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The role of the serotonergic system in the pathogenesis of behavioral disorders such as depression, alcoholism, obsessive-compulsive disorder, and violence is not completely understood. Measurement of the concentration of neurotransmitters and their metabolites in cerebrospinal fluid (CSF) is considered among the most valid, albeit indirect, methods of assessing central nervous system function in man. However, most studies in humans have measured lumbar CSF concentrations only at single time points, thus not taking into account rhythmic or episodic variations in levels of neurotransmitters, precursors, or metabolites. We have continuously sampled lumbar CSF via subarachnoid catheter in 12 healthy volunteers, aged 20-65 years. One ml (every 10 min) CSF samples were collected at a rate of 0.1ml/min for 24-hour (h), and the levels of tryptophan (TRP) and 5-hydroxy indoleacetic acid (5-HIAA) were measured. Variability across all 12 subjects was significantly greater (P < 0.0001) than the variability seen in repeated analysis of a reference CSF sample for both 5-HIAA (32.0% vs 7.9%) and TRP (25.4% vs 7.0%), confirming the presence of significant biological variability during the 24-hr period examined. This variability could not be explained solely by meal related effects. Cosinor analysis of the 24-hr TRP concentrations from all subjects revealed a significant diurnal pattern in CSF TRP levels, whereas the 5-HIAA data were less consistent. These studies indicate that long-term serial CSF sampling reveals diurnal and biological variability not evident in studies based on single CSF samples.

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 CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter.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.

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

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.

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. Depression and Anxiety 6:89–94, 1997.© 1997 Wiley-Liss, Inc.

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 possiblities, we conjecture that our patient's binge eating was an attempt to compensate for impaired postprandial entry of glucose into her CNS. © 1995 by John Wiley & Sons, Inc.

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, p0.05 by ANOVA), as were CSF NE levels (0.33 +/- 0.09 vs. 1.15 +/- 0.51 pmol/ml, respectively, p0.01). 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)

1. 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. 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. 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 abusethan non-misusers. 4. 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.

Abnormalities in central nervous system (CNS) noradrenergic concentrations or dynamics have been postulated to occur in major depression, although direct measurements of norepinephrine concentrations in single samples of lumbar cerebrospinal fluid (CSF) have failed to find significant differences between depressed patients and normal or neurological controls. However, the study of CNS noradrenergic dynamics under physiologic conditions has not been achieved because of the technical limitations of lumbar puncture. In the present study, we used a serial sampling technique in order to longitudinally assess CSF norepinephrine concentrations in ten healthy volunteers and ten depressed patients, smokers as well as non-smokers, while fasting and after the physiologic perturbation of eating. We continuously sampled CSF via indwelling subarachnoid catheters from 1100 to 1700 h and measured norepinephrine at 10 min intervals. A standardized mixed liquid meal was administered at 1300 h, breaking a 17 h fast. We found wide inter-individual variability in CSF norepinephrine concentrations in both groups, but no difference in CSF norepinephrine concentration between depressed patients (1.20 ± 0.85 pmol/ml, mean ± SD) and normal subjects (1.07 ± 0.15 pmol/ml). Significant intra-individual concentration variability over time was observed, which did not differ between healthy subjects and depressed patients. Hourly plasma norepinephrine concentrations were similar in normal volunteers and depressed patients. Mean plasma norepinephrine levels tended to correlate modestly with mean CSF norepinephrine concentrations. Body mass index was inversely correlated with CSF norepinephrine concentration but showed no significant relationship to plasma norepinephrine. Elevated CSF and plasma norepinephrine concentrations were, however, seen in depressed cigarette smokers compared to non-smokers. A rise in CSF norepinephrine was observed during the experiment in all subjects combined, suggesting either a response to a meal or a normal circadian rhythm. These data indicate that CSF norepinephrine concentrations do not distinguish between depressed patients and normal volunteers. Depression 1:149–155 (1993). © 1993 Wiley-Liss, Inc.

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.

CRH, a hypothalamic peptide that is the most potent ACTH secretagogue known, also appears to be produced in the cerebral cortex and spinal cord. Depressed patients have blunted responses to exogenous CRH and normal to high concentrations of CRH immunoreactivity in single morning samples of lumbar cerebrospinal fluid (CSF). Although these data suggest that depression may be associated with hypersecretion of CRH, it has also been postulated that central nervous system insufficiency of CRH might have a pathophysiological role in certain depressive syndromes. We continuously sampled lumbar CSF via indwelling subarachnoid catheters from 1100-1700 h and measured CRH at 10-min intervals in depressed patients and normal subjects. A standardized mixed liquid meal was administered at 1300 h. CSF CRH was strikingly reduced in depressed patients compared to normal subjects [4.2 +/- 1.1 pmol/L vs. 13 +/- 2.1 pmol/L (mean +/- SEM), respectively, P less than 0.01 by Wilcoxon test]. CSF CRH concentrations rose progressively during the experiment in both groups, suggesting a diurnal rhythm and, possibly, response to a test meal. CRH had a very brief half-life in CSF (less than 10 min), suggesting that the spinal cord is the origin of CRH in lumbar CSF. The rapid transients in CSF CRH concentration demonstrate that single samples provide very limited information. There were no intraindividual correlations between CSF CRH concentrations and those of either plasma ACTH or cortisol, both of which rose in response to eating. The present data show that impaired central nervous system secretion of CRH can exist during states of severe depression.

Both biological and psychological factors have been implicated in the etiology and treatment of depression. Simple deficit theories in both domains have given way to more complex models that emphasize multiple regulatory systems. Evidence has accumulated that both biological and psychological factors are important, but questions remain as to how they relate to one another and the extent that each contributes to the etiologies of the various subtypes within the disorder. Current research evidence supports the effectiveness of both pharmacological and psychosocial interventions in the treatment of depression. Although the efficacy of the former is more firmly established, the latter (particularly the cognitive-behavioral approaches) may have a preventive capacity that survives the termination of treatment.

Recent empirical studies have found that schizophrenics exhibit diminished observable facial expressivity in response to emotional stimuli (e.g., Berenbaum and Oltmanns 1992; Kring et al 1993; Kring and Neale 1996) yet report experiencing similar levels of emotion as their normal counterparts; however, it remains unclear whether schizophrenics are completely unexpressive, or if they exhibit more subtle, unobservable facial muscle activity that cannot be seen by observers. Additionally, the diminished facial expressiveness found in schizophrenia may be a function of affective flattening, a side effect of medication (akinesia), or both (Blanchard and Neale 1992). The present study sought to extend previous findings of emotional responding in schizophrenics in two ways. First, because schizophrenics exhibit very little observable facial expressivity, a more sensitive measure of facial expression, facial electromyographic (EMG) activity, was recorded during the presentation of emotional films. Second, to examine more closely the effects of medication on facial expressivity, a within subjects design was employed such that all patients were tested at two time points (approximately six months apart): when they were taking neuroleptic medication and when they were medication free. The present article presents preliminary results from an ongoing longitudinal study of affective response in schizophrenia.

The effects ofacute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration ofa 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 ofanxiety and sexual desire revealed less consistent change over time. Measures ofanger control, inward-directed anger, and affective state were unaffected. (Am J Psychiatry 1994; 15 1:271-273)

The constellation of clinical signs and symptoms that we now call “Cushing’s syndrome” was first described by Cushing in 1932. Cushing’s syndrome results from chronic exposure to excessive concentrations of glucocorticoids. The physical features of Cushing’s syndrome include weight gain, central obesity (i.e., accumulation of adipose tissue in the facial, nuchal, truncal and girdle areas), facial plethora, hirsutism, cutaneous striae, muscle wasting, weakness, and osteoporosis. Other common manifestations of hypercortisolemia include hypertension, glucose intolerance or diabetes mellitus, impotence and testicular atrophy, amenorrhea, mild erythrocytosis, lymphopenia, eosinopenia and frequent fungal infections. Cushing’s syndrome can be divided into two major categories, each of which has two major causes. ACTH-dependent Cushing’s syndrome can be caused by excessive ACTH secretion by a pituitary microadenoma (referred to as “Cushing’s disease”) or by ACTH secretion by a non-pituitary tumor (“ectopic ACTH syndrome”), usually a small cell carcinoma of the lung or a bronchial, thymic or pancreatic carcinoid tumor, which together account for 75% of all cases. ACTH-independent Cushing’s syndrome is caused by adrenocortical tumors that secrete cortisol autonomously or by administration of pharmacologic doses of synthetic glucocorticoids.

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.

This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.

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.

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.

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.

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.

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.

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.

It has been hypothesized that major depression may be divisible into subtypes based, in part, on divergent alterations in the activity of stress-responsive neurohormonal systems (Gold et al 1988; Kling et al 1989; Smith et al 1989). Thus, although the classic farm of major depression, melancholia, is associated with symptoms of dysphoric hyperarousal, including psychomotor agitation, insomnia, loss of appetite, and weight loss; atypical depressive syndromes are characterized by symptoms of hypoarousal, with fatigue, lethargy, anergia, weight gain, and hypersomnia. Whereas hypercortisolemia is consistently observed in melancholic depression (Sachar et ,'tl 1970; Carroll et al 1976, 1981), perhaps re, suiting from central nervous system hypersecretion of fiae adrenocorticotropic hormone (ACTH) secretagoguc corticotropin-releasing hormont:~ (Gold et a! 1984; Nemeroff et al 1984; Gold et al 1986), fewer data are available conc~xning the activity of the hypothalamic-pituitary-adrenal axis in atypical depressions. In the present study, we sought to determ;,ae the relate,reship between mood and adrenocortical activity over a 6-month period in a patient with a depressive syndrome characterized by the atypical features of lethargy, hyperphagia, weight gain, and hypersomnia. We also evaluated pituitary-thyroid function in our patient because abnormalities therein are not uncommon in patients with depressive syndromes (Gold et al 1981; Loosen and Prange 1982) and because controlled longitudinal c~tudies regarding the behavioral effects of thyroid hormone alone are lacking (Prange et al 1984).

Alcoholism is a common and serious illness. It may affect as many as 25% of American men and 4% of American women at some time in their lives.1,2Not surprisingly, 20–40% of all inpatient hospital admis­sions in the United States have been estimated to be alcohol-related.3

1. The nocturnal secretion of plasma ACTH and serum cortisol and their responses to ovine corticotropin-releasing hormone (oCRH) were studied in acutely abstinent alcoholic and normal men. 2. Nocturnal cortisol secretion was similar in alcoholic and normal men, but nocturnal ACTH secretion tended to be decreased during the early morning hours (0600h–0900h) in alcoholic men. ACTH, but not cortisol, responses after oCRH administration tended to be attenuated in alcoholic men. CLUSTER ANALYSIS showed that the changes were not due to alterations in ACTH pulse frequency, amplitude, or interpulse interval. 3. The data suggest an intrinsic defect in response to CRH by the pituitary corticotroph cell, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Twenty-nine alcoholic men who had been abstinent for more than 2 years were evaluated behaviorally and neuroendocrinologically and then followed for 2 years. Mean length of abstinence at intake was shorter in the eight patients with histories of depression (3.3 years) than in the patients without such histories (6.8 years). Six patients relapsed during follow-up, all of whom had been sober less than 5 years. None of the neuroendocrine variables studied was predictive of outcome. In summary, abstinence of less than 5 years and comorbidity with depression were most predictive of poor outcome.

1. 1. The relationship between serum cortisol and thyrotropin (TSH) was studied in 15 normal subjects and in 7 depressed, 15 alcoholic and 13 schizophrenic patients. Serum TSH was measured in the basal state and in response to the intravenous administration of 0.5 mg thyrotropin-releasing hormone (TRH). Cortisol was measured in the basal state immediately before TRH injection. 2. 2. Basal cortisol and TSH peak response (max. TSH concentration observed after TRH injection) showed a significant inverse relationship in normal controls (p < 0.005) and in depressed patients (p < 0.04). Schizophrenic patients, however, tended to show a positive correlation between these two parameters (p < 0.09). 3. 3. Basal cortisol and basal TSH were inversely related in normal subjects (p < 0.05, but in none of the three patient groups. 4. 4. Blunted TSH responses after TRH were found in three depressed and five alcoholic patients but not in schizophrenic patients or normal controls. 5. 5. The present data suggest that physiologic cortisol serum concentrations may suppress TRH-induced TSH response in normal subjects and depressed patients. This seems not to be true for schizophrenic patients in whom cortisol tends to enhance TRH-induced TSH release, suggesting an endocrine dissociation in these patients.

Several investigators have reported a paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in depressed patients, but other studies have failed to confirm this. In the present study, the GH response to TRH was studied in depressed patients and normal subjects. The rate of paradoxical GH response to TRH in depression was no different than that observed in control subjects. This was the case whether the data was examined using mean values or using frequency of abnormal responses. Patients with blunted thyrotropin (TSH) responses did not differ in GH release from patients with normal TSH response. A variety of factors may have contributed to the earlier reports of a positive GH response to TRH, including the definition of paradoxical GH release and the fact that depressed patients exhibit more frequent spontaneous diurnal GH release than do normal subjects.

Fifteen patients with a primary diagnosis of borderline personality disorder were studied with the thyrotropin-releasing hormone (TRH) test. Twelve carried the additional diagnosis of depression, substance abuse, or both. A blunted thyroid-stimulating hormone (TSH) response to TRH was found in seven patients, two of whom were neither depressed nor had the additional diagnosis of depression and/or substance abuse. TSH blunting was unrelated to such factors as thyroid status, serum cortisol, weight, height, or body surface. Since TSH blunting occurs in about 25% of patients with major depression but not in schizophrenia, the findings suggest that some patients with borderline personality disorder share a neuroendocrine abnormality with some affective disorder patients.

Numerous studies show that most depressed patients show abnormal pituitary responses to challenge by intravenous injection of thyrotropin releasin hormone (TRH). Some patients show after TRH diminished thyroid stimulating hormone (TSH) release, some show unexpected growth hormone release; prolactin release may be increased or decreased. The diminished TSH release is the most widely reported finding. It cannot be accounted for by primary changes in the pituitary or thyroid glands. Interference with TRH-induced TSH release by elevated cortisol may account for some observations, but this possibility has not been studied. The present data provide additional evideence that in depression there is often a disruption of hypothalamic regulatory function.

To evaluate the feedback control of thyroid hormones on TSH release, 18 normal subjects and 16 depressed patients received two TRH injections: on days one and nine. Forty eight hours before the second TRH injection subjects and patients received either T3, 100 micrograms orally, or matched placebo. T3 administration resulted in a highly significant and similar reduction of delta max TSH and FT4-index levels in both subjects and patients whereas serum T3 levels were unchanged. These data suggest that the pituitary response to the negative feedback signal of T3 is intact in depressed patients.

The psychoneuroendocrinology of mood disorders and alcoholism is reviewed here. For reasons of both space and clarity, the article focuses on the clinical data and largely omits the basic science data.

In an evaluation of the possible role of dopamine on TRH test results, 21 depressed patients were given TRH before and after one week of treatment with a low dose of haloperidol. Haloperidol significantly increased serum prolactin (both basal and after TRH) and cortisol levels, decreased body temperature, and had no effect on serum TSH, growth hormone, or thyroid hormone levels. Five of six patients with initial TSH blunting were retested with TRH; in four patients the TSH response remained blunted. These data render it unlikely that dopamine exerts a major inhibitory input on TSH secretion in depression.

The effects of pretreatment with a single dose of thyroid hormones (TH) on the subsequent endocrine and behavioral response to TRH was evaluated in unipolar depressed women. TH pretreatment altered neither serum levels of thyroid hormones nor the TRH-induced TSH response. It antagonized, however, the behavioral response to TRH. This was apparent in 2 self-assessment scales but not in an objective rating scale. Taken together the data suggest that (a) there is an impaired pituitary response to TH feedback in depressed patients; (b) TH pretreatment may affect self-assessment of behavioral effects of TRH in depression.

Various peptide hormones appear to exert behavioral and pharmacologic effects apart from their classical endocrine actions. Thyrotropin-releasing hormone (TRH), for example, antagonizes the sedation and hypothermia produced by barbiturate and other depressant drugs and de Wied has shown that ACTH 4–10, TRH, LHRH and certain related substances show some activity in inhibition of extinction of a pole-jumping avoidance response in the rat. These data provided the impetus for screening ACTH 4–10, LHRH, and related peptides for analeptic activity. ACTH 4–10 and ACTH 4-7 were inactive in antagonizing pentobarbital whether administered peripherally or centrally. ACTH 4-7 amide and 4-Met(O 2 ),8-D-Lys,9-Phe-ACTH 4–9 were active regardless of route of administration LHRH and two tripeptide fragments (Glu-His-Trp-NH 2 and p Glu-His-Phe-NH 2 ) showed analeptic activity only after intracisternal administration. Thus, sme peptide fragments related to ACTH 4–10 and LHRH were shown to share were shown to share to some degree the analeptic properties previously demonstrated for TRH.

Neurotensin (NT), an endogenous brain tridecapeptide, produces hypothermia after intracerebroventricular administration in rats and mice. The hypothermie potency of a series of structural analogues of neurotensin has been studied. [d-Arg9]-NT, NT9–13 and physalemin were devoid of hypothermie activity. The most potent peptides studied in reducing body temperature of cold-exposed rats were bombesin and [d-Tyr11]-NT. [d-Arg8]-NT, [Phe11]-NT, [d-Pro7]-NT, NT-MHMe [d-Pro10]-NT and NT8–13 possessed significant hypothermie activity, though the latter two compounds were the least active. These results indicate that the C-terminal end of the neurotensin molecule is essential for hypothermie activity.

1. The tripeptide TRH exerts a spectrum of biological activities in both animals and man. Some of these activities have been extensively studied, particularly in psychiatric patients. 2. Behaviorally, TRH appears to increase the sense of well-being, motivation, relaxation, and coping capacity in both normal subjects and patients with psychiatric and neurologic disease. These effects are not disease-specific; attempts to use TRH as a treatment tool have thus been disappointing. 3. Endocrinologically, administration of TRH stimulates the response of TSH; this response has been reported to be blunted in approximately 30% of patients with major depression. However, TSH blunting is not specific for depression, it has also been observed in a variety of other psychiatric conditions. 4. The relevance of these effects for psychiatry in general, and for psychoneuroendocrinology especially, is discussed in this review.

Thyrotropin releasing hormone (TRH) antagonizes pentobarbital sedation and hypothermia; somatotropin release inhibiting factor amplifies them. Other hypothalamic polypeptide releasing factors, Substance P and a variety of amino acids are ineffective. Three congeners of TRH antagonize pentobarbital; one amplifies it. The potencies of congeners as pentobarbital antagonists are unrelated to their potencies as pituitary thyrotropin releasers.