Reduced dopaminergic activity in depressed suicides

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Psychoneuroendocrinology

MS # 000303

Reduced dopaminergic activity in depressed suicides

William Pitchot, MD, PhD

Jean Reggers,

Emmanuel Pinto, MD

Michel Hansenne,

Sonia Fuchs, MD

Sandrine Pirard, MD

Marc Ansseau, MD, PhD

Psychiatric Unit, CHU Sart Tilman, B-4000 Liège, Belgium

Phone : ++32-4-366.79.60

Fax : ++32-4-366.72.83

E-mail : wpitchot@chu.ulg.ac.be

Submitted to Pychoneuroendocrinology, as a short report.

SUMMARY

Several data are available about the implication of the dopaminergic system in the control of inward-directed aggression. Previously, we suggested an involvement of D2-dopaminergic function in the expression of suicidal behavior by demonstrating a smaller growth hormone (GH) response to apomorphine, a dopaminergic agonist, in depressed patients with a history of suicide attempts in comparison to nonattempters. In the present study, the purpose was to analyze GH responses to apomorphine in depressive patients who later died by suicide. Our sample comprised 8 male depressive inpatients who died by suicide within one year after hospitalisation. These patients were compared to 18 male major depressed inpatients who never attempted suicide. Mean GH peak responses to apomorphine differed significantly between suicide completers and controls (mean ( SD) : for GH peak, 7.6 ( 4.1 ng/ml vs 18.9 ( 14.2 ng/ml, U = 30, Z = -2.33, p = 0.02. Our results tend to confirm the role of dopamine in the biology of suicide in depression.

Key -words : dopamine-D2receptors-suicide-depression

INTRODUCTION

Reduced serotonergic activity has been widely demonstrated in suicide completers and attempters independently of psychiatric diagnosis. The hypothesis of a possible role of dopaminergic function in the control of suicidal behavior has been less extensively studied. However, several studies assessing dopaminergic function by measuring cerebrospinal fluid (CSF) dopaminergic metabolites in suicide attempters have suggested an association between dopaminergic hypoactivity and suicidality. Lower levels of CSF homovanillic acid (HVA) have been found in depressed patients with a history of either violent or nonviolent suicide attempts than in controls (review in Engström et al., 1999). In a 5 years longitudinal study, Roy et al. (1989) observed that patients who reattempted suicide during the follow-up had lower CSF HVA levels compared to controls. This predictive value of low CSF HVA concentrations has been confirmed in another longitudinal study over a period of 2 years (Träskman-Bendz et al., 1993). Recently, Engström et al. (1999) showed reduced CSF HVA concentrations and HVA/5-HIAA ratios in suicide attempters compared to controls. In contrast, Mann and Malone (1997) did not find any association between CSF HVA levels and suicidality in depressed suicide attempters with a high degree of lethality. Post-mortem studies have provided conflicting results. In 1984, Crow et al. reported an increase in HVA concentrations in the hippocampus but not the cortex of suicide victims. Ohmori et al. (1992) observed an increase in HVA levels in the frontal cortex of individuals who committed suicide compared to subjects who died by a physical illness. Bowden et al. (1997a) provided other results supporting reduced dopamine turnover in depressed suicides by demonstrating decreased dihydroxyphenylacetic acid (DOPA) in the basal ganglia of suicide completers who died by non-violents means. In contrast, Arranz et al. (1997) did not find any difference in HVA concentrations at the level of the cortex of suicide victims.

Most of these conflicting studies have been performed in depressed suicide attempters without assessment of the medical lethality of the attempt. Therefore, results observed in suicide attempters could not be easily extended to suicide completers. Indeed, suicide attempters constitute a very heterogenous group and important differences exist between attempted suicide and completed suicide. Previously, we suggested an involvement of D2-dopaminergic function in the expression of suicidal behavior by demonstrating a smaller growth hormone (GH) response to apomorphine, a dopaminergic agonist, in depressed patients with a history of suicide attempts in comparison to nonattempters (Pitchot et al., 1992). In this context, we hypothesized that an impaired GH response to apomorphine could be observed in depressed patients who later died by suicide compared to depressives without history of suicidal behavior.

METHODS

Subjects

Our sample comprised 8 male DSM-IV (APA, 1994 ) major depressed in-patients who died by suicide within one year after hospitalisation. These patients were compared to 18 male major depressed in-patients who never attempted suicide. We excluded patients with psychotic symptoms. All the patients had a score more than 18 on the 17-items Hamilton depression scale (HAMD) (Hamilton, 1960). Overweight (35% above the ideal body weight) patients were excluded from the study. The two groups did not differ in mean weight or psychomotor retardation subscale scores of the HAMD. The apomorphine test was performed after a drug-free period of at least 2 weeks (Pitchot et al, 1995). Moreover, there was no significant difference in washout periods between groups and patients were free of antipsychotic treatments for at least 6 months. During the one year follow-up, patients were treated with antidepressants and low doses of benzodiazepines.

Suicide completers were patients regularly followed in in-patient services between 1989 and 1994. All patients were free of medical illness as evidenced by history, medical examination, electrocardiogram, chest X-ray, electroencephalogram, and routine laboratory tests. Patients with a basal systolic blood pressure less than 100 mmHG were excluded from the study. Moreover, in order to be included, patients had to present a basal (t0) GH level less than 5 ng/ml before the pharmacological challenge. The exclusion of subjects with basal GH values > 5 ng/ml is recommended because "prestimulator" healthy volunteers tend to respond significantly less to a noradrenergic challenge than healthy volunteers with low basal values (Pitchot et al., 1995). Finally, patients had given informed consent for their participation in neuroendocrine studies at the University Hospital of Liège, Belgium.

Neuroendocrine Test Procedure

The apomorphine test was performed in all subjects at bedrest after an overnight fast. At 0700h, an indwelling catheter was inserted in a forearm vein. Blood samples of 10 ml were collected at -20, 0, +20, 40, 60 and 120 min after injection at 0800h of apomorphine 0.5 mg diluted in saline to obtain 0.5 ml subcutaneously.

GH was measured with a double antibody radioimmunoassay (Franchimont, 1968), with intraassay and interassay coefficients of variation of, respectively, 13.3 ( 4.7 % and 14.8 ( 9.6 % and a detection limit of 0.2 ng/ml.

Data analysis.

GH responses to apomorphine were measured by GH peak values following injection. Analyses were performed using absolute GH values as well as differences related to basal (t0) levels (relative values). Since the correlation between absolute and relative values were very high (r > 0.98), only absolute values are reported here. Moreover, since peak and area under the curve values are generaly highly correlated (r > 0.97), we decided to choose GH peak values as the measure of maximal hormonal response to apomorphine. As some variances were quite high compared with mean values, the responses of suicide completers and non-attempters were compared by means of the Mann-Withney U test. We also used ANOVA in order to compare both groups for age and HAMD scores.

RESULTS

We did not observe any statistically significant difference between groups for age (50.6 ( 11.7 years in suicide completers vs 43.8 ( 13.5 years in non-attempters, p = 0.23) or for HAMD scores (24.4 ( 4.8 in completers vs 23.8 ( 4.3 in non-attempters, p = 0.75). Mean GH peak responses to apomorphine differed significantly between suicide completers and controls (mean ( SD) : for GH peak, 7.6 ( 4.1 ng/ml vs 18.9 ( 14.2 ng/ml, U = 30, Z = -2.33, p = 0.02.

DISCUSSION

The results of the present study suggest a dopaminergic dysfunction in suicide completers. More specifically, as GH response to apomorphine is mediated through stimulation of D2-dopaminergic receptors, our study support the hypothesis of a role for D2-receptors in the biology of suicide completion. Indeed, depressed patients who later died by suicide exhibited a significantly lower GH response to apomorphine challenge than depressed patients who never attempted suicide.

These results are in agreement with our previous studies in which we demonstrated an impaired GH response to apomorphine in depressed suicide attempters compared to non-attempters (Pitchot et al., 1992; 1995). However, these clinical data are partially in contrast with postmortem studies assessing the sensitivity and the number of D2-receptor in suicide victims. Indeed, Bowden et al. (1997b) did not observe any differences in the number or affinity of D2 receptors between suicide victims free of antidepressants for more than three months prior to death, and controls. In 1992, Ruiz et al. measured the binding of the D2-receptor antagonist radioligand (3H( raclopride in caudate and frontal cortex of schizophrenic suicide victims and controls. The mean Bmax value in drug-free schizophrenic suicides was increased in comparison to controls subjects. No differences in [3H] raclopride binding were observed between non-schizophrenic suicide victims and matched controls suggesting that the modifications of D2 receptors in schizophrenia are more related to the diagnosis of schizophrenia rather than to suicidal dimension. However, postmortem results could be related to some confounding factors such as small sample size, effects of hypoxia and changes induced by drugs, in particular antidepressants.

Our results should be considered with caution due to the small sample size. Moreover, the sample included only patients with mood disorders, and the impaired GH response to apomorphine could be a biological marker of depression rather than suicide. However, recently, we showed that non-depressed patients with a history of suicidal behavior exhibited a significantly lower GH response to apomorphine challenge than patients who had never attempted suicide (Pitchot et al., unpublished data). Another confounding factor is the possible inadequacy of the drug-free period of 2 weeks. However, we previously demonstrated that GH peak responses after apomorphine did not differ between patients who had never received antidepressants and patients drug-free for at least 15 days, showing that a wash-out period of 2 weeks of antidepressant therapy could be sufficient in studies assessing the GH response to apomorphine (Pitchot et al., 1995). Another limitation is that the dopamine-mediated GH response to apomorphine is occuring at the level of the hypothalamus. Regarding the dopaminergic hypothesis of suicidal behavior, we are particularly interested in dopaminergic function in mesocortical and mesolimbic systems, and it is unclear to what extend a hypothalamically mediated endocrine response is informative about these systems.

GH response to apomorphine could be a reliable marker of suicidal behavior. However, our study should be replicated on a larger sample and across different diagnostic entities. Further studies should also assess the possible relationship between dopaminergic function and psycho-social factors associated with suicidality.

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