L-tryptophan and neuroendocrine regulation in neurologic patients: hormone responses to L-tryptophan loading in patients with hypothalamic lesions

1. Oral administration of 2 g of l-tryptophan induced a marked plasma elevation of total and free tryptophan during the 2 hr of sampling in both normal subjects and in neurologic patients. Plasma free trytophan concentration showed a peak about 60 min after loading with l-tryptophan. 2. Plasma immunoreactive follitrophin (FSH) and lutrophin (LH) levels were not altered after l-tryptophan treatment. 3. Plasma immunoreactive somatotrophin (growth hormone, GH) levels showed a statistically significant elevation after l-tryptophan loading in both normal subjects and in neurologic control patients. In two acromegalic patients there was a very marked elevation of plasma somatotrophin levels 90 min after loading. No responses of plasma somatotrophin to l-tryptophan were observed in patients with hypothalamic lesion or with hypopituitarism. 4. Plasma cortisol levels showed significant morning decline during loading either with l-tryptophan or with l-leucine as placebo in normal subjects and in neurologic control patients. In patients with hypothalamic lesion the monitoring of plasma cortisol concentrations during l-tryptophan loading revealed a primary elevation with a subsequent slight decline. No variation of plasma cortisol was found in patients with hypopituitarism. 5. It was concluded that the brain serotoninergic system can be activated by l-tryptophan treatment which results in alterations of the hypothalamic regulation of somatotrophin secretion. When neuroendocrine dysfunction is due to structural lesions in the hypothalamus or in related regions, l-tryptophan loading is unable to modify somatotrophin secretion. The normal morning decline of plasma cortisol levels is lacking in such patients.     

Neuroendocrine effects of intravenous clomipramine in depressed patients and healthy subjects.

OBJECTIVE: Neuroendocrine challenge paradigms have been used to asses serotonergic systems in depression, but limitations in the specificity of many of these tests have been noted. In this study, the neuroendocrine responses to acute intravenous administration of the serotonin (5-HT) reuptake inhibitor clomipramine were assessed in depressed patients and matched control subjects. METHODS: Thirty hospitalized patients who met DSM-III-R criteria for major depression, and 30 healthy control subjects who were matched for age, sex, and season of year for the time of study, received 12.5 mg of intravenously administered clomipramine. RESULTS: The depressed patients demonstrated significant blunting of prolactin responses to clomipramine, as well as trends toward blunted ACTH and cortisol responses. There was no difference between the patient and control groups in growth hormone responses, plasma clomipramine levels, or self-reports of side effects. CONCLUSIONS: These data support the hypothesis that depressed patients have abnormal neuroendocrine responses to the intravenous administration of the 5-HT reuptake inhibitor clomipramine. Further study is required to delineate the mechanisms responsible for the abnormal response to intravenously administered clomipramine in depression.     

Noradrenergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to clonidine and comparison to healthy controls

To evaluate noradrenergic (NE) function in obsessive-compulsive disorder (OCD), behavioral, physiological, and neuroendocrine responses to the alpha 2-adrenergic agonist clonidine were examined in 18 patients with OCD and 10 healthy subjects. Subjects received single i.v. doses of 2 micrograms/kg of clonidine administered under double-blind, placebo-controlled, random-assignment conditions. Following clonidine, but not following placebo, patients transiently experienced a significant reduction of obsessions and compulsions. Significant drowsiness and a reduction in anxiety were also noted, but the antiobsessional effect appeared independent of the soporific and antianxiety effects. Growth hormone (GH), cortisol, and 3-methoxy-4-hydroxyphenylglycol responses to clonidine did not differentiate patients from healthy controls. Blood pressure and pulse in response to clonidine did not differ between groups. Improvement in OCD symptoms after clonidine significantly correlated with GH response to clonidine, suggesting specific noradrenergic mediation. This finding lends only partial support for a primary defect of noradrenergic function in OCD.     

Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects.

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.     

Prolactin secretion during sleep: a comparison between depressed patients and healthy control subjects

Although several neuroendocrine abnormalities have been described in depressed patients, relatively little attention has been paid to the pattern of prolactin secretion during sleep. Sleep disturbances are frequently found in depressed patients, and the sleep electroencephalogram (EEG) typically shows significant changes in the first and last 100 min, when prolactin secretion frequently occurs. In this study, carefully defined inclusion criteria were used to ensure comparability in the quality of the sleep maintenance, so that the pattern of sleep-related prolactin secretion in a group of 26 depressed inpatients could be compared to that in a group of 20 healthy control subjects. Starting from sleep onset, the patients did not show any statistically significant difference in either the serum prolactin concentration or the pattern of integrated prolactin secretion relative to the control subjects. A statistically significant relationship between prolactin secretion and the REM-non-REM sleep cycle could not be demonstrated in these subjects.     

Neurocognition in depression: patients on and off medication versus healthy comparison subjects

Patients with depression have neuropsychological deficits in attention, memory, psychomotor speed, processing speed, and executive function. It is not clear, however, whether neurocognition in depression is impaired in a global or nonspecific way or if specific cognitive domains are selectively impaired. This naturalistic cross-sectional study employed a computerized neurocognitive screening battery to evaluate 38 depressed, drug-free patients, compared to 31 patients who responded to antidepressant monotherapy and to 69 healthy comparison subjects. There was evidence for global neuropsychological impairment in untreated depressed patients. In patients who had been successfully treated, performance was improved but not normalized. There was also evidence for specific depression-related deficits in executive function and processing speed but not in memory, psychomotor speed, or reaction time. Although depressed patients have global neurocognitive impairments, deficits in certain cognitive domains are more important than in others. In particular, impairments are noted in tests of executive control and in tests that demand effortful attention. Information processing speed is also impaired but not reaction time. Computerized testing in the clinic setting demonstrates a range of neurocognitive problems in patients with depression. These problems may have a bearing on treatment and outcome.     

Adrenergic receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects

Several recent investigations have raised the possibility that the sensitivity of alpha 2-adrenergic receptor may be of etiologic importance in depression. To assess whether abnormalities in presynaptic alpha 2-adrenergic receptor exist in depressed patients not taking drugs, the effects of an alpha 2 agonist, clonidine, on plasma 3-methoxy-4-hydroxyphenelethyleneglycol (MHPG) and on blood pressure (BP) were evaluated in 15 depressed patients and 12 healthy controls of similar age. The ability of clonidine to increase growth hormone (GH) secretion was also assessed. The effect of clonidine on plasma MHPG and BP was not different between the depressed patients and controls. However, the GH response to clonidine was blunted in the depressed patients. These results suggest that in depression (1) the sensitivity of the presynaptic alpha 2-adrenergic receptor is not abnormal, and (2) the sensitivity of postsynaptic adrenergic receptors may be decreased.     

Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Preliminary observations

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed.     

Personality traits in former depressed patients and in healthy subjects without past history of depression

208 patients (81 male and 127 female) in the age range 21-67 years completed a Swedish personality inventory (Karolinska Sjukhusets Personlighetsinventorium; KSP) aimed at measuring stable personality traits after recovering from the depressive syndrome. Diagnostically, the series comprised 62 unipolars, 31 bipolars, 58 neurotic-reactive depressives, and 57 patients with an 'unspecified' depressive disorder, i.e., those patients who did not meet the criteria for inclusion in any of the aforementioned groups. As a contrast group, a series of 75 mentally healthy individuals (27 men and 48 women with a mean age of 39.5 +/- 12.1 years) without any past history of depression was also investigated. The former patients scored differently from the healthy controls in almost all the personality variables covered by the KSP, with the exception of the variable 'social desirability', on which all groups scored alike. A factor analysis of the results yielded three principal factors: factor 1 covering such variables which reflect anxiety proneness, psychasthenia, suspicion, and guilt; factor 2 (bipolar) covering different aspects of aggression; and factor 3 comprising the variables 'impulsiveness' and 'monotony avoidance'. From the present study it is concluded that although inter-group differences do occur, the main characteristics of the personality of the depression-prone individual seem to be anxiety, psychasthenia (covering such traits as orderly, conscientious, bound to routine), suspicion, and guilt. Such characteristics are shared by all diagnostic subgroups. Depression-prone individuals also show a higher level of inhibited aggression and a lower level of manifest aggression than healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects

To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.     

Towards a model of mood responses to sleep deprivation in depressed patients

It is hypothesized that in depressed patients diurnal variation in mood (DV) is a daily recurring phenomenon, which fails to achieve expression on all days (showing a random distribution of DVs). From this perspective a meta-analysis was performed on the raw data of earlier presented studies. The effect of total sleep deprivation (TSD) on mood was examined in 14 so-called prototypical patients, showing on three successive days either positive DVs (feeling better in the evening) or inverse DVs. It was hypothesized that under baseline conditions mood follows a monotonous course with switching points at 7 AM and 11 PM and that during the TSD night the 7-AM switch took place earlier. The position of this switch was calculated, assuming that (1) before the switch the curve ran parallel to the nightly baseline curves, and (2) after the switch the curve showed a monotonous change parallel to the daily baseline curves. The best fit between predicted and measured depression after TSD was found for a switch at 3 AM, varying the switching point during the TSD night with hourly intervals. The characteristics based on prototypical patients contributed significantly to the prediction of the morning and the afternoon depression levels after TSD in a group of 53 patients (prototypical and nonprototypical).     

Multiple hormone responses to clonidine administration in depressed patients and healthy volunteers

Abnormalities in several hypothalamic-pituitary-target organ axes in depression may reflect alterations in central neurotransmitter receptor function. As the alpha 2-adrenergic receptor has been implicated in a variety of neuroendocrine abnormalities in depression, we assessed the role of alpha 2-adrenoceptor dysfunction in mediating response abnormalities of growth hormone, cortisol, and prolactin after intravenous clonidine administration (an alpha 2-adrenergic receptor agonist) in 18 patients with major depression (12 with melancholic features, 6 without melancholic symptoms) and 9 healthy volunteers. In particular, we examined the hypothesis that these abnormalities might be more evident in patients with DSM-III melancholic depression. After clonidine, the mean growth hormone response was significantly lower in melancholic depressives compared to controls (p = 0.02), and the shape of the growth hormone response profile was also significantly different in melancholic patients (p = 0.04). There was an overall decrease in the mean cortisol concentration after clonidine in melancholic patients and control subjects (p = 0.02), as well as a larger cumulative prolactin response in melancholic patients compared to those without melancholic features (p = 0.02). The present results confirm prior observations of a blunted growth hormone response after clonidine and suggest that alterations in alpha 2-adrenergic receptor activity might also contribute to several neuroendocrine abnormalities in patients with melancholic depression.     

A neuroendocrine test battery in bipolar patients and healthy subjects

Abnormalities of hormonal responses to a number of neuroendocrine challenges have been reported in depressed patients. Most studies have examined responses in a single neuroendocrine axis. We used a series of four neuroendocrine challenges (thyrotropin-releasing hormone test, gonadotropin-releasing hormone test, insulin tolerance test, and dexamethasone suppression test) to examine eight hormonal responses in 22 healthy subjects and 22 patients with bipolar disorder. Variability of hormonal responses in bipolar patients was examined by evaluating the number of abnormal hormonal responses as compared with responses from healthy volunteers. Abnormalities were observed after all four neuroendocrine tests. Nine control subjects (40.9%) and 17 bipolar patients (77.3%) had at least one abnormal response. More strikingly, 12 bipolar patients (54.5%), but no controls, had two or more abnormal responses. These findings suggest that manic-depressive patients show increased variability in hormonal response from multiple neuroendocrine axes.     

Serotonin function in panic disorders. The effect of intravenous tryptophan in healthy subjects and patients with panic disorder before and during alprazolam treatment

Preclinical evidence suggests that alterations in serotonin function may relate to the development of anxiety and the therapeutic effectiveness of antianxiety treatments. Serotonin increases prolactin release, and intravenous administration of the serotonin precursor, tryptophan, produces reliable elevations in serum prolactin levels. To evaluate serotonergic function, the effects of intravenous tryptophan on prolactin secretion were determined in 23 drug-free patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder and 21 age- and sex-matched healthy subjects. In nine of the patients the tryptophan infusion was repeated during long-term alprazolam treatment. The ability of tryptophan to increase prolactin levels was not different between the patients and healthy subjects and was not altered by alprazolam treatment. These findings suggest serotonin function may be normal in panic anxiety disorders and the antipanic mechanism of action of alprazolam may be unrelated to effects on serotonin activity.     

Physiologic and neuroendocrine responses to intravenous naloxone in subjects with Alzheimer's disease and age-matched controls.

BACKGROUND: Prior work showed that administration of naloxone HCl had different behavioral effects in patients with Alzheimer's disease (AD) than controls. The aim of the present study was to contrast the physiologic and neuroendocrine responses to administration of a wide range of doses of intravenous naloxone of patients with probable Alzheimer's disease to aged-matched controls. METHODS: This was a double-blind, placebo-controlled, study of 12 patients with probable Alzheimer's disease and 8 age-matched normal controls who each received intravenous infusions of naloxone HCl on 3 different days in doses of 0.1 mg/kg and 2.0 mg/kg preceded by test doses of 0.5 mcg/kg. Order of treatment condition was randomized. Vital signs and plasma cortisol and prolactin were obtained at regular intervals. RESULTS: Both groups showed increased cortisol after naloxone 0.1 mg/kg and 2.0 mg/kg (p < .0001), but the increase was significantly greater and longer lived in controls than in patients. Patients, but not controls, also experienced a significant hypothermic response after naloxone 2.0 mg/kg (p < .05). Prolactin, heart rate, and blood pressure did not change following naloxone and did not differ between groups. CONCLUSIONS: These findings support a growing body evidence that HPA axis activity is increased in AD, and further suggest that at least part of this may be due to decreased opiatergic tonic inhibition.     

Visceral pain and public speaking stress: neuroendocrine and immune cell responses in healthy subjects

Whereas responses to psychological stressors are well-characterized, little is known regarding responses to painful visceral stimuli. We analyzed the emotional, cardiovascular, neuroendocrine, and cellular immune responses to painful rectal stimulation and psychological stress in healthy individuals. Eleven healthy subjects were studied in three conditions on separate days: painful rectal distension, public speaking stress, and rest. Blood was drawn for endocrinological and immunological analyses; heart rate and blood pressure were measured continuously; state anxiety was assessed with a questionnaire (STAI-S). Anxiety scores were highest in the rectal distension condition. This was evident following rectal distension (mean STAI-S scores: 44.2+/-3.5 post-distension vs. 36.6+/-3.8 post-speech, p<.05), but anxiety was also elevated at baseline (41.6+/-3.9 vs. 32+/-3.2 recovery, p<.01). This anticipatory effect was reflected by elevated baseline cortisol (p<.05) and baseline ACTH (p<.01) levels, as well as circulating lymphocytes and lymphocyte subsets, including decreased basal CD3+CD4+ cells (p<.05) and increased CD16+CD56+ cells (p=.06) compared to rest. Both public speech and rectal distension induced cardiovascular activation, but the effect was more pronounced following rectal distension (+63.8+/-9.4 mmHg in response to distension vs. +36.4+/-6.2 mmHg in response to speech for systolic BP, p<.05). Different response patterns were also observed in the distribution of circulating leukocytes and lymphocyte subsets, including CD16+CD56+ cells (p<.05). An acute visceral pain stimulus causes profound emotional, neuroendocrine, and immune cell responses, which are markedly affected by anticipatory anxiety. These findings may have implications for conditions associated with visceral hyperalgesia.     

Facial expressiveness in patients with schizophrenia compared to depressed patients and nonpatient comparison subjects

OBJECTIVE: Blunted affect is a major symptom in schizophrenia, and affective deficits clinically encompass deficits in expressiveness. Emotion research and ethological studies have shown that patients with schizophrenia are impaired in various modalities of expressiveness (posed and spontaneous emotion expressions, coverbal gestures, and smiles). Similar deficits have been described in depression, but comparative studies have brought mixed results. Our aim was to study and compare facial expressive behaviors related to affective deficits in patients with schizophrenia, depressed patients, and nonpatient comparison subjects. METHOD: Fifty-eight nondepressed inpatients with schizophrenia, 25 nonpsychotic inpatients with unipolar depression, and 25 nonpatient comparison subjects were asked to reproduce facial emotional expressions. Then the subjects were asked to speak about a specific emotion for 2 minutes. Each time, six cross-cultural emotions were tested. Facial emotional expressions were rated with the Facial Action Coding System. The number of facial coverbal gestures (facial expressions that are tied to speech) and the number of words were calculated. RESULTS: In relation to nonpatient comparison subjects, both patient groups were impaired for all expressive variables. Few differences were found between schizophrenia and depression: depressed subjects had less spontaneous expressions of other-than-happiness emotions, but overall, they appeared more expressive. Fifteen patients with schizophrenia were tested without and with typical or atypical antipsychotic medications: no differences could be found in study performance. CONCLUSIONS: The patients with schizophrenia and the patients with depression presented similar deficits in various expressive modalities: posed and spontaneous emotional expression, smiling, coverbal gestures, and verbal output.     

HPA-Axis hormones and prolactin responses to dextro-fenfluramine in depressed patients and healthy controls

1. Like other authors we have established disturbances in central serotonergic neurotransmission in severely depressed patients by implementing hypothalamic pituitary adrenal (HPA)-axis hormones and prolactin responses to serotonin agonists or precursors.

2. Challenge probes with D,L fenfluramine have yielded controversial results. This substance, however, is not as serotonin-selective as previously believed.

3. Dextro(D)-fenfluramine, the dextrorotatory isomer of fenfluramine, constitutes a specific and potent serotonergic agonist.

4. In the present study the authors determined the following in healthy volunteers, and in depressed inpatients: the adrenocorticotropic hormone (ACTH), B endorphin, prolactin and cortisol responses to D-fenfluramine administration (45 mg orally), total L-tryptophan and the 8 a.m. postdexamethasone cortisol values.

5. We found no significant differences in any of the post-D-fenfluramine hormone levels across healthy controls, minor, simple major and melancholic depressives. There were no significant correlations between L-tryptophan or postdexamethasone cortisol on the one hand, and any of the post-D-fenfluramine hormone values on the other.     

Cognitive function in unipolar major depression: a comparison of currently depressed, previously depressed, and never depressed individuals

There is a lack of consensus upon a conclusive cognitive profile characterizing unipolar major depression. Currently depressed (n?=?37), recovered previously depressed (n?=?81), and never depressed controls (n?=?50) underwent assessment of executive functions, working memory, attention, and psychomotor speed. Currently depressed yielded significantly lower test scores than previously and never depressed subjects on a measure of working memory. Both currently depressed and previously depressed scored significantly lower than never depressed subjects on measures of processing speed. Recurrent depressed performed similarly to subjects with a single depressive episode. These findings indicate a mild and limited cognitive impairment during the course of a mild to moderate major depressive disorder among relatively young adults. Impaired processing speed should be considered in further studies as a potential irreversible marker for recurrent depression.     

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.