Mihály Arató

Elevated CSF CRF in suicide victims

Introduction It has been suggested that several indices of enhanced hypothalamic-pituitary-adrenal axis activity, including dexamethasone nonsuppression, may be indicators of suicidal tendencies. However, recent studies have failed to prove that the Dexamethasone Suppression Test (DST) could be a predictor of suicidal behavior (Dam et al. 1985; Ennis et al. 1985; Kocsis et al. 1986; Secunda et al. 1986; Arato et al. 1986a; Modestin and Ruef 1987). Encouraged by a recent study of Stanley et al. (1985), we resorted to postmortem cerebrospinal fluid postmortem (CSF) analyses as a new research tool in the investigation of completed suicides (Arato et al. 1986b). We found no differences in CSF cortisol and adrenocorticotrophic hormone (ACTH) in suicides and controls. We now report on an extension of that investigation, involving measurement of the concentration of immunoreactive corticotropinreleasing factor (CRF) in CSF. It is quite plausible that excessive, long-lasting and/or uncontrollable stress could lead to a breakdown of the psychological defensive mechanisms and to the suicidal act. In that case,

Biochemical markers in suicidal patients. Investigations with cerebrospinal fluid amine metabolites and neuroendocrine tests

141 female psychiatric patients, suffering from major depression, schizophrenia, alcohol dependence or adjustment disorder, were investigated for their 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and cortisol level in the cerebrospinal fluid (CSF). Dexamethasone suppression tests were also performed in 111 cases, and TRH/TSH tests in 40 subjects. Fifty-two patients were hospitalized following a recent suicide attempt, 18 of which were made using a violent method. The other 34 attempters took tranquilizer or sedative overdoses. CSF 5-HIAA was significantly lower in violent attempters in all 4 diagnostic categories. CSF HVA was higher in those taking drug overdoses, but only in depression (and less markedly in schizophrenia). CSF cortisol did not differ among either diagnostic or suicidal subgroups. Dexamethasone suppression was more frequently abnormal in suicidal patients than in nonattempters, and this difference was more important where the overall nonsuppression rate was lower. Maximal TSH response to TRH showed an inverse correlation with CSF 5-HIAA, and it was lowest in the nonattempter group. The difference between violent suicide attempters and nonattempters in their TSH response was significant. Since these biochemical changes were more or less independent of clinical diagnoses, it seems relevant to explore further the biological background of human aggression and suicide as a separate research direction.

Amine metabolites and neuroendocrine responses related to depression and suicide

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the lumbar cerebrospinal fluid of 57 drug-free female patients with DSM-III diagnoses of major unipolar or bipolar depression (n = 14), schizophrenic disorder (n = 18), alcohol dependence (n = 13) and a group of other disorders (n = 12). Following lumbar punctures all patients received a dexamethasone suppression test. Fourteen patients had attempted suicide immediately before admission, 4 of them by violent methods. Severity of depression, independent of the diagnosis, was assessed in every patient on the 24-item Hamilton scale. No significant differences in means and variances of amine metabolite or postdexamethasone plasma cortisol concentrations were found among the diagnostic subgroups. Suicidal patients, and in particular those who used violent methods, tended to have lower 5-HIAA, but not HVA, in their CSF; they also more often had non-suppression of cortisol after dexamethasone. Since correlation matrices in the diagnostic subgroups were homogeneous, we calculated partial correlations for the total group: here suicide attempts but not depression, seemed to be significantly correlated with CSF 5-HIAA. Thyrotropin stimulation tests were administered to 6 patients: maximal TSH responses showed a borderline significant correlation with CSF 5-HIAA, and a significant correlation with severity of depression. Neither suicide nor postdexamethasone cortisol levels showed any relation to maximal TSH changes.

Suicide in subtypes of primary major depression

Among 100 consecutive suicide victims with primary major depression at the time of their suicide, 46% were found to have had bipolar II depression, 1% bipolar I disorder and 53% non-bipolar major depression. Since the lifetime prevalence rates of bipolar II and bipolar I depressions are relatively low compared to primary major non-bipolar depression, the present findings suggest that bipolar II disorder gives a particularly high risk of suicide among the different subtypes of primary major affective illness. Fifty-nine percent of the patients had medical contact during the depressive episode, but the depression was frequently undiagnosed, untreated or undertreated. The implications of these findings for suicide prevention are discussed briefly.

Localization and Quantification of Pro-Opiomelanocortin mRNA and Glucocorticoid Receptor mRNA in Pituitaries of Suicide Victims

Suicidal behavior has been associated with hypothalamic-pituitary-adrenal overactivity in humans, as measured by increased corticosteroid secretion. To investigate whether this overactivity is reflected at the pituitary level, we have studied the localization of pro-opiomelanocortin (POMC) mRNA, and glucocorticoid receptor (GR) mRNA, in human anterior pituitaries, and quantified these messages relative to controls. Pituitaries from 7 suicide victims and 11 cardiac deaths were sectioned into 10-microns slides, stained with thionin and processed for in situ hybridization using a riboprobe complementary to human POMC mRNA. To correct for possible postmortem cell loss, hybridization with P1B15, a cDNA complementary to rat cyclophillin mRNA, was used in adjacent sections. POMC mRNA containing cells were found to be localized in clusters and were highly associated with corticotropin-releasing hormone (CRH) receptors. In contrast, GR mRNA containing cells were distributed through the pituitary, although areas of increased density were associated with POMC mRNA cells. Quantification with a computerized image analysis system revealed a 25% increase in POMC message in suicide victims. Analysis of the corticotrophic cell clumps showed that the suicide victims had higher POMC mRNA density per cell (p = 0.04) and larger corticotrophic cell size (p = 0.04) than the cardiac death victims. No differences in GR mRNA were detected between the two groups, although GR and POMC mRNA levels were highly and significantly correlated (r = 0.8, p < 0.001). There were no differences in P1B15 message between the two groups. We conclude that in situ hybridization is a useful tool to study gene regulation in human neuroendocrine tissue and that suicide victims show evidence of chronic hypothalamic-pituitary-adrenal axis activation.

Hypothalamic-Pituitary-Adrenal Axis and Suicide

1. An objective indicator of excessive stress/distress may inform us about a subjective unpleasant or hardly bearable affect. 2. According to another interpretation, the activated HPA may reflect a disturbance of limbic-hypothalamic monoamine metabolism, something that has been implicated in the pathophysiology of affective disorders. 3. A third, and comparatively neglected, aspect is the possible effect of steroids on the central nervous system (CNS) and mental functioning? Adrenal steroids have a regulatory role in adrenergic and opiate receptor Instead of looking for the solution to the “egg or chicken dilemma,” we should face the complex interplay between steroid hormonal systems and CNS neurotransmitter functions.

Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts

Magnesium and calcium concentrations were measured in the cerebrospinal fluid (CSF) of 15 neurological controls and 41 psychiatric patients suffering from major depression (n = 16), schizophrenic disorder (n = 15), or adjustment disorder (n = 10). All subjects were women 19-67 years of age and free from drugs at the time of the study. CSF was evaluated for 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol (CS) levels, and all patients received a dexamethasone suppression test (DST) following lumbar puncture. CSF calcium levels did not differ among groups, although we found a trend toward higher mean levels in both depression and schizophrenia. By contrast, CSF magnesium was found to be significantly lower in both depression and adjustment disorder; if, however, patients who had made suicide attempts were excluded, the difference became insignificant. Patients who had made suicide attempts (by using either violent or nonviolent means) had significantly lower mean CSF magnesium level irrespective of the diagnosis. CSF calcium did not correlate with magnesium, 5-HIAA, HVA, CS, global severity, therapeutic response, or DST, but CSF magnesium correlated significantly with CSF 5-HIAA, especially after correcting for age and body height. Both variables seemed to be primarily related to recorded suicide attempts, but decreased magnesium was not limited to violent cases.

Amine metabolites, neuroendocrine findings, and personality dimensions as correlates of suicidal behavior

Levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid (CSF) of 62 female inpatients with major depression (n = 19), schizophrenic disorder (n = 18), alcohol dependence (n = 13), and other disorders (n = 12). Nineteen patients had attempted suicide immediately before admission, and six had used violent methods. Fifty-three patients received a dexamethasone suppression test (DST) following lumbar puncture and all completed the Marke-Nyman Temperament Scale (Hungarian version) within 10 days. CSF 5-HIAA was significantly lower in patients who had made violent suicide attempts, but did not differ between suicide attempters who had taken drug overdoses and nonattempters. CSF HVA showed no significant differences. Dexamethasone nonsuppression occurred more frequently among attempters, but this difference did not reach statistical significance. Among the three personality dimensions of the Marke-Nyman Scale, validity was lower and stability higher in suicidal patients; both findings were more pronounced in the violent subgroup. CSF 5-HIAA and Marke-Nyman validity were inversely correlated to each other in all three subgroups, and violent attempters could be separated from the other two groups by their simultaneously low CSF 5-HIAA values and Marke-Nyman validity scores.

Serotonergic interhemispheric asymmetry: Neurochemical and pharmaco-EEG evidence ☆

1. Postmortem neurochemical investigations revealed interhemispheric asymmetry in the mediofrontal region of human brain. Significantly higher right hemisphere serotonin metabolite (5HIAA) content as well as increased maximal imipramine binding (IB) were found in the right hemisphere than in the left side. 2. IB did not show a gender difference in the mediofrontal area. However, women had higher IB in the right orbital frontal cortex than did men. 3. In vivo pharmaco-EEG results tend to support the postmortem neurochemical data. Intravenous chlorimipramine resulted in an asymmetric topographic distribution of the P300 auditory evoked potential, peak amplitudes were shifted to the right hemisphere.

The role of psychosocial and biological variables in separating chronic and non-chronic major depression and early-late-onset dysthymia

Psychosocial (sociodemographic characteristics, loss and separation and family atmosphere in childhood, recent life events) and biological (family history, DST, TRH-test) variables were investigated in 180 patients with Major Depression (MD) and Dysthymic Disorder (DD). The aim of the study was to reveal certain differences between the chronic and non-chronic course of MD and the early- and late-onset subtypes of dysthymia. When comparing the two course patterns of MD, a higher rate of malignant tumours among first-degree relatives, a greater number of long-lasting stress situations before the index depressive episode, longer duration of the previous episodes, less frequent DST nonsuppression, and a blunted TSH response to TRH were found in patients with a chronic course of MD. Several factors seem to influence the course pattern of MD, or else the chronic form represents a subgroup within MD. The late-onset dysthymics were mainly women with a low level of education, a lower suicidal tendency, normal suppression in DST, and a lack of blunted TSH responses to TRH administration during the period of double depression. The early-onset dysthymics showed a higher number of persons who had never married, who presented a more traumatic and frustrating childhood background, and who had a higher rate of DST non-suppressors and blunted TSH responses after TRH administration during the period of their double depression. Our data suggest that late-onset dysthymia might be a biologically distinct subgroup of chronic depression.