Serotonergic 'vulnerability' in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders.

A double-blind study of the tryptophan depletion (TD) challenge was performed on a sample consisting of 20 patients with a major depressive disorder in clinical remission after citalopram treatment. TD was induced by the intake of 43 g of an amino acid mixture containing the five large neutral amino acids. The control group received the same mixture, to which 2.3 g tryptophan had been added. Five of the 12 challenged patients showed a worsening of depressive symptoms during the day of the test. In contrast, there was no mood alteration in the eight control patients. Baseline cortisol levels were significantly higher in responders to TD compared to those in non-responders and controls. Platelet serotonin-receptor function and plasma prolactin levels were correlated. There was a significant positive correlation in the baseline data between rated mood state and plasma cortisol and a significant inverse correlation between related mood state and plasma tryptophan concentration. Thus low mood appeared to be associated with low serotonin precursor availability as well as with high cortisol levels.

Age, alcoholism and depression are associated with low levels of urinary melatonin.

Two normal control populations, separated by 8,000 miles and 24 degrees of latitude, had similar six-month mean values for overnight urinary melatonin concentrations. These values were significantly higher than six-month values for depressed subjects and abstinent alcoholic subjects, while the means for the two clinical populations were similar. Age and urinary melatonin concentration in the control and clinical populations were inversely related, but the slopes of the linear regression equations were ten times steeper for the control populations than for the clinical populations. Differences in age and sex distributions accounted for some of the differences in values between controls and the clinical populations, although controls still differed from the clinical populations, even after sex and age were factored out. The disparate slopes for age and melatonin concentrations may contribute to some of the conflicting findings of studies comparing populations of different ages. The total melatonin content in the samples from alcoholic subjects, but not the depressed subjects, was lower than that for controls. The difference in the urinary melatonin concentration between the controls and the two patient groups was not accounted for by difference in duration of urine collection period, hours of sleep or body weight.

Hypothalamic-pituitary-adrenal axis interaction with prostaglandins.

1. The major PGE2 plasma metabolite, 15-keto-13, 14-dihydro-PGE (PGEM) was measured during metyrapone, dexamethasone and ACTH tests in order to elucidate if plasma PGE was affected by short term changes of the hypothalamic-pituitary adrenal axis function in man. 2. Plasma PGEM, serum cortisol and serum 11-deoxycortisol were determined by RIA. 3. Metyrapone (an inhibitor of adrenal 11 beta-hydroxylase), 250-1000 mg was given orally at 4 hour intervals for 20 hours. PGEM, cortisol and 11-deoxycortisol were measured before and 10 and 22 hours after the start of metyrapone in 10 patients evaluated for pituitary disease. 4. Dexamethasone, 1 mg orally, was given at 23 hours on day one and 25 IU (1-24) ACTH were given iv at 8 hours on day two. Blood was drawn for determination of PGEM and cortisol at 8 hours day one, and 8 hours day two. After the ACTH injection, blood was drawn at 90 minutes (for PGEM) and at 120 minutes (for PGEM and cortisol). 10 subjects aged 21-62 years were studied. 5. Plasma PGEM levels were significantly increased after metyrapone, concomitantly with the lowering of serum cortisol levels. 6. No difference in the PGEM increase between patients with normal or subnormal 11-deoxycortisol response was found. 7. A significant increase in plasma PGEM levels was found when serum cortisol was suppressed 9 hours after dexamethasone administration. 8. Glucocorticoids inhibit synthesis of eicosanoids and the present results suggest that short term decrease in cortisol may stimulate PG synthesis.

Electroconvulsive therapy and plasma prostaglandin E2 metabolite in major depressive disorder.

1. Animal experiments show that PGE2 affects the release of ACTH and corticosteroids. In depressed subjects, plasma concentrations of the same hormones are increased immediately following ECT. Consequently we explored possible effects of ECT on PGE2. 2. The major plasma PGE2 metabolite (PGEM), ACTH, and cortisol were determined by RIA. 3. PGEM did not change with time alone and anesthesia without ECT also did not have a consistent effect. PGEM was significantly elevated at all post ECT sampling times. The maximum increase, about fifty percent, was attained at 15 and 30 minutes. Similar changes were observed following ECT-I and ECT-VI. 4. Positive correlations between PGEM, ACTH and cortisol were obtained. 5. The results demonstrate that following ECT stimulus there is a robust increase in circulating PGEM. The increased release of PGE2 may, in part, account for the elevated plasma ACTH and cortisol.

Growth hormone and somatomedin serum levels in patients with major depressive illness undergoing electroconvulsive therapy.

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum growth hormone (GH) levels were measured 30, min before and 1, 5, 15, 30 and 60 min after treatment. Six of the patients were studied 2 days before the first ECT (ECT-1) while receiving anaesthesia only. The anaesthesia given appeared to depress GH levels, which were significantly lower at 1 and 5 min after ECT than before treatment. When ECT was given there was a recovery of the GH level at 60 min, indicating a stimulatory effect of ECT on GH secretion. In 26 of the patients also investigated during the sixth and last ECT (ECT-6) in a series, no such recovery was observed. This may be due to changes in the sensitivity of intracerebral monoaminergic receptors in neurons controlling GH secretion from the pituitary gland. Since inhibition of GH secretion is mediated via beta-adrenergic pathways, the depression of GH secretion may be due to ECT-induced supersensitivity of postsynaptic beta-adrenergic receptors. In 27 of the patients serum somatomedin A, measured by radioreceptorassay (SMA-RRA), was analysed before ECT-1 and in 19 patients before ECT-6. In seven subjects the SMA-RRA was measured 30 min before and 1, 5, 15, 30, and 60 min after ECT-1. SMA-RRA levels were mainly within the normal range for age and did not change during ECT. No difference in SMA-RRA levels was observed before ECT-1 and ECT-6. This indicates that, although abnormalities in the GH-response to challenge stimuli have been reported in adults with major depressive disorder, their GH production is normal.

Hormone pattern and post-treatment attitudes in patients with major depressive disorder given electroconvulsive therapy.

As a follow-up study of a psychoendocrinological investigation of 33 patients with major depressive illness undergoing ECT, attitudes towards ECT were examined and hormones measured in remission. Two thirds of the group had a positive attitude towards ECT. Cortisol, prolactin and TSH levels differed significantly from the depressive state. In contrast, there was no difference in ACTH levels.

Effects of electroconvulsive therapy on neuropsychological function and circulating levels of ACTH, cortisol, prolactin, and TSH in patients with major depressive illness.

Thirteen patients with major depressive illness received unilateral electroconvulsive therapy (ECT). Memory and some other neuropsychological functions were studied concomitantly with changes in clinical symptoms. ACTH in plasma and cortisol, prolactin (PRL) and TSH in serum were measured 30 min before and 1, 5, 15, 30 and 60 min after treatment. Memory functions, impaired after the ECT series, were completely regained 1 month later. ACTH, cortisol, PRL and TSH were significantly increased by ECT. The maximum hormone level after ECT was lower at the last ECT in the series as compared with the first. After the last treatment, nonverbal memory performance was negatively associated with the maximum ACTH level after ECT and verbal learning was negatively correlated to the maximum cortisol level. The reason for these relationships is not known. Since both the ACTH secretion and memory function may be dependent upon the intracerebral catecholamines, the present findings may reflect variations in central monoaminergic receptor function.

Prolactin and thyrotropin in serum during electroconvulsive therapy in patients with major depressive illness.

Thirty-three patients with major depressive illness received electroconvulsive therapy (ECT), and serum prolactin (PRL) and thyrotropin (TSH) levels were measured 30 min before and 1, 5, 15, 30, and 60 min after the treatment. There was a threefold increase in PRL levels with a maximum after 15 min. The TSH plasma levels rose significantly with a maximum at 30 min after ECT. No change in PRL and TSH concentrations was seen in control experiments when the patients received anaesthesia only. In 15 patients the hormone levels were studied both during the first and sixth (last) ECT. The PRL and TSH levels were significantly higher following the first as compared to the sixth ECT. Patients on phenothiazines had higher PRL and lower TSH levels than those on other drugs or without medication, but there was no significant difference in the mean increment by ECT. Dopamine depresses PRL and TSH secretion. The diminished hormone release after a series of ECT may be explained by ECT-induced increase of postsynaptic dopamine receptor function leading to inhibition of PRL and TSH release from the pituitary gland.

Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome.

Maximum nocturnal serum melatonin level (MTmax) in relation to some clinical variables was studied in 32 patients with a major depressive episode and in 33 healthy subjects with reference to the outcome of the dexamethasone suppression test (DST). Significant regressions were found between MTmax levels and clinical rating scores in CPRS, interpreted as retardation symptoms. Four healthy subjects with disposition for dysthymic reactions had subnormal MTmax levels, which differed from MTmax levels in subjects without such disposition. Patients but not the healthy subjects, who reported parental loss before 17 years of age, had subnormal MTmax levels and differed from patients with no reported parental loss. Patients with no reported suicidal behaviour in clinical history had significantly lower MTmax levels than patients with reported suicide attempts. No relations were found between low MTmax levels and diagnoses, duration of illness, reported inheritance for depressive illness or sleep disturbances. A hypothetical low melatonin syndrome in depression is proposed: low nocturnal melatonin, abnormal dexamethasone suppression test, disturbed 24-h rhythm of cortisol, less pronounced daily and annual cyclic variation in depressive symptomatology.

Plasma pattern of adrenocorticotropin and cortisol during electroconvulsive therapy in patients with major depressive illness.

Thirty-three patients with major depressive illness were treated with electroconvulsive therapy (ECT) and plasma adrenocorticotropin (ACTH), and cortisol levels were measured 30 min before and 1, 5, 15, 30 and 60 min after ECT. There was an immediate release of ACTH with a maximum after 5 min. The maximum cortisol plasma levels were measured 30 min after ECT. No change in ACTH and cortisol concentrations was seen in control experiments when the patients received only anaesthesia. ACTH release was seen in patients treated with ECT in the morning and in the evening. In 15 patients the levels were studied at the first and sixth (last) ECT. ACTH and cortisol levels were significantly higher after the first ECT as compared with the sixth. This alteration in ACTH release might reflect ECT-induced changes in the central monoaminergic transmission with stimulation of beta-adrenergic pathways leading to inhibition of ACTH-release.