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.     

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.     

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.     

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid levels in women with comorbid depression and panic disorder

Major depression comorbid with panic disorder has a more severe clinical picture and adverse course than either disorder alone, and both conditions are associated with abnormalities in the serotonin system. Therefore, we hypothesized that central serotonergic function in the patients with comorbid panic disorder would be more disturbed than in major depression alone. Concentrations of cerebrospinal fluid (CSF) monoamine metabolites of serotonin, norepinephrine, and dopamine were assayed by high-pressure liquid chromatography, and compared in female subjects with DSM-IV-diagnosed major depressive disorder and a lifetime diagnosis of panic disorder (MDD+PD, n=13), major depressive disorder and no lifetime panic disorder (MDD-, n=35), and a healthy volunteer (HV, n=15) group. All subjects were free of antidepressant medication for at least 14 d prior to the lumbar puncture procedure. CSF 5-hydroxylindoleacetic acid (5-HIAA) was higher in the MDD+PD group (124.0+/-43.0 nmol/l) compared with the MDD- group (100.1+/-28.8 nmol/l, p=0.03) and the HV group (93.3+/-33.6 nmol/l, p=0.02). The MDD- group and HV group did not differ in CSF 5-HIAA. There were no group differences in the CSF metabolites of norepinephrine and dopamine, 3-methoxy-4-hydroxyphenylglycol and homovanillic acid respectively. Higher CSF 5-HIAA in women with comorbid major depressive disorder and lifetime panic disorder is indicative of greater serotonin release, increased serotonin metabolism, and/or decreased 5-HIAA clearance in this group. This difference in pathophysiology is potentially related to the greater morbidity and poorer treatment response of this group.     

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.     

Rapid liquid chromatographic determination of 5-hydroxyindoles and dihydroxyphenylacetic acid in cerebrospinal fluid of the rat

A stainless steel guide was implanted in the anterior third ventricle of the anesthetized rat and an internal needle shorter than the guide was used to continuously collect cerebrospinal fluid (CSF) at a constant outflow of 1 microliter/min. Five microliter samples were injected directly into a liquid chromatographic column. The mobile phase was adjusted for selective separation of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA). Electrochemical detection with a limit of 0.05 pmol was used, 5-HTP and 5-HT concentrations were in the 10(-8) M range in controls while DOPAC and 5-HIAA were in the 10(-7) and 10(-6) M range. Brain aromatic amino acid decarboxylase inhibition with high doses of benserazide corresponded to an increased CSF level of 5-HTP. Monoamine oxidase inhibition with tranylcypromine resulted in a diminution of DOPAC and 5-HIAA. L-Tryptophan loading associated with monoamine oxidase inhibition induced an increase in CSF level of serotonin. These pharmacologically induced changes in serotonin and dopamine metabolite levels exemplify the usefulness of these CSF determinations as indices of brain function.     

Vasopressin in CSF and plasma in depressed suicide attempters: preliminary results.

Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic-pituitary-adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.     

Enhanced selective serotonin re-uptake inhibitors as antidepressants: 2004 – 2006

Depression is a major psychiatric disorder. It affects millions of people worldwide and inflicts tremendous economic burden on societies. The advent of selective serotonin re-uptake inhibitors as antidepressants has been a revolutionary advance in the treatment of depression and related disorders. However, selective serotonin re-uptake inhibitors are also associated with several undesirable properties, such as delayed onset of action, low response rate and side effects. The present search for a newer generation of antidepressants is focused on overcoming these issues. The patent literature covered in this review, during 2004 – 2006, illustrates several strategies employed by the pharmaceutical industry in the development of enhanced serotonin re-uptake inhibitors. Encouraged by the success of venlafaxine and duloxetine, several companies have pursued dual-acting serotonin and noradrenaline re-uptake inhibitors as drug candidates for depression treatment. Molecules with combined serotonin re-uptake inhibitor and 5-HT autoreceptor (5-HT_1A and/or 5-HT_1B) antagonist properties are being developed. In particular, recent research suggests that serotonin 5-HT_1B antagonists alone or combined with selective serotonin re-uptake inhibitors might hold unique promise as efficacious antidepressants. Finally, efforts are underway to formulate new drug candidates with both serotonin re-uptake inhibitor and neurokinin 1 (NK₁) antagonist activities. Despite mixed results from clinical trials with several NK₁ antagonists, effective therapeutic agents for depression may still emerge from compounds with combined serotonin reuptake inhibitor/NK₁ antagonist properties.     

Tryptophan depletion selectively reduces CSF 5-HT metabolites in healthy young men: results from single lumbar puncture sampling technique

Plasma tryptophan (Trp) depletion is a commonly used tool for determining the role of brain serotonin (5-HT) function in a variety of psychiatric disorders. This study measured the cerebrospinal fluid (CSF) monoamine metabolite response to Trp depletion and control testing in five healthy subjects utilizing a single lumbar puncture. Testing was done in a placebo-controlled, double-blind, randomized, cross-over design. Plasma-free and total Trp levels and behavioural ratings were obtained prior to and 5 h after ingestion of each amino-acid drink. CSF was obtained by performing a standard lumbar puncture 7 h after ingestion of the drink. Compared to control testing, Trp depletion caused a significant decrease of CSF 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.03), but not of homovanillic acid or 3-methoxy-4-hydroxy-phenylglycol. Behavioural ratings were minimally affected in all subjects. This confirms that plasma Trp depletion reduces central nervous system measures of 5-HT function and suggests that the single lumbar puncture technique may be sufficient to detect the extent of CSF 5-HIAA changes during Trp depletion studies.     

Involvement of catecholamines and serotonin in human hypertension

Lumber cerebrospinal fluid (CSF) concentrations of metabolites of noradrenaline, adrenaline and serotonin were estimated in patients of sustained hypertension (n = 20), and healthy controls (n = 15). Platelet uptake of serotonin and its basal contents were also estimated in the same individuals. CSF 5-hydroxy indole acetic acid level (5-HIAA) (major metabolite of serotonin) was significantly higher in hypertensives than controls (p less than .01). CSF 3-methoxy, 5-hydroxy phenyl glycol (MHPG) (major metabolite of adrenaline and noradrenaline) level was also raised significantly in cases of hypertension (p less than .01). However, platelet uptake of serotonin as well as its basal contents in hypertension were significantly lower than controls (p less than .01). It can thus be postulated that there exists an increased central serotonergic and catecholaminergic activity in hypertension. Furthermore, alterations observed in platelet serotonin uptake and its basal content suggest the involvement of platelet serotonergic system in hypertension.     

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.     

Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid,and total blood serotonin content during clozapine treatment

Cerebrospinal fluid 5-hydroxyindoleacetic acid level, and total blood serotonin content was measured in groups of manic and schizophrenic patients before and after 2, 4, 6, 10, 20, and 30 days of clozapine treatment. CSF 5-HIAA values were elevated after 2 and 4 days and returned to baseline levels after 6 days or more. Blood serotonin content, in contrast, increased gradually and remained high even after 30 days. Neither CSF 5-HIAA nor blood 5-HT correlated with age, drug dose, or clinical effectiveness, but some relationship between these and the sedative component of the clozapine action was observed.     

Effects of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: Pharmacology and electron microscopic cytochemistry

2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) reduced the uptake of 5-hydroxy-3-indoleacetic acid (5-HIAA) by the choroid plexus in a dose-related manner, while treatment with quinolinic acid at comparable concentrations did not inhibit 5-HIAA uptake. The role of carrier-mediated transport in the clearance of 5-HIAA from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced competitively in the presence of 2,4,5-T. However, the clearance was not affected by quinolinic acid. The effect of 2,4,5-T on transport enzyme systems was also studied by electron microscopic cytochemistry. Na+-K+-ATPase and cytochrome oxidase activities in the choroid plexus were reduced by 2,4,5-T. Since this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the CSF and the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of neurotoxicity.     

Pharmacological strategies for trichotillomania

Pharmacotherapy for trichotillomania (TTM) is not well established, due to a paucity of positive, controlled, long-term studies. Although selective-serotonin re-uptake inhibitors (SSRIs) seem to be the safest and best-established medication choices, positive treatment response is not consistent in the literature. Treatment response is often disrupted by significant relapse. Behavioural therapy may be a more effective treatment for some patients. For other patients, other antidepressants, neuroleptics or even topical agents may be helpful. Future investigations should include more controlled studies and longer observation for relapse.     

A double-blind comparative clinical trial of citalopram vs maprotiline in hospitalized depressed patients

In a double-blind clinical trial comprising 29 depressed patients citalopram, a highly selective 5-HT re-uptake inhibitor and maprotiline, a specific NA re-uptake inhibitor, were compared. Allowing for the small sample and taking into consideration that both groups consisted of severely ill, hospitalized patients, it is notable that half of them appeared to respond to treatment. Comparison of the clinical efficacy of the two drugs showed no significant difference, but the profiles of the side-effects appeared to be different. The patients treated with citalopram showed increased sweating, drowsiness, restlessness and headache. These side-effects were almost entirely reported by the non-responders. The maprotiline patients had anticholinergic symptoms, such as dryness of mouth and constipation, side-effects which were also reported by the responders. No correlation was found between plasma steady-state levels of either drug and clinical outcome. The Dexamethasone Suppression Test (DST) appeared to show some predictive value as regards treatment response. There was a tendency towards better overall treatment results in the non-suppressor group. Determination of post-probenecid 5-HIAA, HVA and MHPG concentrations in lumbar-CSF was made in 22 patients. There was a significant negative correlation between HVA and the severity of depression, as well as a significant negative correlation of MHPG with the Newcastle score. The 5-HIAA concentration was found to be correlated with HVA, but not with MHPG. Rather surprisingly significant negative correlation between 5-HIAA and treatment results with maprotiline was found, but no correlation with MHPG. The lumbar-CSF MHPG and HVA values did not appear to have any predictive value as regards treatment response to citalopram or maprotiline. As expected the serotonin (5-HT) concentration in blood and thrombocytes in patients treated with citalopram showed a highly significant reduction after 2 and 4 weeks of treatment.     

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.     

Individual differences in basal cisternal cerebrospinal fluid 5-HIAA and HVA in monkeys. The effects of gender, age, physical characteristics, and matrilineal influences.

We examined the effects of gender, age, weight, length, body shape (ectomorphy), and matrilineal influences on cisternal cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and homovanillic acid (HVA) in 78 socially living adult and adolescent vervet monkeys. CSF 5-HIAA and the 5-HIAA:HVA ratio were higher (by 27% and 18%, respectively) in females. In both sexes, CSF 5-HIAA and the 5-HIAA:HVA ratio increased with age. Neither weight nor length were independently related to CSF 5-HIAA or HVA; however, shape correlated with CSF 5-HIAA and HVA in males (higher in thin, long subjects). Male offspring had CSF 5-HIAA concentrations and 5-HIAA:HVA ratios that were significantly closer to their mothers than did age-matched, maternally unrelated males. Repeated measures of CSF 5-HIAA and HVA in another 22 males living in unvarying settings showed that individual differences in these measures persisted over time. The data underscore the impact of gender, age, and matrilineal relationships on individual differences in CSF monoamine metabolites and highlight the importance of controlling for age and gender in neuropharmacological investigations of clinical populations.     

Physiological predictors of reproductive outcome and mother-infant behaviors in captive rhesus macaque females (Macaca mulatta).

Previous research has shown that offspring of females with low cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations are less likely to survive the first year of life than are offspring of females with high CSF 5-HIAA concentrations. In addition, studies of free-ranging rhesus macaque males have suggested that individuals with low CSF 5-HIAA concentrations suffer reduced reproductive success relative to their high serotonin counterparts. We examined CSF concentrations of the monoamine metabolites 5-HIAA and homovanillic acid (HVA), and plasma cortisol concentrations as predictors of first-time adult reproductive potential, maternal behavior, and overall social interactions in two groups of captive female rhesus macaques and their first offspring. Repeated CSF and blood samples were obtained from adult females in two social groups, and focal observations were performed for both new mothers and infants during the first month following parturition. We found that the reproductively aged nulliparous females who failed to give birth to their first offspring showed significantly lower CSF 5-HIAA concentrations than those females who gave birth. Among those females that gave birth to offspring, females with low CSF 5-HIAA concentrations and females with high plasma cortisol concentrations were overly protective and restrictive with their infants. CSF HVA concentration was not associated with reproductive output, social behavior, aggression, or mother-infant interactions in this sample of rhesus macaque females. We conclude that low CNS serotonin activity and high stress, measured by high plasma cortisol, are correlated with reduced reproductive success and patterns of high maternal restrictiveness in young adult female rhesus macaques.     

Cerebrospinal fluid 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) following probenecid in unipolar depressives treated with amitriptyline

Lumbar cerebrospinal fluid 5-HIAA, HVA, and the ratio 5-HIAA/HVA were measured followed probenecid administration in eleven patints with unipolar depression before and during treatment with amitriptyline (AMI). Control values were obtained from a group of inmate volunteers. Prior to treatment CSF 5HIAA formation in the depressives was not different from controls. During treatment with AMI, CSF 5-HIAA formation decreased. One patient with psychotic symptoms prior to AMI and two patients who developed psychotic reactions on AMI showed relatively low CSF 5HIAA formation prior to antidepressant therapy. Compared to controls CSF HVA values were higher in the depressives prior to AMI therapy.     

Fluvoxamine: a selective serotonin re-uptake inhibitor for the treatment of obsessive-compulsive disorder

Fluvoxamine is the selective serotonin re-uptake inhibitor with the largest database in the treatment of obsessive-compulsive disorder, a severe, and often chronic, anxiety disorder associated with substantial impairment in functioning. The selective serotonin re-uptake inhibitors represent a first-line treatment in patients with obsessive-compulsive disorder. These agents work primarily by blocking the re-uptake of serotonin into the presynaptic nerve terminal, which is believed to be mediated by their effects on the serotonin transport system. In the last two decades, the anti-obsessional effect of fluvoxamine has been tested in several double-blind, placebo-controlled and active-comparison studies, demonstrating its superior efficacy over obsessions and compulsions compared with non-serotonergic antidepressants (i.e., desipramine) and equal efficacy to clomipramine (a tricyclic antidepressant with potent serotonin re-uptake inhibition) and other selective serotonin re-uptake inhibitors (paroxetine and citalopram). However, compared with clomipramine, the selective serotonin re-uptake inhibitor fluvoxamine showed fewer side effects and better tolerability. This reflects the poor affinity of this compound for adrenergic, muscarinic, cholinergic or histaminergic receptors.