Low HVA and normal 5HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: Correlations to symptomatology and family history

doi:10.1016/0165-1781(85)90095-2

Psychiatry Research

Volume 14, Issue 4, April 1985, Pages 265-273

https://doi.org/10.1016/0165-1781(85)90095-2 Get rights and content

Abstract

Cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5- hydroxyindoleacetic acid (5HIAA) were determined in 40 drug-free schizophrenic patients and 21 healthy volunteers by a mass fragmentographic method. Twenty-one of the schizophrenic patients were first admissions who had never received neuroleptics. Significantly, lower levels of HVA but not 5HIAA were found in the patient group, and no difference was found between chronic, previously neuroleptic-treated and never-medicated patients. HVA levels correlated positively with social interest and total positive scores on the Nurses Observation Scale for Impatient Evaluation (NOSIE-30) and negatively with lassitude and slowness of movements on the Comprehensive Psychopathological Rating Scale (CPRS). Low levels of 5HIAA were correlated to the CPRS items delusions and apparent sadness. There were slightly higher CSF levels of 5HIAA in patients with a family history of schizophrenia, but no such difference was seen for HVA. In both schizophrenic and control subjects CSF levels of HVA and 5HIAA showed a strong intraindividual correlation. The results indicate decreased central nervous system dopaminergic turnover in schizophrenia which seems to be associated with “negative” symptomatology.

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Several studies have shown a correlation between CSF monoamine metabolite concentrations and schizophrenia. For example CSF HVA has been shown to be lower in patients with psychotic morbidity compared to healthy controls, whereas CSF MHPG has been reported to be higher in patients (Bjerkenstedt et al., 1985; Hsiao et al., 1993; Lindström, 1985; Wieselgren and Lindström, 1998). CSF monoamine metabolites have also been implied as intermediate phenotypes between glutamate- and dopamine-related genes and schizophrenia (Andreou et al., 2014, 2015, 2016).
Metabolism of the monoamines dopamine, serotonin and noradrenaline, is altered in the central nervous system of people with schizophrenia, and their major metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), respectively, have been intensively studied as indirect measures of these neurotransmitters in cerebrospinal fluid (CSF). Regular tobacco smoking has been shown to alter neurotransmitter metabolism in the brain and studies have found CSF monoamine metabolite concentrations to be substantially lower in smokers. However, few studies investigating these monoamines in CSF have controlled for regular tobacco smoking. We investigated if regular tobacco smoking influences CSF HVA, 5-HIAA and MHPG concentrations in patients treated for psychotic disorders (n = 69) and healthy non-psychotic human volunteers (n = 200). After lumbar puncture CSF samples were analyzed with mass fragmentography. CSF HVA, 5-HIAA and MHPG concentrations did not significantly differ between smokers and non-smokers neither in patients, nor in healthy subjects, whereas back-length predicted HVA and 5-HIAA and antipsychotic medication MHPG concentrations. The results indicate that regular tobacco smoking has no significant effect on monoamine metabolite concentrations in CSF. This suggests that lack of controlling for regular tobacco smoking should not substantially violate the results in studies of the major monoamine metabolites in CSF.
Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis
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CSF 5-HIAA concentrations have been associated with negative and disorganization dimensions (Anand et al., 2002), deficit characteristics (Csernansky et al., 1990), hallucinations (Gattaz et al., 1982) and delusions (Lindström, 1985). CSF HVA concentrations have been associated with the psychosis dimension in first episode drug naive patients with schizophrenia (Anand et al., 2002) as well as the patients’ social interest (Lindström, 1985). Regarding antipsychotics, quetiapine and olanzapine administration have been found to be associated with a significant increase in CSF HVA (Scheepers et al., 2001; Nikisch et al., 2010).
Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.
Changes in gene expression and methylation in the blood of patients with first-episode psychosis
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Another evidence of the importance of the BH4 pathway in psychosis is the profound deficit in total plasma biopterin levels (a measure of BH4) in schizophrenia and schizoaffective patients (reductions of 34% and 25%, respectively) compared to normal controls (Richardson et al., 2005, 2007). In addition, several studies found lower levels of dopamine and serotonin metabolites in the cerebrospinal fluid (CSF) of schizophrenia patients (Gattaz et al., 1982; Potkin et al., 1983; Bjerkenstedt et al., 1985; Lindstrom, 1985); it is therefore possible that BH4 could be contributing to these results. The expression of DRD2, which encodes the dopamine D2 receptor, was also found to be decreased during high delusional states in a sample of schizophrenia patients (Kurian et al., 2011).
Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n = 51) and healthy controls (n = 51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was observed in FEP patients relative to controls. Also, when we compare the FEP patients after risperidone treatment with controls, this difference remains significant, and no significant differences were observed in GCH1 mRNA levels when comparing patients before and after risperidone treatment. Additionally, although the differences were non-significant after Bonferroni correction, the expression of GCH1 seemed to be correlated with PANSS scores, and the GCH1 promoter region was more methylated in FEP than in controls, thus corroborating the results obtained at the mRNA level. Few studies have been conducted on GCH1, and future studies are needed to clarify its potential role in the progression of schizophrenia.
Neuropeptide Y, social function and long-term outcome in schizophrenia
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Two nurses performed the ratings (interrater reliability 0.86) using a 0–4 frequency of occurrence format for each item. The assessments reflected the patient's behavior during the 48 h preceding the lumbar puncture (Lindström, 1985). NOSIE-30 is a ward behavior rating scale consisting of 30 items that yield six factors.
There is a lack of biomarkers in schizophrenia and the mechanisms underlying the observed deficits in social functioning are poorly understood. This cohort study aimed to explore whether neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from patients with schizophrenia is correlated to social function and clinical variables. A further aim was to determine whether baseline levels of NPY were associated with subsequent 3-year outcome. Fifty-six consecutively admitted patients with schizophrenia were included and underwent lumbar puncture and symptom ratings before antipsychotic treatment. NPY levels in CSF were determined by radioimmunoassay. Social function (Social Competence and Social Interest) was assessed by Nurses' Observation Scale for Inpatient Evaluation while psychiatric symptoms were rated using the Comprehensive Psychopathological Rating Scale. Three-year outcome was assessed with the Strauss–Carpenter Outcome Scale. Cross-sectional analysis showed a correlation between level of NPY and Social Competence at index admission (r_s = 0.37, p < 0.05). The longitudinal analysis (i.e. at the 3-year follow-up) indicated that, for each standard deviation increase in baseline NPY, there was an increased risk of being unemployed (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.07–3.82), having moderate or severe symptoms (OR 3.09, CI 1.30–7.32) or being hospitalized at least 6 months the previous year (OR 3.24, CI 1.09–9.64). However, NPY was not correlated to Social Interest or clinical variables at index admission. In conclusion, NPY levels in CSF are correlated to Social Competence and seem to predict some aspects of longitudinal outcome in schizophrenia.
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This study evaluates the relationship between plasma homovanillic acid (pHVA) levels, which have been used to study the role of central dopamine in schizophrenia, and the positive/negative syndrome in first episode schizophrenic patients before and after antipsychotic treatment. Forty neuroleptic-naive first episode schizophrenic patients were monitored at baseline and on days 7, 14 and 28. Clinical status was evaluated with the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Brief Psychotic Rating Scale. Plasma HVA levels were also measured. Patients were divided into predominantly positive or negative syndrome groups by subtracting SAPS from SANS scores, at baseline. A healthy control group was also enrolled. Schizophrenic patients as a group had significantly higher pHVA levels than controls at baseline (20.50 ± 11.85 vs. 13.04 ± 7.22 ng/ml). Moreover, 12 predominantly negative syndrome patients had similar mean baseline pHVA levels (21.30 ± 12.36 ng/ml) to those of 28 predominantly positive syndrome patients (19.40 ± 11.33 ng/ml). During follow-up, there was a different evolution of pHVA levels in the predominantly positive syndrome group than in the predominantly negative syndrome group, with a significantly greater global reduction of pHVA levels in the former. Although both groups showed clinical improvement following 4 weeks of treatment with risperidone, pHVA levels at endpoint were lower (13.29 ± 5.91 ng/ml) than at baseline in patients in the predominantly positive syndrome group, while among those in the predominantly negative syndrome group there was no difference in pHVA levels before and after treatment (21.02 ± 13.06 ng/ml). The different pHVA level profiles observed in predominantly positive and negative syndrome first episode patients after 4 weeks of treatment with risperidone suggest that each syndrome may have a different underlying neurobiology.
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Citation Excerpt :
However, such studies have not revealed any consistent aberration from levels found in control groups. In patients with schizophrenia low CSF levels of HVA have been found in some (Bjerkenstedt et al., 1985; Lindström, 1985; Wieselgren and Lindström, 1998) but not in all studies (Berger et al., 1980; Nybäck et al., 1983; Persson and Roos, 1969; Post et al., 1975). In recent years, it has been proposed that DA only plays an intermediary role in the pathophysiology of schizophrenia and that, in particular, deficits in brain glutamatergic systems are of major importance for the disease (Carlsson et al., 2001; Javitt, 2004; Javitt and Zukin, 1991; Jentsch and Roth, 1999).
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Low HVA and normal 5HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: Correlations to symptomatology and family history

Abstract

Neuropharmacology

Neuropharmacology

Psychiatry Research

Lancet

Journal of Psychosomatic Research

Journal of Psychiatric Research

Biological markers in major depressive disorders. A clinical and multivariate study

Acta Universitatis Upsaliensis: Abstracts of Uppsala Dissertations From theFaculty of Medicine

Life at risk: Markers of suicidality in depression

Psychiatric Developments

The CPRS: Development and applications of a psychiatric rating scale

Acta Psychiatrica Scandinavica

5-HIAA in the cerebrospinal fluid: A biochemical suicide predictor?

Archives of General Psychiatry

CSF monoamine metabolites in depression and schizophrenia

American Journal of Psychiatry

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) following probenecid in acute psychotic patients treated with phenothiazines

Psychopharmacologia

Central dopamine turnover in schizophrenic

Archives of General Psychiatry

Effect of chlorpromazine and haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain

Acta Pharmacologica et Toxicologica

Amphetamine Psychosis

3H-Flupenthixol binding in post-mortem brains of schizophrenics: Evidence for a selective increase in dopamine D2 receptors

Psychopharmacology

Molecular pathology of schizophrenia: More than one disease process?

British Medical Journal

³H-Flupenthixol binding in post-mortem brains of schizophrenics: Evidence for a selective increase in dopamine D₂ receptors