Reduced dopamine turnover in the basal ganglia of depressed suicides

doi:10.1016/S0006-8993(97)00692-6

Brain Research

Volume 769, Issue 1, 19 September 1997, Pages 135-140

https://doi.org/10.1016/S0006-8993(97)00692-6 Get rights and content

Abstract

We have measured the concentrations of dopamine, and the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), in five brain regions from suicide victims with a firm retrospective diagnosis of depression, and matched controls. The suicides were divided into those free of antidepressant drugs and those in whom prescription of antidepressant drugs was clearly documented. DOPAC concentrations were significantly lower in caudate, putamen and nucleus accumbens of antidepressant-free suicides compared to controls. In antidepressant-treated suicides, lower concentrations of DOPAC were observed in the basal ganglia, reaching statistical significance in caudate. Lower DOPAC concentrations were largely restricted to those suicides who died by non-violent methods. There were no significant differences in dopamine and HVA concentrations in either suicide group compared to controls, although there was a trend for HVA concentrations to be lower in suicides. This study provides evidence for reduced dopamine turnover, as judged from reduced DOPAC levels, in depressed suicides, although we cannot exclude the possibility that this may be due to ingestion of toxic agents.

Introduction

Since the mid-1960s the biological basis of depression has been dominated by the monoamine hypothesis. This has focused in particular on the involvement of 5-hydroxytryptamine (5-HT) and noradrenaline. The possible involvement of the monoamine dopamine in depression has been less thoroughly investigated.

The strongest evidence implicating dopaminergic involvement in depression derives from studies of the dopamine metabolite homovanillic acid (HVA) in cerebrospinal fluid (CSF). The concentration of HVA has been consistently reported to be lower in the CSF of drug-free depressed patients compared to controls 2, 6, 11, 14, 17, indicating reduced central dopamine turnover. The concentration of the dopamine metabolite DOPAC (dihydroxyphenylacetic acid) has also been reported to be lower in the CSF of depressed patients [23]. The magnitude of the reduction in dopamine turnover in depressed patients is comparable with the reduction in 5-HT turnover (as indicated by CSF 5-hydroxyindoleacetic acid (5-HIAA) concentration) 1, 22.

Relatively few studies have examined dopamine and dopamine metabolites in post-mortem brain in relation to depression. Studies of brain samples from suicides have consistently found dopamine concentrations to be unaltered compared to controls 3, 16, 20. HVA concentrations have been reported to be increased 3, 18or unaltered [9]in frontal cortex, and unaltered in caudate [3]of suicides compared to controls. In subjects with an ante-mortem diagnosis of depression who died by natural causes, HVA concentration was reported to be increased in hippocampus but unaltered in three cortical areas [9]. One study has specifically examined brain samples from bipolar patients (some of whom died by suicide) and reported unaltered dopamine concentrations in eight brain regions [27]. HVA concentration was also unaltered, apart from a lower concentration in parietal cortex. Thus, studies in post-mortem brain to date have not confirmed the decrease in dopamine turnover inferred from studies of CSF in depressed patients. This may in part reflect the heterogeneity of psychiatric illness within the suicides, and the small sample sizes.

In the present study we have measured the concentrations of dopamine and the dopamine metabolites, DOPAC, which is mostly of intraneuronal origin and HVA, which is extraneuronally synthesized [12], in post-mortem brain tissue from suicides with a firm retrospective diagnosis of depression, and matched controls. We have studied separately those suicides who were free of antidepressant drugs for at least three months prior to death, and those in whom prescription of antidepressant drugs was clearly documented. Since there is a well established relationship between reduced 5-HT turnover, as indicated by CSF 5-HIAA measurements [1], and violent suicide attempts, we have also analysed our results in respect of violent and non-violent methods of suicide.

Section snippets

Subject selection

Suicide deaths, as recorded at Coroners' inquest, were subjected to retrospective diagnosis by a psychiatrist (C.L.E.K.), using hospital and Coroners' records and interviews with the subject's medical practitioner. Forty-nine subjects, in whom there was sufficient documentary evidence to establish a retrospective diagnosis of depression according to the criteria of Beskow et al. [3]were selected for study. Information on previous and current drug-treatment was sought and blood samples, obtained

Results

There were no significant differences in age or post-mortem delay between AFS or ATS and controls (Table 2). Significant negative correlations were observed between age and dopamine concentration in caudate (P=0.004) and putamen (P=0.03) and between age and HVA concentration in caudate (P=0.001), putamen (P=0.05) and nucleus accumbens (P=0.005). There were no significant correlations with age in amygdala and hippocampus, and none between age and DOPAC concentration in any region. No significant

Discussion

Dopamine and HVA concentrations in the present study are of a similar magnitude, although generally somewhat higher, than in other studies 4, 13, 19, 21, 25. The higher values that we report are likely to be due to the lower mean age of the subjects included in the present study (46±3 years compared to a range of 64–78 years for the above studies). In agreement with others 3, 26, 15, we found significant negative correlations between dopamine and HVA concentrations and age. Therefore, a group

Acknowledgements

We thank Knoll Pharmaceuticals for financial support and Richard Brammer of Knoll Pharmaceuticals for performing the statistical analysis. C.B. gratefully acknowledges a research studentship from the British Pharmacological Society.

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¹: Present address: Novo Nordisk Pharmaceuticals Ltd., Crawley, W. Sussex RH11 9RT, UK.

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Research reportReduced dopamine turnover in the basal ganglia of depressed suicides

Abstract

Introduction

Section snippets

Subject selection

Results

Discussion

Acknowledgements

Eur. J. Pharmacol.

Int. J. Neuropharmacol.

Brain Res.

Neuropharmacology

Brain Res.

Biol. Psychiatry

Lancet

Psychiatry Res.

Brain Res.

Biol. Psychiatry

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

Arch. Gen. Psychiatry

Correlation between CSF metabolites and psychomotor activity in affective disorders

J. Neurochem.

Determination of monoamines and monoamine metabolites in the human brain: post-mortem studies in a group of suicides and in a control group

Acta Psychiatr. Scand.

Research report
Reduced dopamine turnover in the basal ganglia of depressed suicides