The effect of olanzapine treatment on monoamine metabolite concentrations in the cerebrospinal fluid of schizophrenic patients.

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twenty-three male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days +/- 43; median 16 days), underwent a lumbar puncture (LP). Patients were subsequently treated with olanzapine 10 mg/day for 6 weeks, after which the LP was repeated. CSF was assayed for HVA and 5-HIAA concentrations. Psychiatric symptoms were rated once a week. Olanzapine significantly increased HVA concentrations and the HVA/5-HIAA ratio while 5-HIAA concentrations were not altered. These changes did not significantly correlate with treatment response. A negative correlation was found between HVA concentrations and negative symptoms after olanzapine treatment. In conclusion, olanzapine treatment increases HVA concentrations and the HVA/5-HIAA ratio in CSF of schizophrenic patients, but these changes are unrelated to its clinical efficacy.     

Dopamine and serotonin metabolites in rat cerebroventricular fluid following withdrawal of haloperidol or electroshock treatment

Levels of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the CSF of rats at various times after repeated electroshock treatment (EST) or chronic administration of haloperidol. The acidic metabolites were analyzed in 25 l CSF using HPLC with an electrochemical detector. A significant decrease in the CSF levels of DOPAC and HVA was found 4 days after the last administration of chronic haloperidol, EST, or both. The decrease in the level of the dopamine metabolites indicated a slower dopamine turnover, which might have resulted from hypersensitivity of presynaptic dopamine receptors after these treatments. Rats treated with haloperidol also showed an increase in 5-HIAA levels, possibly due to enhanced serotonin turnover. The 5-HIAA increase following haloperidol was prevented by a concurrent administration of EST, suggesting attenuation by EST of the haloperidol-induced enhancement of serotonin turnover.     

Absence of effect of para-chlorophenylalanine on 5-hydroxyindoleacetic acid in cerebrospinal fluid in man

The effect of para-chlorophenylalanine (PCPA) on the 5-hydroxy-indoleacetic acid (5-HIAA) content in human cerebrospinal fluid (CSF) has been studied. There was no effect on the CSF-content of 5-HIAA 12, 24 or 48 h after a single dose of PCPA 1 g p.o. Neither was there any effect after 1 g/day during 4 days. The increase of 5-HIAA after administration of probenecid was reduced during treatment with PCPA 1 g/day. This reduction, however, is not due to a diminished production of 5-HIAA by PCPA but probably caused by a pharmacological interaction between probenecid and PCPA since the concentrations of probenecid in CSF were lower during administration of PCPA than without that drug.It is concluded that PCPA in the doses used in this study gives no effects on the CSF-concentrations of 5-HIAA.     

CSF monoamine metabolite concentrations vary according to age,rearing, and sex,and are influenced by the stressor of social separation in rhesus monkeys

In humans, CSF monoamine metabolite concentrations have been shown to vary as a complex function of age, sex, psychiatric diagnosis, and stress. To test for such relationships in rhesus monkeys, 28 subjects, reared either in anxiety producing peer-only groups or in mother-infant dyads, were studied at 6, 18 or 50 months of age. Each monkey underwent a series of four 4-day social separations, each followed by 3 days of reunion. Prior to and during the first and fourth separations, CSF was obtained from the cisterna magna and assayed for the serotonin metabolite 5-HIAA, the dopamine metabolite HVA, and the norepinephrine metabolite MHPG. CSF 5-HIAA showed an age-related decline which was greater in the mother-reared subjects. Peer-only-reared males had an increased 5-HIAA concentration relative to females, and higher 5-HIAA levels than mother-reared males. MHPG was also higher in peer-only-reared monkeys than in mother-reared subjects at all ages. In both groups HVA declined across the three ages, and MHPG increased from the 18- to the 50-month measurements. Both MHPG and 5-HIAA concentrations increased during the initial social separation, although only MHPG remained elevated across the repeated separations; HVA, on the other hand declined during social separation. These results are discussed in terms of established anxiety and aggression differences between peer-only and mother-reared monkeys.     

Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias.Part of this work was presented at the 9th C.I.N.P. Congress, Paris, July 7–12, 1974.     

Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenaline in depression

Summary The serotonin and noradrenaline metabolites 5-hydroxyindole-3-acetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were determined in cerebrospinal fluid (CSF) from 18 depressed patients. HMPG levels in CSF decreased significantly when the patients were treated either with chlorimipramine or nortriptyline. 5-HIAA fell from 20.2±7.1 to 11.2±4.9 ng/ml (p<0.001) during chlorimipramine treatment, whereas it was not decreased significantly by treatment with nortriptyline. There was a significant correlation between the CSF concentration of each metabolite before and after treatment. In the seven patients who received nortriptyline the percentage fall of HMPG was more marked than that of 5-HIAA; the converse effect occurred in ten of the eleven treated with chlorimipramine. The relative effects of the two drugs on the CSF levels of 5-HIAA and HMPG were consistent with earlier studies of uptakein vitro and of turnover in animals. Chlorimipramine was a potent inhibitor of the uptake of serotonin, whereas nortriptyline had more influence on noradrenergic mechanisms.     

Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans.

A number of studies have reported decreased human lumbar cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), following chronic administration of selective serotonin reuptake inhibitors (SSRIs). This decrease has been thought to be a consequence of elevated extracellular serotonin and to be mediated through terminal autoreceptor feedback inhibition of serotonin turnover. We wished to study the previously unexamined acute effects of SSRI administration on human CSF 5-HIAA. A serial lumbar puncture (LP) procedure was used to collect CSF samples before and after a single oral 40 mg dose of the SSRI paroxetine (PAR) or matching placebo in eight healthy adult humans in a randomized, double-blind fashion. CSF 5-HIAA concentrations did not change following placebo, but showed a statistically significant 27% mean increase 3 h following PAR. Our findings stand in contrast to the decreases reported for CSF 5-HIAA after chronic SSRI treatment in humans and the decreases seen in brain extracellular 5-HIAA after acute or chronic administration of SSRIs to animals.     

Day/night variation of 5-hydroxyindole acetic acid concentration in rat cerebrospinal fluid after acute and long-term administration of a selective serotonin reuptake inhibitor, fluvoxamine

When 30 mg/kg, p.o. of fluvoxamine, a selective serotonin reuptake inhibitor, was administered, significant increases of 3-methoxy-4-hydroxyphenylglycol (MHPG) and 5-hydroxy indole-3-acetic acid (5-HIAA) contents in rat cerebrospinal fluid (CSF) were observed from two days after administration of fluvoxamine in both the light and dark periods and in the dark period of the light/dark cycle, respectively. In long-term treatment with 15 mg/kg, p.o. of fluvoxamine, the level of MHPG in CSF exhibited no difference, whereas the levels of 5-HIAA showed a significant increase during the light periods. These results suggest that fluvoxamine enhances the 5-HT system, but only with long-term treatment.     

Determinations of 5-hydroxyindoleacetic acid and homovanillic acid in human CSF with monitoring of probenecid levels in CSF and plasma

The accumulation of 5-HIAA and HVA in cerebrospinal fluid (CSF) was studied in eight healthy volunteers after oral administration of probenecid. Simulation indicated that a dose of 4.5 g probenecid should be used to achieve probenecid plasma concentrations between 200 and 400 g/ml. Almost complete inhibition of the active transport of the acidic metabolites was assumed to be obtained at these concentrations. Probenecid 4.5 g was administered in two doses (2.5 g and 2 g), separated by 4 h. Plasma samples were drawn at varying intervals over a period of 46 h and lumbar puncture (LP) was performed at either 14 h or 20 h after the first administration of probenecid. The concentration of probenecid, 5-HIAA and HVA in CSF was estimated and the probenecid-induced accumulation of 5-HIAA and HVA was compared with their baseline values. There were no statistically significant differences (P>0.05) in the accumulation of the monoamine metabolites between the two LP (14 h and 20 h), neither were there any differences in CSF concentrations of probenecid at the time of LP. There were only small differences in probenecid plasma concentrations, although statistically significant. Due to maximum blockade of the active transport system no correlation was observed between the CSF concentration of probenecid and the induced accumulation of 5-HIAA and HVA, respectively. The range of probenecid-induced accumulation for 5-HIAA and HVA in these volunteers was 156–429% and 183–600%, respectively. The suggested monitoring of probenecid plasma levels is proposed as a suitable model to investigate central neuronal activity of dopamine and serotonin in the central nervous system.     

The dopamine-serotonin relationship in clozapine response

The effects of clozapine on the dopamine and serotonin systems may underlie its atypical pharmacologic and clinical profile. To examine this hypothesis, we measured dopamine and serotonin plasma and cerebrospinal (CSF) metabolites and the relationship of these values to treatment response in 19 neuroleptic refractory and intolerant schizophrenic patients. Only a small change in the CSF and plasma homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) levels was found. However, the pretreatment CSF HVA/5HIAA ratio and, to a lesser extent, the CSF HVA level predicted treatment response. These results suggest that the modest relationship between HVA and 5-HIAA and treatment response supports the involvement of both neurotransmitters in the pathophysiology of schizophrenia.     

HPLC assays of 5-HIAA and tryptophan in cerebrospinal fluid and 5-HT and tryptophan in blood: a methodological study with clinical applications

HPLC methods were developed for the assay of 5-hydroxy-tryptamine (5-HT) and tryptophan in blood after a simple precipitation step, and 5-hydroxy-indolamine acetic acid (5-HIAA) and tryptophan in CSF by direct injection of CSF. Using these methods, CSF and blood contents were studied in drug-free volunteers and patients treated with tricyclic antidepressant (TCA) drugs. Previously reported variations in the CSF concentrations of 5-HIAA with sex and age were confirmed. No significant difference between patients and healthy subjects were seen in the concentrations of tryptophan in blood or CSF, which were significantly positively intercorrelated. There was no intercorrelation between the concentrations of tryptophan and 5-HIAA in CSF. Highly significant differences between patients and healthy subjects in the platelet-content of 5-HT could be ascribed to the TCA medication. Three TCA drugs, amitriptyline, clomipramine, and imipramine, were compared regarding influence on the platelet-content of 5-HT. Patients treated with clomipramine were found to have considerably lower 5-HT values than imipramine- and amitriptyline-treated patients. A logarithmic model indicated a positive correlation between the two serotonin markers studied, i.e., the amount of platelet-bound 5-HT and the CSF concentrations of 5-HIAA.     

Modification of serotonin metabolism in rat brain after acute or chronic administration of morphine

The steady state concentration of 5-hydroxyindoleacetic acid (5-HIAA) was elevated in rat brain for at least 4 hr after administration of a single dose of morphine sulfate (30 mg/kg, s.c.), and for more than 40 hr after subcutaneous implantation of pellets of morphine alkaloid. The concentration of 5-HIAA returned to normal 3 days after pellet implantation at a rate that paralleled the development of tolerance to the analgesic and other overt actions of morphine. Morphine did not modify the steady state concentration of serotonin under any of the treatment conditions. The turnover of brain serotonin was increased significantly during the 90-min period following a single injection of morphine sulfate (30 mg/kg, s.c.), as indicated by an increased rate of accumulation of 5-HIAA after blockade of efflux of 5-HIAA by probenecid in morphinetreated animals. As judged either by the rate of accumulation of 5-HIAA after administration of probenecid, or by the rate of accumulation of serotonin after treatment with pargyline, an increase in turnover of serotonin was evident in brains of tolerant rats 72 hr after pellet implantation. The rate of efflux of 5-HIAA from the brain was the same in control and morphine-tolerant rats. These results indicate that changes in brain serotonin metabolism are associated with both the acute effects of morphine and with morphine tolerance.     

Effects of local MAO inhibition in the locus coeruleus on extracellular serotonin and 5-HIAA during exposure to sensory and cardiovascular stimuli

Previously, we have shown that in the presence of pargyline the release of serotonin (5-HT) in the locus coeruleus is modulated by various sensory stimuli and blood pressure fluctuations. The aim of the present study was to investigate whether local inhibition of monoamine oxidase (MAO) influences basal and stimulus-induced release of 5-HT in the locus coeruleus. For this purpose, the locus coeruleus was superfused in the absence and in the presence of the MAO inhibitor pargyline. Additionally, we examined whether the release of the 5-HT metabolite 5-hydroxy-indole acetic acid (5-HIAA) in the locus coeruleus is altered in response to stimuli. The locus coeruleus of the conscious rat was superfused through a push-pull cannula with artificial cerebrospinal fluid (CSF). 5-HT and 5-HIAA were determined in the superfusate. The basal release rate of 5-HT and the basal outflow of 5-HIAA averaged 2.0 fmol/min and 69 fmol/min, respectively. The basal release rate of 5-HT and the 5-HIAA outflow were tetrodotoxin (TTX)-sensitive. In the absence of pargyline, the sensory stimuli noise stress or tail pinch, applied for 10 min, increased 5-HT and 5-HIAA outflow by 50–70%. In contrast, an experimentally induced rise in blood pressure for 10 min enhanced 5-HT release by 50%, but had no effect on 5-HIAA outflow. The release of 5-HT and/or 5-HIAA elicited by sensory stimuli or a blood pressure rise was abolished by TTX. Addition of pargyline to the CSF enhanced 5-HT release fourfold and slightly decreased 5-HIAA outflow. These levels remained stable throughout the entire observation period of 8 h. In the presence of pargyline, 5-HT release elicited by noise, tail pinch and increase in blood pressure was enhanced. It is concluded that superfusion with pargyline enhances 5-HT release and reduces 5-HIAA outflow in the locus coeruleus. Furthermore, the ability of sensory stimuli and baroreceptor activation to enhance 5-HT release is preserved during a prolonged pargyline-induced increase in extracellular 5-HT. Since sensory stimuli enhanced, while baroreceptor activation did not influence 5-HIAA outflow, 5-HIAA is not a reliable index for short-term changes in the activity of serotonergic neurons in the locus coeruleus. Received: 13 July 1998 / Accepted: 10 December 1998     

Serotonin and Disruptive Behaviour; A Critical Evaluation of the Clinical Data

Over the past two decades, several clinical studies have addressed the relationship between aggression, impulsivity and other aspects of disruptive behaviour and indicators of central serotonergic function, particularly hormonal challenge tests and CSF 5-HIAA measurements. Analysis of the 23 studies on CSF 5-HIAA and the 11 studies using challenge tests does not reveal unequivocal support for the serotonin–aggression hypothesis. Taking all the data together, it appears the disturbances in central serotonin neurotransmission, as reflected by lower CSF 5-HIAA levels or blunted prolactin response to a serotonergic challenge compound, may be present in a subgroup of relatively young, male, personality-disordered patients. It is furthermore hypothesized that the functional state of monoaminergic neurotransmission should be studied in relation to the corticosteroid–stress neurobiological systems in order to obtain relevant data about the contribution of genetic, developmental and biological components in the evolvement of aggressive spectrum disorders.     

Effects of chronic fenfluramine on blood serotonin,cerebrospinal fluid metabolites,and behavior in monkeys

The effects of long term (70 days) fenfluramine treatment on selected physiological and behavioral measures were examined in four adult male vervet monkeys (Cercopithecus aethiops sabaeus). Relative to pretreatment baseline values, whole blood serotonin (WBS) and cerebrospinal fluid 5-hydroxyindole acetic acid (5-HIAA) were reduced, cerebrospinal fluid homovanillic acid (HVA) was unaltered, and aggressive and locomotor behavior were increased. Both physiological and behavioral effects were reversible: all measures returned to baseline values in the 35 day post-treatment period, with WBS resuming pretreatment values more rapidly than CSF 5-HIAA. At the relatively low doses (1–4 mg/kg/day) employed in the present study fenfluramine produced behavioral effects similar to those resulting from PCPA and opposite to those following tryptophan administration. Thus the behavioral effects of long-term fenfluramine may involve reductions in serotonergic transmission.     

Behavioral syndrome induced by allylnitrile, crotononitrile or 2-pentenenitrile in rats.

A single oral administration of allylnitrile, crotononitrile or 2-pentenenitrile in rats induced behavioral abnormalities, such as head-twitching, head weaving, hindlimb abduction, backward pedaling and pivoting. The head-twitching, which was most consistently observed, was suppressed by serotonin (5-HT) antagonists, cyproheptadine or methysergide or by the 5-HT depleter, dl-p-chlorophenylalanine but was accentuated by the 5-HT releaser, dl-p-chloroamphetamine. The results suggest that the 5-HT system is involved in producing the behavioral abnormalities. To discover the effects of allylnitrile, crotononitrile and 2-pentenenitrile on the metabolism of 5-HT and dopamine, 6 areas of the brain of the rat were examined on days 1, 6, 15 and 30 after injection. Each of the nitriles caused significant increases in the level of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and in the ratio of 5-HIAA/5-HT, one day after injection. The increase in 5-HIAA was most remarkable, suggesting an enhancement of the serotonergic system. The three nitriles had no effect on the metabolism of dopamine, over a period of 30 days.     

Accelerated metabolism of probenecid during long-term treatment of rats with anticonvulsant drugs: effect on central serotonin turnover studies

Studies were carried out in rats to determine the effects of long-term administration (once daily for 9 days) of phenytoin (50 mg kg^?1), sodium phenobarbital (25 mg kg^?1), primidone (50 mg kg^?1), and l-5-hydroxytryptophan (l-5-HTP; 50 mg kg^?1) on probenecid metabolism and on serotonin turnover rates as estimated by probenecid-induced accumulation of 5-hydroxyindoleacetic acid (5-HIAA) in brain. Without probenecid, mean brain 5-HIAA levels were similar in control and drugtreated rats, suggesting that the turnover rate of brain serotonin was not affected by the chronic anticonvulsant drug pretreatment. But, in the rats treated with phenobarbital, the rate of accumulation of 5-HIAA in brain during the first 90 min after probenecid (200 mg kg^?1) was significantly lower than the rate of accumulation in the control rats. Also, at 6 hr after probenecid, brain 5-HIAA levels were similar to pre-probenecid values in the rats pretreated with phenobarbital or primidone, while 5-HIAA levels were still increased in the rats treated with phenytoin, l-5-HTP, or vehicle. Examination of serum revealed that the concentration of probenecid in serum decreased more rapidly in rats pretreated with either primidone or phenobarbital than in rats given vehicle, l-5-HTP, or phenytoin. It is likely, therefore, that the decreased 5-HIAA accumulation in the brains from these animals were due to decreased inhibition of 5-HIAA efflux and not to a decreased rate of serotonin turnover in brain. Since a sustained inhibition of acid transport by probenecid is required, drug interactions with probenecid may be important in clinical studies using probenecid-induced accumulations of 5-HIAA in cerebrospinal fluid to estimate central serotonin turnover rates.     

Acute and chronic effects of carpipramine, clozapine, haloperidol and sulpiride on the metabolism of biogenic amines in the rat brain (author's transl)]

In acute and chronic experiments investigations were made concerning the effect of clozapine, haloperidol, sulpiride and carpipramine on MHPG, HVA and 5-HIAA in rat brain and on motor activity of the animals. The activity of the rats treated with clozapine and haloperidol was reduced on the first day. After 10 days of treatment this effected of clozapine was significantly diminished. The MHPG level increased slightly on the first day of treatment with all four drugs. This elevation was maintained after chronic treatment with carpipramine and sulpiride, whereas clozapine and haloperidol decreased the MHPG content. 5-HIAA values did not show significant changes in acute experiments, whereas in chronic ones there was an increase. Haloperidol and clozapine induced a strong increase of HVA which decreased after 11 days in those animals treated with haloperidol. In comparison to haloperidol, after clozapine application the percentage of HVA-increase was higher in the limbic system than in the nigrostriatum.     

Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment.

This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment.     

Minipump clorgyline administration and CSF amine metabolites in unrestrained monkeys.

The irreversible MAO-A inhibitor clorgyline was administered in doses of 0.5 mg/kg (N = 1), 1 mg/kg (N = 3), and 2 mg/kg (N = 1) to 5 young (age 5.5 to 23.9 months) pigtail (M. nemestrina) monkeys using a 28-day (Alza 2ML4) osmotic minipump. CSF MHPG, 5-HIAA, HVA, and plasma MHPG were measured before and at approximately weekly intervals after pump implantation. Implants were well tolerated. CSF MHPG decreased about 75%, 5-HIAA 30%, and HVA from 30-50% with a tendency to plateau by the second week. Plasma MHPG decreased to undetectable levels. The findings demonstrate that long-term inhibition of MAO-A can be produced in unrestrained monkeys by minipump administered clorgyline. There is an apparently greater effect on the norepinephrine system relative to the serotonin and dopamine systems.