar CSF (P < 0.01). 5-HT was detectable in the CSF of the right ventricle of hydrocephalic patients. 5-HIAA was higher in right ventricular CSF than in cisternal and lumbar CSF (P < 0.01), both in controls and in hydrocephalic patients. However, there was a higher concentration of 5-HIAA in right ventricular (P < 0.05) and cisternal (P < 0.01) CSF in hydrocephalic patients in comparison with controls. In the CSF samples withdrawn during neuroendoscopy, 5-HT presented the highest concentrations in the pineal recess. The highest amounts of 5-HIAA were found in the choroid plexus, third and right ventricles, pituitary recess, and aqueduct, and the lowest in pineal recess, subarachnoid space, infundibulum, and interpeduncolar cistern. These results provide new insight into the fate of tryptophan and its metabolites via serotonin in the CSF and suggest the feasibility of the new neuroendoscopic technique for brain metabolic studies.     

CSF monoamine metabolites of depressed patients during illness and after recovery

Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness.     

CSF monoamine metabolites and somatostatin in Alzheimer's disease and major depression.

Decreased cerebrospinal fluid (CSF), somatostatinlike immunoreactivity (SLI) and alterations in the CSF monamine metabolites 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) have been reported in patients with probable Alzheimer's disease (AD) and in patients with major depression. In this study, we found CSF SLI to be significantly lower in a large group of AD patients (n = 60) and in a group of age-matched patients with major depression (n = 18) as compared with normal controls (n = 12). Mean CSF, MHPG, 5-HIAA, and HVA levels were not significantly different among diagnostic groups. Within a group of "depressed" AD patients, CSF levels of 5-HIAA showed a significant positive correlation (p = 0.03) with CSF SLI; a similar relationship was found within the group of patients with major depression. Further exploration of the relationship between the somatostatin and serotonin systems may provide clues as to how neuropeptides interact with monoamine neurotransmitters and what role they have in depression.     

Pathomechanism of dyskinesia associated with treatment of Parkinson disease with levodopa

The 5-HIAA/HVA ratio was determined in the cerebrospinal fluid in 5 patients with Parkinson's disease with L-DOPA preparations in which drug-induced dyskineses developed, in 5 patients treated with L-DOPA without dyskineses, and 10 controls. A decrease in the 5-HIAA/HVA ratio was observed in the group with dyskineses as compared with patients without dyskineses and in controls. The directions of further investigations on hte pathomechanism of drug-induced dyskineses are discussed.     

Neurotransmitters in CSF of idiopathic adult-onset dystonia: Reduced 5-HIAA levels as evidence of impaired serotonergic metabolism

Summary While several radiological findings point towards the basal ganglia as a possible anatomical site of the lesion in dystonia patients the biochemical basis of the disorder is still unknown. 5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels — the respective metabolites of serotonin and dopamine — were measured in lumbar cerebrospinal fluid (lCSF) of 15 patients with idiopathic adult-onset focal dystonia and in lCSF of 11 controls. 100 l lCSF were analyzed for 5-HIAA and HVA by reversed-phase HPLC with electrochemical detection. 5-HIAA levels were significantly reduced in dystonia patients (11.4g/ml) compared to controls (18.4ng/ml) (p < 0.02). HVA levels in dystonia patients (30.3ng/ml) were below control values (41.6ng/ml) but this finding did not reach statistical significance. Decreased lCSF levels of 5-HIAA suggest an impaired serotonin metabolism in patients with idiopathic adult-onset dystonia. This observation may provide a biochemical basis for a more specific pharmacotherapy in dystonia patients.     

A comparative study on neurochemistry of cerebrospinal fluid in advanced Parkinson's disease

This study addresses two issues: (1) the comparative neurochemistry of classic tremor type of Parkinson's disease or PD-A and akinetic type of Parkinson's disease or PD-B; and (2) the neurochemistry of levodopa failure syndrome (LDFS). Cerebrospinal fluid from the lateral ventricle was collected from 50 patients with idiopathic Parkinson's disease of PD-A and PD-B. Levels of monoamine neurotransmitters and metabolites were determined using high performance liquid chromatography. We have found that (1) 5-hydroxylindoleacetic acid (5-HIAA) level is significantly lower in PD-B than in PD-A; (2) 5-HIAA level is inversely associated with score of part one of United Parkinson's Disease Rating Score (UPDRS); (3) 5-HIAA level is inversely associated with score of part four of UPDRS; (4) 3-O-methyldopa (3-OMD) level is positively associated with levodopa failure syndrome (LDFS) assessed by part four of UPDRS and inversely associates with 5-HIAA. From these data, it can be inferred that serotonergic activity is decreased in PD-B to a greater extent than in PD-A and that decreased serotonergic activity plays a role in LDFS.     

L-5-hydroxytryptophan in treatment of several different syndromes in which myoclonus is prominent.

The serotonin precursor L-5-hydroxytryptophan is useful therapy for patients with posthypoxic intention myoclonus. L-5-hydroxytryptophan plus carbidopa was administered to eight patients with this disorder or other syndromes in which myoclonus is prominent. This treatment (1) decreased the frequency of occurrence and amplitude of intention myoclonus in two patients with posthypoxic intention myoclonus and in one with idiopathic myoclonus, (2) had no effect in one patient with congenital encephalopathy and myoclonus, and (3) increased the frequency of occurrence and amplitude of myoclonus in two patients with lipid storage disease, one with myoclonic epilepsy, and in an additional patient with idiopathic myoclonus. Therefore, L-5-hydroxytryptophan does not effect improvement in all forms of myoclonus; it should be given with caution because it produces a high incidence of side effects. A patient's response to L-5-hydroxytryptophan therapy may be important in a diagnostic classification of myoclonic syndromes based on differences in indoleamine neurotransmitter function.     

Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (zimelidine) in chronic pain patients

Both the endorphin and the serotonin systems seem to be involved in pain perception, and a significant positive correlation between the levels of endorphins and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) has been established. In the present study, 20 chronic pain patients were treated with zimelidine, a rather selective inhibitor of serotonin reuptake, or placebo. Zimelidine produced a significant pain relief and a significant reduction of the levels of endorphins and 5-HIAA in CSF, while no significant changes occurred during placebo treatment. The results indicate that both the endorphin and the serotonin systems are involved in pain perception and that the systems are functionally related.     

Clinical, biochemical, and pharmacological observation in a patient with postasphyxic myoclonus: association to serotonin hyperactivity

Posthypoxic action myoclonus is usually associated with impaired serotonin (5-HT) neurotransmission but in some patients 5-HT precursors aggravate and 5-HT blockers improve action myoclonus. We studied a 65-year-old man who presented with action myoclonus following a prolonged episode of moderate hypoxia and severe hypercarbia. The myoclonus increased with 5-hydroxytryptophan (5-HTP) 1,200 mg/day plus carbidopa 300 mg/day and sodium salt of valproic acid (SVA) 800 mg/day, and improved with 1 mg of clonazepam (CNZ) in an intravenous bolus. Biochemical analysis of the cerebrospinal fluid (CSF) prior to any drug therapy did not reveal abnormalities in the levels of homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) but 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated in comparison with controls (33 versus 21 ng/ml). SVA therapy produced a moderate increase and 5-HTP plus carbidopa a threefold elevation of 5-HIAA in CSF and marked aggravation of action myoclonus. Methysergide (3 mg/day) totally suppressed myoclonus and decreased CSF 5-HIAA to undetectable levels. Methysergide also reduced CSF tryptophan to 40% of baseline levels. Discontinuation of methysergide and substitution by placebo was followed by reappearance of myoclonus. A partial and incomplete spontaneous remission of symptoms took place 7 months after the asphyxic episode. Action myoclonus and enhanced 5-HT neurotransmission may be present in patients in which acidosis reverses the effects of hypoxia on 5-HT neurotransmission.     

Monoamine metabolites in human cerebrospinal fluid. HPLC/ED method

Catecholamines and indolealkylamines are of clinical interest in neurological and psychiatric disorders. We measured 3-methoxy-DOPA, 3-methoxy-4-hydroxyphenylglycol, dihydroxyphenylacetic acid, tryptophan, 5-hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid with a simple, sensitive , inexpensive, rapid and accurate procedure using high performance liquid chromatography coupled to an electrochemical detector. Patients with Parkinson's disease have a decrement in homovanillic acid that is reversed by treatment with L-3,4-dihydroxyphenylalanine. After this medication, 3-methoxy-DOPA is measurable in cerebrospinal fluid. Patients with depression show a decrease in serotonin turnover expressed by diminished 5-hydroxyindoleacetic acid content in cerebrospinal fluid. Depressed patients also show low levels of tryptophan. Monoamine metabolites are augmented in patients with subarachnoid hemorrhage.     

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。     

Obsessive-compulsive disorder and serotonin: is there a connection?

Reports of the antiobsessional efficacy of clomipramine have led to a "serotonin hypothesis" of obsessive-compulsive disorder (OCD). To test this hypothesis, 16 outpatients with DSM-III OCD were studied using several measures of serotonergic function. Platelet 3H-imipramine binding and serotonin uptake were not significantly different between the OCD patients and a normal, age-matched control group. The level of the metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) was significantly higher in a small cohort of obsessionals compared with healthy volunteers, possibly reflecting increased brain serotonin turnover. In a direct test of the role of serotonin uptake in clomipramine's antiobsessional effects, the serotonin uptake inhibitor zimelidine was compared with the noradrenergic uptake inhibitor desipramine in a double-blind, controlled study. Zimelidine reduced CSF 5-HIAA, but was clinically ineffective in this group. Desipramine had weak but significant clinical effects. Nonresponders to zimelidine or desipramine improved significantly during a subsequent double blind trial of clomipramine. These findings demonstrate that pharmacological blockade of serotonin reuptake alone is not sufficient for an antiobsessional response.     

Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter.

Recently, a functional polymorphism in the promoter region of the serotonin transporter gene has been linked to anxiety. In cell culture, the short allele of this polymorphism synthesizes less serotonin transporter, resulting in a reduction of the removal of serotonin from the synaptic cleft. This pilot study examines depression and anxiety in Parkinson's disease patients as a function of the variation in this polymorphism. Thirty-two patients were genotyped and then blindly administered the Hamilton Depression and Anxiety Scales. Clinical data on the neurologic features of the disease were also gathered. Patients with the short allele of the serotonin transporter promotor scored significantly higher on both the depression and anxiety measures. There were no differences between groups for any neurologic variable. Patients with the short allele were more likely to have scores for anxiety and depression that indicated "caseness." This study suggests that the short allele of the serotonin transporter gene may represent a significant risk factor for the development of anxiety and depression in Parkinson's disease patients.     

5-HIAA and HVA in CSF in patients with idiopathic pain disorders

Patients with idiopathic pain syndromes were compared with healthy volunteers and with patients suffering from chronic pain syndromes of neurogenic origin, with respect to the concentrations of the metabolites 5-hydroxy-indole-acetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). Patients with idiopathic pain syndromes were subdivided according to the presence or absence of somatic lesions. It was found that these groups did not differ in concentrations of 5-HIAA or HVA, at least not when values were corrected for age, sex, and body height. Patients with idiopathic pain syndromes were found to have low concentrations of 5-HIAA, but not of HVA, in CSF. These differences were also obvious when the values were corrected for age, sex, and body height. As low concentrations of 5-HIAA in CSF have previously been demonstrated in patients with depressive disorders, our results support the suggestion by Blumer and Heilbronn (1982) that the idiopathic pain syndrome is a variant of depressive disease. At least the two syndromes share a common pathogenetic mechanism--a disturbance in serotonergic turnover.     

Chronic, multiple tics of Gilles de la Tourette's disease. CSF acid monoamine metabolites after probenecid administration.

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.     

Treatment of myoclonus with l-5-hydroxytryptophan and carbidopa: Clinical,electrophusiological, and biochemical observations

Six patients with myoclonus of varying cause were treated with L-5-hydroxytryptophan (L-5-HTP) and carbidopa. While spontaneous myoclonus decreased in three of the patients and action myoclonus in four, only two patients had marked functional improvement. Side effects included gastrointestinal and affective disturbances. L-5-HTP therapy caused a diminished frequency of paroxysmal discharges in the electroencephalograms of three patients which did not always correlate with clinical improvement. Lumbar cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration after probenecid was decreased in all patients prior to therapy, but this reduction did not predict treatment response. Urinary excretion patterns for 5-HTP, serotonin, and 5-HIAA during treatment were similar in responders and nonresponders. It is concluded that while some patients with myoclonus do benefit from L-5-HTP therapy, biochemical and electrophysilogical tests are not useful predictors of treatment response, and the high incidence of side effects limits the usefulness of this therapy.     

Drug-induced dyskinesia during the treatment of Parkinson disease--biochemical studies

The concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were determined in the cerebrospinal fluid in 17 patients with Parkinson's disease and 10 controls. The patients with Parkinson's disease were on long-term treatment with L-DOPA preparations. In 9 of them drug-induced dyskineses were observed. The HVA/5-HIAA ratio was determined in the cerebrospinal fluid separately in cases with dyskineses, in cases without dyskineses and in controls. It was found that this ratio was significantly higher in patients with drug-induced dyskineses as compared to patients without dyskineses, and especially to controls. It is suggested that this may mean that in cases of drug-induced dyskineses disturbances exist in the equilibrium between the dopaminergic and serotoninergic systems in favour of the former, which may be one of the causes of involuntary movements.     

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.