The influence of age, height, and body weight on cerebrospinal fluid amine metabolites and tryptophan in women.

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5HIAA), homovanillic acid, and tryptophan were measured in 33 depressed, 36 alcoholic, and 32 neurological control female patients selected by strict operational criteria and investigated under controlled circumstances. Plasma total tryptophan was also measured in blood samples taken simultaneously with lumbar punctures. A multivariate regression analysis was done to discover the effect of age, height, and body weight on these four biochemical measures. Only CSF 5HIAA was significantly dependent on the nonspecific patient variables: height, but neither age nor weight, accounted for more than 10% of the variance of 5HIAA. The same analysis was carried out in all three separate patient groups: the relationship between height and CSF 5HIAA was present throughout, and only 2 of 12 correlations proved to be non-homogeneous. To demonstrate the significantly of these clinical parameters a multivariate analysis of covariance was done to eliminate their effect on the four biochemical variables. As a result significant differences emerged in CSF 5HIAA and total plasma tryptophan for some of the patient groups which were not demonstrable without this correction.

Cerebrospinal fluid biochemical examinations: do they reflect clinical or biological differences?

5-Hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), cortisol (CS), tryptophan (TRY), and calcium (Ca) concentrations were measured in the spinal fluid of 85 female psychiatric inpatients in a drug-free state; 32 women suffered from major depression, another 32 had schizophrenic (or schizophreniform) disorder, and 21 had alcohol dependence as defined by DSM-III criteria. A dexamethasone suppression test (DST) was carried out following lumbar punctures in all patients. Biochemical results were analyzed by two-way analysis of variance to test the effect of diagnosis and dexamethasone nonsuppression. CS concentration proved to be significantly higher in dexamethasone nonsuppressors, independent of the diagnosis. HVA was lower in nonsuppressors, particularly in alcohol-dependent patients; 5HIAA showed a tendency to be higher in nonsuppressor depressed patients. TRY was again higher in nonsuppressors, significant only in schizophrenic patients. Ca concentration was higher in depression and lower in alcohol dependence, and within the depression group it was higher in normal DST patients. The results indicate that the primarily biological dysfunction, i.e., the limbic-hypothalamic disinhibition reflected in the DST, may be more closely related to spinal fluid biochemistry than clinical syndromes.

Cerebrospinal fluid neuropeptides in dementia.

Cerebrospinal fluid concentrations of corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH) and somatostatin (SRIF) were measured in 77 female inpatients with moderate to extreme dementia and in 17 elderly female controls. Both multi-infarct (MID) and Alzheimer-type (SDAT) demented patients had equally elevated CSF CRH and TRH but not SRIF levels as compared with the controls. This elevation was, however, not seen in patients with simple dementia while it was most prominent in those exhibiting marked depressive symptoms. It is concluded that depression rather than dementia itself may be associated with CSF CRH and TRH elevation in elderly patients with cognitive impairment.

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.

Prolactin response to fentanyl in depression.

Ten unmedicated female inpatients with major depression (DSM-III) and 10 healthy volunteer women were given an intravenous injection of 0.1 mg fentanyl at 9:00 AM and 9:00 PM on different days. The prolactin secretory response to this opioid agonist was investigated for 1 h with serial blood sampling. Repeated measures Analysis of Variance yielded a significant effect of fentanyl administration on prolactin secretion (p less than 0.0001), and there were elevated hormone responses in the evening (p less than 0.005). No group difference was seen between healthy volunteers and depressed patients, but four of the depressives showed the most blunted response, and three of these low responders committed suicide within 1 year.

Elevation of immunoreactive CSF TRH in depressed patients.

The concentration of thyrotropin-releasing hormone (TRH), a tripeptide (pyroglutamylhistidylprolin-amide), in the CSF of drug-free patients with DSM-III major depression, somatization disorder, and peripheral neurological disorders was measured with a sensitive and specific radioimmunoassay. The depressed patients had markedly higher CSF TRH concentrations than the other patient groups, and this finding could not be attributed to any demographic variables. The elevation of TRH in CSF provides further evidence of hypothalamic-pituitary-thyroid dysfunction in depression.

CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia.

To further investigate the hypothesis that hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with depression may be mediated by hypersecretion of corticotropin-releasing factor (CRF), the authors measured CRF-like immunoreactivity in CSF samples from 138 neurological control, 54 depressed, and 27 nondepressed (23 schizophrenic and four manic) subjects. The CSF CRF concentration was markedly higher (almost twofold) in depressed patients than in control subjects and nondepressed psychiatric patients. The concentration of CSF CRF was slightly but significantly higher in schizophrenic patients than in control subjects. These findings provide further support for the hypothesis that CRF hypersecretion occurs in major depression.

Diurnal variation in fentanyl-induced hormone responses and side effects.

The prolactin (PRL) and thyrotropin (TSH) secretory response to the opioid agonist fentanyl (0.1 mg IV) was investigated with serial blood sampling in ten healthy women at 9 AM and 9 PM on different days. In five subjects saline control trials were also performed. A repeated-measures analysis of variance yielded a highly significant effect of fentanyl administration both on PRL and TSH secretion. In every case there were elevated hormone responses in the evening, and more drug-related subjective symptoms were reported at this time than before noon. These findings indicate a diurnal variation of opioid responsiveness, with lower sensitivity in the morning.

Multiple hormonal responses to morphine: relationship to diagnosis and dexamethasone suppression.

Plasma cortisol, prolactin (PRL), growth hormone (GH), and thyroid stimulating hormone (TSH) responses to intravenous morphine (0.1 mg/kg body weight) were investigated in five healthy women and 22 female psychiatric inpatients (eight with major depression, 12 with schizophrenia and two with personality disorders) during a 120 min period. The results were also related to a subsequent dexamethasone suppression test (DST). Morphine caused a strong and progressive decline in plasma cortisol which was uniform in controls, depressed, and nondepressed patients. DST nonsuppressors had significantly higher cortisol levels during the entire period, but the same response to morphine. Morphine strongly stimulated PRL secretion, which was found to be significantly smaller in patients than in controls, but no difference was seen between depressed and nondepressed subjects. GH and TSH showed only minor and variable changes after morphine, with no overall significant differences. The data in this study do not support the assumption of a major alteration in opiate receptor responsivity either in depression or in DST nonsuppressor patients insofar as the regulation of the adrenal, thyroid, GH and PRL hormone secretion is concerned.

Associations among dexamethasone non-suppression and TRH-induced hormonal responses: increased specificity for melancholia?

TRH-induced thyrotropin (TSH), prolactin (PRL), and growth hormone (GH) responses were investigated together with a dexamethasone suppression test in female psychiatric inpatients with major melancholic depression (n = 21), schizophrenic disorder (n = 20), alcohol dependence (n = 11), and adjustment disorder with predominantly depressed mood (n = 13), as well as in 15 healthy women. Abnormal responses for all four endocrine variables were noted most frequently in melancholia; however, a significant number of the non-depressed patients also had abnormal hormonal responses in the individual test. The association of two or three abnormalities proved to be quite specific for the melancholic group. There were no statistically significant differences in TRH-induced TSH responses among the patient subgroups. Non-suppression of cortisol after dexamethasone was associated with blunted TSH-responses only in melancholia. There was a tendency for non-suppressor schizophrenics to show more abnormal GH-responses to TRH administration.

Alterations of cerebrospinal fluid 5-hydroxyindoleacetic acid, and total blood serotonin content during clozapine treatment.

Cerebrospinal fluid 5-hydroxyindoleacetic acid level, and total blood serotonin content was measured in groups of manic and schizophrenic patients before and after 2, 4, 6, 10, 20, and 30 days of clozapine treatment. CSF 5-HIAA values were elevated after 2 and 4 days and returned to baseline levels after 6 days or more. Blood serotonin content, in contrast, increased gradually and remained high even after 30 days. Neither CSF 5-HIAA nor blood 5-HT correlated with age, drug dose, or clinical effectiveness, but some relationship between these and the sedative component of the clozapine action was observed.

Aminergic studies and cerebrospinal fluid cations in suicide.

Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) measurements have been collected over six years from 275 drug-free, recently hospitalized psychiatric patients, almost exclusively females. In accord with other observations from various countries, patients who had attempted suicide shortly before admission had significantly lower mean CSF 5-HIAA concentration and this was particularly true for those using violent methods. This finding could be replicated in five subsequent samples of patients evaluated separately and using different assay procedures, and proved to be independent of the clinical diagnoses. CSF HVA also showed similar tendencies but it had much larger variance with respect to suicide attempts and therefore fell short of statistical significance. In two patient populations CSF calcium and magnesium measurements have been obtained. CSF calcium did not prove to be related to either suicidal behavior or the diagnosis of major depression; on the other hand, CSF magnesium was found to be significantly lower in the suicide attempters and also correlated with CSF 5-HIAA. Nonsuicidal depressives had comparable CSF calcium and magnesium levels to the controls.

The relationships of neuroendocrine tests in endogenous depression.

Amphetamine induced growth hormone (GH) response (Study 1) and TRH induced TSH response (Study 2) were assessed in patients with endogenous depression (n = 20 and n = 22, respectively), who underwent a dexamethasone suppression test (DST) on the following day. The GH response to the amphetamine was significantly lower in the group of depressed patients than in the healthy controls (n = 13). There was no difference between the DST nonsuppressors (n = 12) and suppressors (n = 8) in the GH peak values. This data strongly suggests that the two tests are independent from each other. There was no significant relationship between the DST and TRH-TSH results. Patients with blunted TSH response to TRH have had significantly higher cerebrospinal fluid 5-HIAA levels.

CSF corticotropin-releasing hormone and somatostatin in major depression: response to antidepressant treatment and relapse.

Immunoreactive corticotropin-releasing hormone (CRH) and somatostatin (SRIF) were measured in the cerebrospinal fluid (CSF) of 24 female in-patients, suffering from DSM-III-R major depression, both before and after antidepressant treatment. In the total group there were no significant differences between pre- and post-treatment CSF-CRH and SRIF concentrations despite satisfactory clinical improvement in each patient. However, there was a significant post-treatment reduction of the CSF-CRH concentration in the 15 patients who remained depression-free for at least 6 months following treatment, in contrast to the tendency for elevation in those 9 subjects who relapsed within 6 months. CSF-SRIF showed no similar pattern. High, or even increasing, CSF-CRH concentration during antidepressant treatment may indicate lack of normalization of an underlying process in major depression despite symptomatic improvement and predicted early relapse.

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.

Cerebrospinal fluid amine metabolites, tryptophan and clinical parameters in depression. Part 1. Background variables.

5-Hydroxyindoleacetic acid, homovanillic acid, and tryptophan were measured in the lumbar cerebrospinal fluid of 33 female patients with severe hospitalized depression. Total plasma tryptophan was also determined in blood samples taken simultaneously at the time of lumbar puncture. Twelve clinical parameters were recorded using operational definitions for variables not measurable in physical units, and were compared in patient subgroups containing individuals with the highest and the lowest metabolite levels. Only age proved to be significantly higher in patients with low CSF 5-HIAA, and body height showed the same tendency. The lack of other significant differences indicates that there are no close relations between these clinical parameters and the biochemical variables except the two mentioned above.

Cerebrospinal fluid amine metabolites, tryptophan and clinical parameters in depression. Part 2. Psychopathological symptoms.

The group of 33 severely depressed female patients was divided into 3 equally large subgroups, separately according to their CSF 5-HIAA, HVA, tryptophan and total plasma tryptophan, and the severity of 17 operationally defined psychopathological symptoms was compared between the subgroups containing the highest and lowest biochemical values. Nonparametric statistical testing yielded significant results on several symptoms, when the subgroups were formed from CSF 5-HIAA and HVA. There was only one significant symptom difference between subgroups separated by CSF tryptophan and a few other differences by plasma tryptophan level. The results indicate that lumbar CSF metabolites correlate more with certain individual symptoms than with the global severity of depression.

Parkinsonian symptoms with lithium, lithium-neuroleptic, and lithium-antidepressant treatment.

Eighty-one patients treated for a least 3 months with lithium were examined for the presence of parkinsonian symptoms. Twenty-four patients were receiving treatment with lithium alone, 30 with lithium and 1 or more neuroleptics, and 27 with lithium and antidepressant. Twenty-four of the patients were found to be free from parkinsonian symptoms. Severe rigidity was not found. Two patients receiving neuroleptic with lithium and 6 on lithium-antidepressant combinations exhibited severe tremor. Neuroleptics administered concomitantly with lithium did not aggravate parkinsonian symptoms. The combination of lithium and an antidepressant significantly increased tremor in comparison to lithium alone.

Cerebrospinal fluid neuropeptides in mood disorder and dementia.

Cerebrospinal fluid (CSF) concentrations of immunoreactive corticotropin-releasing hormone (CRH) and somatostatin (SRIF) were measured in female psychiatric inpatients with DSM-III-R diagnoses of major depression, mania, generalized anxiety and somatization disorder. In addition, elderly patients with dementia disorders, with or without concomitant major depression, were also investigated. CSF SRIF was not significantly different among these groups; on the other hand, mean CSF CRH concentrations were significantly higher in major depression and in dementia with depression as compared with neurological controls with no psychiatric disorders. CSF CRH levels in mania, simple dementia, or anxiety or somatization disorder were not significantly different from the controls. Background physical or clinical variables did not account for the differences in CRH concentrations. It is concluded that CSF CRH elevation may be present in some patients with major depression independent of age and an underlying dementia disorder.

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.