The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in humans.

Corticotropin-releasing hormone (CRH) is a neuropeptide thought to play a role in appetite regulation. In this report, we used a serial cerebrospinal fluid (CSF) sampling technique to examine the relationship between CSF CRH, plasma ACTH and cortisol and perceptions of hunger and satiety in fasting and sated volunteers. CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter. Fed subjects received a meal at 1:00 PM. Subjects who were fed had lower post-prandial ratings on hunger scales and higher ratings on satiety scales. Fed subjects also had slightly lower levels of CSF CRH after feeding. Furthermore, fed subjects had higher ACTH and cortisol concentrations in the first 3 h; by the fourth h the opposite was true. Our findings do not support the hypothesis that CNS CRH is a central satiety factor in the human. Instead our findings of slightly diminished CSF CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on CNS CRH. Alternatively, our findings could also reflect changes in CRH levels associated with feeding in multiple brain areas and in the spinal cord with the net effect being in the negative direction.

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression.

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.

Intra- and inter-individual correlations between cholecystokinin and corticotropin-releasing hormone concentrations in human cerebrospinal fluid.

Despite strong evidence of a physiologic relationship between cholecystokinin (CCK) and corticotropin-releasing hormone (CRH) in the rat central nervous system (CNS), evidence of such a relationship between the two hormones in the human CNS is lacking. A post hoc analysis of serial concentrations of immunoreactive CCK and CRH, obtained every ten minutes from CSF continuously collected over six hours, was performed. A total of 30 subjects were studied: 15 normal volunteers, 10 patients with major depression, and 5 recently-abstinent, alcohol-dependent patients. Overall, we observed an average intra-subject correlation of +.273 (P < 0.001) between CSF CRH and CCK. Inter-subject correlations between mean CSF levels of CRH and CCK were +.948 (P = 0.0001) and +.959 (P = 0.005) in the depressed and abstinent alcoholic patients, respectively. These inter-individual correlations were significantly greater than that seen within the group of normal volunteers (r = +.318, n.s.). The present data suggest that interactions between CCK and CRH are significant in the human CNS, particularly perhaps in depressed and alcoholic patients, and that CSF samples may be used to assess elements of the relationship between these hormones.

Low cerebrospinal fluid corticotropin-releasing hormone concentrations in eucortisolemic depression.

Hypersecretion of corticotropin-releasing hormone (CRH) and resulting hypercortisolism have been implicated in the pathogenesis of major depression. To test this CRH hypersecretion hypothesis, cerebrospinal fluid (CSF) was continuously withdrawn from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter (placed at 8:00 AM), and immunoreactive CRH concentrations were determined at 10-min intervals in 10 depressed patients, the majority of whom exhibited at least one "atypical" symptom, and in 15 normal volunteers. CSF CRH was low, plasma adrenocorticotropin (ACTH) tended to be low, and plasma cortisol was normal in the depressed patients. Also, tobacco smokers had lower CSF CRH than nonsmokers. CRH increased acutely in response to lumbar puncture, had a brief half-life, showed rapid variability in concentration over time, and displayed a diurnal concentration rhythm that was preserved in fasting individuals and in most depressed patients. CSF CRH did not correlate with plasma ACTH or cortisol; this and its rapidly fluctuating levels suggest a primarily extrahypothalamic origin of lumbar CSF CRH.

Uncoupling of serotonergic and noradrenergic systems in depression: preliminary evidence from continuous cerebrospinal fluid sampling.

We used the technique of continuous cerebrospinal fluid (CSF) sampling to test the following hypotheses regarding CNS monoaminergic systems in depression: (1) absolute concentrations of the informational substances tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) are altered in the CNS of depressed patients (2) abnormal rhythms of tryptophan and/or 5-HIAA, or defective conversion of tryptophan to serotonin (5HT), exist in the CNS of depressed patients, and (3) the relationship between the CNS 5HT and norepinephrine (NE) systems is disrupted in depressed patients. We obtained 6-h concentration time series of tryptophan, 5-HIAA, NE, and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF of 10 patients with major depression and in 10 normal volunteers. No significant differences in CSF tryptophan, 5-HIAA, NE, or MHPG concentrations or rhythms were observed between normal volunteers and depressed patients. Neither were there differences in the mean tryptophan-to-serotonin ratio. However, a negative linear relationship was observed between mean concentrations of 5-HIAA and NE in the CSF of the normal volunteers (r = 0.916 [r2 = 0.839], df = 9, P < 0.001) while, in contrast, depressed patients showed no such relationship (r = +0.094 [r2 = 0.00877], df = 9, n.s.). Furthermore, the correlation coefficients expressing the relationship between CSF MHPG and CSF 5-HIAA within the normal and depressed groups were significantly different. These data support the hypothesis that a disturbance in the interaction between the serotonergic and noradrenergic systems can exist in depressive illness in the absence of any simple 5HT or NE deficit or surplus.

Individual differences in repressive-defensiveness predict basal salivary cortisol levels.

Prior studies assessing the relation between negative affective traits and cortisol have yielded inconsistent results. Two studies assessed the relation between individual differences in repressive-defensiveness and basal salivary cortisol levels. Experiment 1 assessed midafternoon salivary cortisol levels in men classified as repressors, high-anxious, or low-anxious. In Experiment 2, more rigorous controls were applied as salivary cortisol levels in women and men were assessed at 3 times of day on 3 separate days. In both studies, as hypothesized, repressors and high-anxious participants demonstrated higher basal cortisol levels than low-anxious participants. These findings suggest that both heightened distress and the inhibition of distress may be independently linked to relative elevations in cortisol. Also discussed is the possible mediational role of individual differences in responsivity to, or mobilization for, uncertainty or change.

Fasting and postprandial cerebrospinal fluid glucose concentrations in healthy women and in an obese binge eater.

OBJECTIVE: We hypothesized that abnormal entry of glucose into the central nervous system (CNS) might exist in some chronic binge eaters of carbohydrates, as either a cause or consequence of binge eating. The purpose of this study was thus to determine fasting and postprandial glucose concentrations in the cerebrospinal fluid (CSF) of healthy women, and to obtain similar data in an obese, irritable woman with chronic binge eating of postpartum onset. METHOD: CSF was sampled continuously at 0.1 ml/min from 1100 hr to 1700 hr from the binge eating patient, who consumed 5,000 to 10,000 calories per day (preferentially binging on refined carbohydrates), and 4 healthy women via an indwelling, flexible spinal canal catheter. CSF aliquots were obtained at 10-min intervals for measurement of glucose concentrations. Simultaneously, blood was withdrawn at 30-min intervals to obtain serum for glucose assay. A glucose-rich mixed liquid meal was consumed by participants at 1300 hr. RESULTS: In striking contrast to the normal women, our bulimic patient showed no postprandial rise whatever in CSF glucose concentrations. Fasting CSF glucose concentrations were slightly lower whereas fasting serum glucose levels were normal in the bulimic patient, compared with the normal women. After eating, serum glucose levels increased in all participants, but less so in our patient. DISCUSSION: This is the first description of a lack of postprandial elevation in CSF glucose concentration in a patient with a binge eating disorder. Defective transport of glucose across the blood-brain barrier might account for the observed abnormality. While considering other possibilities, we conjecture that our patient's binge eating was an attempt to compensate for impaired postprandial entry of glucose into her CNS.

Concentrations of corticotropin-releasing hormone, norepinephrine, MHPG, 5-hydroxyindoleacetic acid, and tryptophan in the cerebrospinal fluid of alcoholic patients: serial sampling studies.

Abnormalities in corticotropin-releasing hormone (CRH) secretion, noradrenergic neurotransmission, and serotonergic activity in the central nervous system (CNS) have all been hypothesized to exist in alcoholic patients, as have abnormalities in hypothalamic-pituitary adrenal function. To test these hypotheses, we continuously sampled cerebrospinal fluid (CSF) from alcoholic patients after 38-124 days of abstinence and from normal volunteers via a flexible, indwelling lumbar subarachnoid catheter and measured CRH, norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), tryptophan, and 5-hydroxyindoleacetic acid (5-HIAA) concentrations at 10-min intervals, from 11:00 through 17:00 h. The spinal canal catheter was inserted at approximately 08:00 h. Serial plasma ACTH, cortisol, and NE concentrations were also measured. A mixed liquid meal was consumed at 13:00 h. CSF CRH concentrations were lower in alcoholic patients than in normal volunteers (26 +/- 15 vs. 60 +/- 30 pg/ml, respectively, p < 0.05 by ANOVA), as were CSF NE levels (0.33 +/- 0.09 vs. 1.15 +/- 0.51 pmol/ml, respectively, p < 0.01). Plasma NE and CSF MHPG levels were normal in the alcoholic patients. CSF tryptophan and 5-HIAA and plasma ACTH and cortisol concentrations did not differ between the groups. These studies extend our finding of reduced spinal canal CSF CRH concentrations in depressed patients to abstinent chronic alcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects on behavior of modulation of gonadal function in men with gonadotropin-releasing hormone antagonists.

The effects of acute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration of a newly developed, potent gonadotropin-releasing hormone antagonist induced azoospermia and reduced levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone. These effects coincided with a reduction in outward-directed aggression in all men. Self-reported measures of anxiety and sexual desire revealed less consistent change over time. Measures of anger control, inward-directed anger, and affective state were unaffected.

Thyroid and adrenal dysfunction in abstinent alcoholic men: locus of disturbance.

Certain neuroendocrine abnormalities (e.g., blunted plasma adrenocorticotropic hormone [ACTH] response to corticotropin-releasing hormone [CRH] administration and blunted serum TSH response to thyrotropin-releasing hormone [TRH] administration) are common in alcoholic patients. It was the objective of this study to evaluate whether they are centrally mediated: that is, whether they are secondary to increased activity of CRH and/or TRH neurons. We evaluated the nocturnal secretion (2200 hours to 1000 hours, q 15 min) of plasma ACTH, serum cortisol, and serum TSH, and their responses to the combined administration of CRH and TRH, in 28 acutely abstinent alcoholic (age range: 32 to 57 years; mean: 42.4 years) and 19 normal men (age range: 21 to 52 years; mean: 32.1 years). To assess the validity of administering CRH and TRH simultaneously, we gave 10 additional abstinent alcoholic men (age range: 36 to 53 years; mean: 45.8 years), in random order and at least 4 days apart, either CRH, TRH, placebo, or CRH plus TRH. Nocturnal ACTH, cortisol, and TSH secretion, as well as cortisol and TSH responses after CRH plus TRH administration, were similar in alcoholic and normal men. However, ACTH peak responses to CRH plus TRH were reduced in the alcoholic men (p < 0.05). The ACTH, but not cortisol, response was greater after combined CRH plus TRH administration than after CRH alone (p < .002). The blunted ACTH response does not appear to be the result of increased endogenous CRH activity, because all parameters of nocturnal ACTH pulsatility were normal in the alcoholics. It rather appears to be secondary to an intrinsic defect in the CRH responsiveness of the pituitary corticotroph, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Cholecystokinin in human cerebrospinal fluid: concentrations, dynamics, molecular forms and relationship to fasting and feeding in health, depression and alcoholism.

Very little is known about the physiologic significance of the gut-brain hormone cholecystokinin (CCK) in the human central nervous system, although the hormone has been hypothesized to be involved in the regulation of both appetite and anxiety. We continuously collected lumbar cerebrospinal fluid (CSF) via indwelling subarachnoid catheters in ten normal volunteers, ten patients with major depression and five abstinent alcoholic humans, while fasting and after eating. Five other healthy subjects were fasted throughout the experiment. We quantified CSF immunoreactive cholecystokinin (IR-CCK) and glucose concentrations at 10-min intervals from 11.00 to 17.00 h. No difference in CSF IR-CCK concentration, half-life or rhythm was observed between normal volunteers and either depressed or alcoholic patients. Fasting CSF IR-CCK concentrations were 1.3 +/- 0.18, 1.3 +/- 0.21 and 1.2 +/- 0.21 fmol/ml (mean +/- S.E.M.) in normal volunteers, depressed patients and alcoholic patients, respectively. After eating, CSF IR-CCK concentrations rose to 1.5 +/- 0.21, 1.5 +/- 0.24 and 1.4 +/- 0.26 fmol/ml, respectively. Normal volunteers who did not eat had similar basal CSF IR-CCK concentrations (1.1 +/- 0.1 fmol/ml) which similarly rose to 1.4 +/- 0.13 fmol/ml during the sampling interval. In contrast, CSF glucose concentrations rose only in the subjects who ate, beginning to rise after about 1 h and remaining elevated for at least 3 h after eating. These data suggest the existence of a diurnal rhythm of IR-CCK release into CSF, as opposed to a response to feeding. The disappearance half-time of CCK in human CSF is less than 13 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Two patients with Cushing's disease in a kindred with multiple endocrine neoplasia type I.

Cushing's disease (pituitary ACTH-dependent Cushing's syndrome) has been described in association with the syndrome of multiple endocrine neoplasia type I (MEN-I). Cushing's disease is uncommon in MEN-I and has not been reported in more than one member of a kindred. Here we describe a mother and her daughter with Cushing's disease and major depressive disorder. The mother, her other daughter, and two other relatives also had primary hyperparathyroidism. We believe this to be the first reported instance of hereditary Cushing's disease as a manifestation of MEN-I.

Alprazolam in panic disorder: a retrospective analysis.

1. The charts of 78 panic disorder outpatients treated with alprazolam (mean dose 4.30 mg/day, mean duration 31.9 months) were reviewed for demographics, past history (including substance abuse and major depression), and evidence of alprazolam abuse. In addition, the patients were evaluated by Clinical Global Index for improvement at last contact. 2. Moderate to significant recovery was found in 77% of patients. Major depression was seen in 41%. Depressed patients were more likely to have coexisting agoraphobia and a past history of alcohol abuse than non-depressives. 3. There was no DSM-III-R anxiolytic abuse, but 12% showed unauthorized use of the alprazolam. These subjects were three times more likely to have a history of drug abuse than non-misusers. 4. These results indicate that alprazolam is effective in the long-term treatment of panic disorder, but that prolonged management may be required. Further, the data raise concerns about use in panic patients with substance abuse histories.

Sleep deprivation accelerates the response to nortriptyline.

1. The authors examined the effect of total sleep deprivation (SD) in combination with nortriptyline in 20 patients with major depressive disorder (MDD). Patients underwent a 36-hour SD procedure followed by nortriptyline started on the evening after SD, with ratings for two weeks. 2. Eleven (55%) patients were responders; they showed a rapid and sustained remission after SD, whereas non-responders demonstrated the delayed results expected with nortriptyline. 3. High initial depression scores and absence of depersonalization were associated with response to SD, while being female and middle insomnia were associated with response to the combined regimen. 4. The combination of SD with antidepressants proves to be an effective and safe treatment modality.

The effects of antidepressants on the thyroid axis in depression.

Thirty-nine patients with major depression were studied to determine the differential effects of desipramine (DMI) and fluoxetine (FLU) on thyroid hormones. Twenty-six percent showed some abnormality in baseline thyroid hormone levels. There were no demonstrable differences for any of the thyroid indices from baseline to the 3- or 6-week samples for the total group or for either drug by repeated measures analysis of variance. There was a significant group by time interaction for total thyroxine (TT4) between the drug treatment groups, which was caused by a small but significant increase in TT4 in the DMI sample. Correlations were performed between the change in hormones over the 6 week period and treatment response. There was a significant association between a decline in triiodothyronine (T3) levels and response to FLU but not DMI. The implications of these findings for the pathophysiology of depression and antidepressant drug mechanisms are discussed.

Evidence for normal feedback inhibition of triiodothyronine on the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in abstinent male alcoholics.

Disturbances in the hypothalamic-pituitary-thyroid (HPT) axis have been reported in abstinent, noncirrhotic alcoholics, including a reduction in thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) and reductions in triiodothyronine (T3). Some evidence has suggested that a portion of alcoholics may also exhibit a disturbance in the feedback inhibition of thyroid hormone on TSH release. To evaluate the function of the HPT axis negative feedback system in abstinent, noncirrhotic alcoholic men we compared the TSH response with TRH before and after a standard suppressive dose of T3. Ten alcoholic subjects were studied and compared with four control subjects from a previous study and to literature values. The mean percent reduction in TSH response in the alcoholic subjects of 74 +/- 7% was almost identical to the 71 +/- 9% reduction observed in normal subjects. The present findings indicate that noncirrhotic, abstinent alcoholic men exhibit normal suppression of the TSH response to TRH following T3.

Effects of thyroid hormones on central nervous system in aging.

Support for the many relationships between thyroid hormones and brain function comes from both laboratory and clinical studies. Studies in laboratory animals provide convincing evidence for a neuroregulatory role of thyroid hormones in the brain, suggesting that they may affect behavior. This notion is supported by human studies which have revealed that the effects of thyroid hormones on brain function are most important during the development and maturation of the brain; thereafter, age does not seem to critically affect brain-thyroid hormone relationships.

Psychiatric phenomenology in Cushing's disease.

We evaluated 20 patients with Cushing's disease (i.e., Cushing's syndrome due to ACTH-secreting pituitary microadenoma) and 20 patients with Major Depressive Disorder (MDD) using the Structured Clinical Interview for DSM-III-R (SCID) and Research Diagnostic Criteria. The diagnosis of Generalized Anxiety Disorder (GAD) was most common in Cushing's disease (79%), followed by MDD (68%), and Panic Disorder (PD) including subthreshold PD (53%). The combination of MDD and GAD and/or PD was also common in Cushing's disease (63%). Behavioral symptoms, if present, usually first occurred at or after the onset of the first physical symptoms. However, the onset of PD was associated with more chronic stages of Cushing's disease. In both Cushing's disease and MDD, more female than male relatives suffered from MDD, whereas more male than female relatives suffered from substance abuse. The data demonstrate a syndrome of anxious depression in patients with active Cushing's disease; such comorbidility has not been previously noted. The data also point to intriguing epidemiological, clinical, and biological associations between Cushing's disease, MDD and substance abuse.

The pathogenesis of Munchausen syndrome. A review and case report.

The authors present a case of Munchausen syndrome notable for an extended premorbid length and lack of early identifiable antisocial behavior. The patient's life history has been reconstructed, and an integrated psychobiological evaluation of the patient is given including neuroanatomical, neurohormonal, and neuropsychological assessments. Frontotemporal cerebral atrophy and lack of thyroid-stimulating hormone response to thyroid-releasing hormone infusion were found. Although self-object losses did appear to precipitate the Munchausen syndrome in a step-wise fashion, it appears that central nervous system deterioration might have been related to the development of the disorder.