Cerebrospinal Fluid Homovanillic Acid Research Articles

HPT axis, CSF monoamine metabolites, suicide intent and depression severity in male suicide attempters

A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters.

Circadian rhythm of CSF monoamines and hypocretin-1 in restless legs syndrome and Parkinson’s disease

The symptoms of restless legs syndrome (RLS) have a circadian pattern and central nervous system dopamine has been implicated in the pathogenesis of the condition. We sought to characterize circadian variation in dopamine and related compounds in human cerebro-spinal fluid (CSF). CSF was continuously withdrawn for 22 h from an implanted lumbar intradural catheter and sampled from three patients with RLS, three patients with Parkinson’s disease (PD) and three healthy volunteers. Patients had moderate disease severity and took no medications. We assayed CSF dopamine (DA), homovanillic acid (HVA), dihydroxy-phenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) from samples every 30 min by reversed-phase HPLC coupled with electrochemical detection. We also measured CSF levels of hypocretin-1 every hour by RIA. The procedure was well-tolerated. One patient ended the study early due to lumbar radicular pain and was not included in the analysis. There were no changes in CSF cell counts or protein levels from the first to the last samples. There was no difference in any of the compounds between groups, so we fit 24-h cosines to examine if the entire group had significant phase consistency. There was a peak for dopamine at 10 a.m. ( p < 0.025) and for HVA at 2 p.m. ( p < 0.01), but no evidence of a significant 24-h rhythm for DOPAC, 5-HIAA, the HVA/5-HIAA ratio, or hypocretin-1. These results demonstrate a circadian rhythm for CSF dopamine and HVA concentrations in humans, with higher levels in the daytime than at nighttime. This circadian variation could underlie the symptoms of RLS and sleep-related variation in motor function in PD.

A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species.

Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits.

Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene

Tyrosine hydroxylase (TH) deficiency (OMIM 191290) is one cause of early-onset dopa-responsive dystonia. We describe seven cases from five unrelated families with dopa-responsive dystonia and low homovanillic acid in cerebrospinal fluid who were suspected to suffer from TH deficiency. Analysis of part of the TH promotor showed five homozygous and two heterozygous mutations in the highly conserved cyclic adenosine monophosphate response element. Our data suggest that, if no mutations are found in the coding regions of the gene in patients strongly suspected of TH deficiency, the search for pathogenic mutations should be extended to regulatory promotor elements.

Cerebrospinal fluid kynurenic acid in male patients with schizophrenia - correlation with monoamine metabolites.

The tryptophan metabolite kynurenic acid (KYNA) is an endogenous glutamate/nicotinic receptor antagonist. Previous studies have shown that the concentration of the compound is increased in cerebrospinal fluid (CSF) of patients with schizophrenia. Furthermore, it has been found that the CSF concentration of KYNA is positively correlated to CSF concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) in healthy control subjects. To study the correlations between KYNA and the monoamine metabolites HVA, 5-HIAA and 4-hydroxy-3-methoxyphenylglycol (HMPG) in CSF of male patients (n= 53, ranging from 20 to 48 years of age) with verified schizophrenia. CSF was obtained by lumbar puncture, and KYNA analysis was performed with an isocratic reversed-phase high-performance liquid chromatography system connected to a fluorescence detector. HVA, 5-HIAA and HMPG concentrations were measured by mass fragmentography with deuterium-labelled internal standards. Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA, while CSF content of HMPG did not correlate to KYNA or any of the monoamine metabolites in CSF. The results of this study suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover in male patients with schizophrenia.

A study of CSF catecholamine and its metabolites in acute and convalescent period of encephalitis

Aims To evaluate cerebrospinal fluid (CSF) catecholamine (CA) and its metabolites in encephalitis patients in acute and convalescent period and correlate these with clinical and magnetic resonance imaging (MRI) features. Subjects and methods Patients with acute encephalitis diagnosed on the basis of clinical, CSF, MRI and virological parameters underwent detailed neurological evaluation including Glasgow Coma Scale (GCS), Unified Parkinson's Disease Rating Scale (UPDRS) and Dystonia Rating Scale. Cranial MRI was carried out and CSF dopamine (DA), norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxytryptamine (5HT) levels were estimated by High Performance Liquid Chromatography (HPLC). The CSF catecholamine levels were compared with convalescent phase as well as with controls. These levels were also correlated with parkinsonian features, dystonia and radiological abnormalities. Results There were 29 encephalitis patients; whose age ranged between 2 and 65 years, 4 were females and 11 children. 25 patients had Japanese encephalitis (JE) and 4 nonspecific encephalitis. The mean GCS score was 8 and 13 had seizures. Movement disorders were present in 13 patients and included parkinsonian features in 5, dystonia in 1 and combination of both in 7 patients. MRI revealed abnormalities in 15 out of 21 patients and included thalamic lesion in 10, globus pallidus in 4, putamen in 5, caudate in 4 and midbrain in 9 patients. In acute stage NE, DOPAC, 5HT and HVA levels were significantly lower compared to controls. NE levels significantly correlated with dystonia and thalamic lesions. Convalescent CSF study revealed significantly lower levels of DOPAC compared to acute phase. CSF catecholamine levels in encephalitis patients with and without movement disorders were not significantly different. Conclusion In encephalitis, catecholamine and its metabolites are lower in acute and convalescent phase. Norepinephrine level correlates with dystonia and thalamic lesions.

Diagnosis and treatment of neurotransmitter disorders

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

A prospective study of the association of cerebrospinal fluid monoamine metabolite levels with lethality of suicide attempts in patients with bipolar disorder

Bipolar disorder is a severe illness that is associated with suicidal behavior. A biological predictor of highly lethal suicide attempts in patients with bipolar disorder would be valuable. We hypothesized that cerebrospinal fluid (CSF) monoamine metabolite levels are related to lethality of suicide attempts in bipolar patients and examined the relation between CSF 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and maximum lethality of suicide attempts at baseline and during a 2-year follow up. Twenty-seven bipolar depressed patients participated in the study. Demographic and clinical parameters were examined and recorded. Lumbar punctures were performed and CSF 5-HIAA, HVA, and MHPG were assayed by high-performance liquid chromatography with electrochemical detection. Following discharge, patients were evaluated after 3 months, 1 year, and 2 years. Each follow-up interview included an in-depth assessment of suicidal behavior during the intervening time period. Six subjects made suicide attempts during the 2-year follow-up. Bipolar patients who attempted suicide during the follow-up period had higher aggression and hostility scale scores compared to bipolar subjects who did not make a suicide attempt during the follow-up period. CSF 5-HIAA, HVA, and MHPG levels were negatively correlated with the maximum lethality of suicide attempts during the 2-year follow-up period. Our finding is the first observation that CSF monoamine metabolite levels may be predictors of lethality of suicide attempts in patients with bipolar disorder. Further studies are necessary to answer the question whether CSF monoamine metabolite levels are clinically useful biochemical predictors of highly lethal suicide attempts or completed suicides.

A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index

Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.

CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence

Background: Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism. Methods: We compared 16 high- and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined. Results: The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels. Conclusion: Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.

Monoamines and Neurosteroids in Sexual Function During Induced Hypogonadism in Healthy Men

Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans. To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism. Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design. National Institutes of Health, Bethesda, Md. Twelve healthy male volunteers. We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month. Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites. The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure. These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Cerebrospinal fluid kynurenic acid in male and female controls – Correlation with monoamine metabolites and influences of confounding factors

The concentrations of the tryptophan metabolite kynurenic acid (KYNA) and the monoamine metabolites homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in the cerebrospinal fluid (CSF) from 43 healthy volunteers (30 males and 13 females). Healthy female controls displayed higher CSF concentration of KYNA (1.91 nM ± 0.20) compared to healthy male controls (1.06 nM ± 0.07) and lower CSF levels of HMPG (39.2 nM ± 2.0 and 43.4 ± 1.2, respectively). CSF levels of HVA and 5-HIAA did not differ between females (181.3 nM ± 21.9 and 93.7 nM ± 11.4, respectively) and males (138.9 nM ± 12.6 and 74.8 nM ± 5.9, respectively). Positive intercorrelations were found between CSF KYNA, HVA and 5-HIAA while CSF content of HMPG did not correlate with KYNA or the other monoamine metabolites in CSF. A negative correlation was found between back length and CSF concentrations of KYNA, HVA and 5-HIAA and also between CSF KYNA levels and body height. The results of the present study suggest that concentrations of KYNA and the monoamine metabolites in CSF from healthy controls are dependent on gender and back length, which must be taken in consideration when analysing mixed groups of men and women. The higher KYNA concentration found in female controls compared to male might be attributed to a shorter back in women compared to men. Furthermore, these findings suggest that increased KYNA formation is associated with an increased dopamine and serotonin turnover.

Early maternal rejection affects the development of monoaminergic systems and adult abusive parenting in rhesus macaques (Macaca mulatta).

This study investigated the effects of early exposure to variable parenting style and infant abuse on cerebrospinal fluid (CSF) concentrations of monoamine metabolites and examined the role of monoaminergic function in the intergenerational transmission of infant abuse in rhesus monkeys (Macaca mulatta). Forty-three infants reared by their biological mothers and 15 infants that were cross-fostered at birth and reared by unrelated mothers were followed longitudinally through their first 3 years of life or longer. Approximately half of the infants were reared by abusive mothers and half by nonabusive controls. Abused infants did not differ from controls in CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylgycol (MHPG). Abused infants, however, were exposed to higher rates of maternal rejection, and highly rejected infants had lower CSF 5-HIAA and HVA than low-rejection infants. The abused females who became abusive mothers in adulthood had lower CSF 5-HIAA than the abused females who did not. A similar trend was also observed among the cross-fostered females, suggesting that low serotonergic function resulting from early exposure to high rates of maternal rejection plays a role in the intergenerational transmission of infant abuse.

Lower cerebrospinal fluid homovanillic acid levels in depressed suicide attempters

Background Studies suggest that the dopaminergic system is involved in the pathogenesis of major depression, Axis II disorders, and suicidal behavior. Depressed suicide attempters constitute a heterogenous group and important differences may exist between depressed suicide attempters with or without Axis II disorders. Therefore, we compared demographic and clinical parameters, and cerebrospinal fluid (CSF) homovanillic acid (HVA) levels in depressed suicide attempters without comorbid Axis II disorders, depressed non-attempters without comorbid Axis II disorders, and normal controls. Methods Thirty-one depressed subjects with a history of a suicide attempt, 27 depressed subjects without a history of a suicide attempt, and 50 healthy controls were included in the study. Subjects with comorbid Axis II disorders were excluded. Demographic and clinical parameters, and CSF HVA levels were examined. Results The two depressed groups did not differ with regard to depression, aggression, hopelessness, and total hostility scale scores. Depressed suicide attempters had higher current suicidal ideation scores compared to depressed non-attempters. Depressed suicide attempters had lower CSF HVA levels compared to depressed non-attempters ( t = 4.4, df = 56, p < 0.0001) and to controls ( t = − 4.09, df = 79, p < 0.0001). There was no difference in CSF HVA levels between depressed non-attempters and controls ( t < 1, df = 75, NS). Conclusions Dopaminergic abnormalities are associated with suicidality but not with depression. The variability in the rates of comorbid Axis II disorders and in the prevalence of suicide attempters in different patient populations may affect both clinical and biological results of studies of mood disorders.

Administration of secretin for autism alters dopamine metabolism in the central nervous system

We evaluated the clinical effects of intravenously administered secretin in 12 children with autism (age range: 4–6 years, median age: 9 years, boy:girl=8:4). In addition, we investigated the association between improvement in symptoms and changes in the cerebrospinal fluid (CSF) homovanillic acid (HVA),5-hydroxyindole-3-acetic acid (5-HIAA), and 6R-5,6,7,8-tetrahydro-L-biopterin (BH 4) levels after administration. After administration of secretin, the Autism Diagnostic Interview-Revised (ADI-R) score improved in 7 of the 12 children. However, the score deteriorated in 2 of the 12 children (in the item of ‘restricted and repetitive, stereotyped interests and behaviors’). The HVA and BH 4 levels in CSF were increased in all children with improvement in the ADI-R score. In contrast, no patient without the elevation of the BH 4 level showed improvement in the score. These findings suggest that secretin activated metabolic turnover of dopamine in the central nervous system via BH 4, improving symptoms.

The concept of post-traumatic mood disorder

Post-traumatic stress disorder (PTSD) is frequently comorbid with depression. A number of studies have been conducted to compare individuals suffering from comorbid PTSD and depression with individuals suffering from PTSD alone or depression alone. Comorbidity of PTSD and depression is associated with more severe symptoms as well as higher levels of disability compared to individuals with PTSD alone. A severity of overall symptoms is three to fivefold greater in subjects with comorbid PTSD and depression compared to those with PTSD alone. The comorbid group is five times more likely to manifest functional impairment compared to those diagnosed with PTSD alone. Patients with comorbid PTSD and depression have higher depression, impulsivity, and hostility scores and are significantly more likely to make a suicide attempt compared to subjects with depression alone. Depressed subjects with comorbid PTSD tend towards earlier age of first hospitalization and a higher number of hospitalizations compared to depressed individuals without comorbid PTSD. Lower affinity of alpha-2 adrenoreceptors and higher plasma tyrosine availability to the brain are associated with comorbid PTSD and depression, but not with PTSD alone. Individuals with comorbid PTSD and depression do not exhibit the classic rapid eye movement sleep architectural modifications associated with depression, despite the fact that several other psychophysiological indices of dysphoria are detectable in their sleep. In fenfluramine challenge studies, depressed patients with comorbid PTSD have lower plasma cortisol compared to depressed patients without comorbid PTSD. Cortisol levels increase with age and the number of previous major depressive episodes is a predictor of the cortisol response to fenfluramine administration in depressed patients without PTSD, but not in depressed patients with comorbid PTSD. Depressed subjects with comorbid PTSD have higher cerebrospinal fluid homovanillic acid levels compared with depressed subjects without comorbid PTSD. Thus, studies suggest that patients suffering from comorbid PTSD and depression differ clinically and biologically from individuals with PTSD alone or depression alone. It is possible that some or all individuals diagnosed with comorbid PTSD and depression have a separate psychobiological condition that can be termed "post-traumatic mood disorder". Future clinical and neurobiological studies may not only advance our understanding of the role of environmental and genetic factors in the etiology and pathogenesis of stress-related disorders, but also be useful in refining conceptions of stress-related disorders themselves and possible approaches to the treatment of these conditions.

Higher cerebrospinal fluid homovanillic acid levels in depressed patients with comorbid posttraumatic stress disorder

Major depression and posttraumatic stress disorder (PTSD) are often comorbid, resulting in more impairment compared than with either diagnosis alone. Both major depression and PTSD are thought to be associated with monoamine transmitter abnormalities. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in drug-free depressed subjects with a current major depressive episode (MDE) without comorbid PTSD, subjects with a current MDE and comorbid PTSD, and healthy volunteers. Depressed subjects with comorbid PTSD had higher CSF homovanillic acid (HVA) levels compared with depressed subjects without comorbid PTSD or healthy volunteers. Higher HVA was present after adjustment for sex, lifetime aggression severity and depression scores, alcoholism, tobacco smoking, comorbid cluster B personality disorder, reported childhood abuse, and psychosis. We found no group difference in CSF 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels. Higher dopaminergic activity may contribute to alterations in memory and other cognitive functions, anhedonia, and hypervigilance observed in PTSD.

Changes in cerebrospinal fluid neurochemistry during pregnancy

Little is known about changes in brain function that may occur during pregnancy. Studies in rodents and sheep suggest that several brain neurotransmitter and neurohormonal systems known to modulate anxiety may be altered during pregnancy. Cerebrospinal fluid (CSF) and plasma samples were obtained from 21 women (during weeks 38-39 of pregnancy) who were undergoing elective cesarean section and from 22 healthy nonpregnant women. The CSF levels of g-aminobutyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycolwere reduced in pregnant women. There were no changes in CSF glutamate, 5-hydroxyindoleactic acid, and homovanillic acid. There was a large increase in CSF prolactin in pregnant women and also a trend toward an elevation in CSF oxytocin. Levels of prolactin, but not oxytocin, in CSF and plasma were correlated in pregnant women. These results suggest that pregnancy alters regulation of brain GABA, norepinephrine, and prolactin, which may play a role in changes in vulnerability to anxiety and depression during pregnancy and postpartum. Prolactin circulating in the bloodstream seems to be the major source of CSF prolactin during pregnancy.

Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients

Vagus nerve stimulation (VNS) has shown promising antidepressant effects in treatment-resistant depression, but the mechanisms of action are not known. Cerebrospinal fluid (CSF) studies in epilepsy patients show that VNS alters concentrations of monamines and gamma-aminobutyric acid (GABA), neurotransmitter systems possibly involved in the pathogenesis of depression. Twenty-one adults with treatment-resistant, recurrent, or chronic major depression underwent standardized lumbar puncture for collection of 12 mL CSF on three separate but identical procedure days during participation in the VNS D-02 clinical trial. All subjects remained on stable regimens of mood medications. Collections were made at baseline (2 weeks after surgical implantation but before device activation), week 12 (end of the acute-phase study), and week 24. Cerebrospinal fluid concentrations of norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined with high-performance liquid chromatography. Concentrations of GABA were assayed with mass spectrometry. Comparison of sham versus active VNS revealed a significant (mean 21%) VNS-associated increase in CSF HVA. Mean CSF concentrations of NE, 5-HIAA, MHPG, and GABA did not change significantly. Higher baseline HVA/5-HIAA ratio predicted worse clinical outcome. Although several of the CSF neurochemical effects we observed in this VNS study were similar to those described in the literature for antidepressants and electroconvulsive therapy, the results do not suggest a putative antidepressant mechanism of action for VNS.

Pituitary-Thyroid State Correlates with Central Dopaminergic and Serotonergic Activity in Healthy Humans

Data from lower animals suggest anatomic and physiological interactions between brain dopamine and serotonin (5-hydroxytryptamine, 5-HT) systems and the hypothalamic-pituitary-thyroid axis. However, in humans, investigations of interactions between these central neurochemical systems (especially the dopaminergic system) and thyroid function are rare; in healthy humans they are practically nonexistent. Using cerebrospinal fluid (CSF) and blood samples simultaneously obtained from indwelling subarachnoid and venous catheters in healthy humans, we determined the CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid, the major metabolites of dopamine and 5-HT, and plasma concentrations of TSH, total triiodothyronine (T₃), free T₃, total thyroxine (T₄) and free T₄. CSF HVA concentrations were significantly and negatively correlated with plasma TSH and T₃ (free and total), but not with T₄ (free or total). CSF 5-HIAA concentrations were significantly and negatively correlated with plasma TSH and total T₃ but not with free T₃ or T₄ (free or total). These results indicate that CNS monoamine-thyroid interactions are of physiological significance in the normal, euthyroid human.