Neuroendocrine aspects of primary endogenous depression. II. Serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response.

To determine the contribution of serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity before dexamethasone administration to the dexamethasone suppression test (DST) response, a series of stepwise discriminant function analyses were performed for 40 patients with definite endogenous depression and 40 matched normal control subjects. The 24-hour serum cortisol concentration before dexamethasone administration and the serum dexamethasone concentrations at 8, 16, and 24 hours after administration served as the independent variables, and the DST "escaper"/"suppressor" dichotomy served as the dependent variable. While both types of independent variables significantly influenced the DST response, the major factor that contributed to the discrimination of escapers from suppressors was the 24-hour cortisol concentration before dexamethasone administration. Sixteen hours after dexamethasone administration, when the DST had the highest positive predictive value, serum dexamethasone concentrations significantly influenced DST outcome only when they were below a certain threshold level. At this time, hypothalamic-pituitary-adrenal cortical hyperactivity before dexamethasone administration accounted for approximately two thirds of the incidence of DST nonsuppression.

Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls.

To examine both predexamethasone and postdexamethasone cortisol measures in depression, we determined circadian serum cortisol patterns, cortisol responses to dexamethasone, and 24-hour urinary free cortisol excretion before and after dexamethasone administration in 40 patients with primary, definite endogenous depression diagnosed by Research Diagnostic Criteria and in 40 individually matched normal control subjects. Fifteen patients (38%) were dexamethasone nonsuppressors; they had significantly higher predexamethasone serum and urine cortisol measures than both their matched controls and the 25 suppressor patients. Both the predexamethasone and postdexamethasone cortisol measures were unimodally distributed across the patients and the controls. Circadian cortisol rhythms of similar magnitude occurred in both groups. The cortisol measures before and after dexamethasone administration were positively correlated to a similar degree in the patients and their controls, suggesting that predexamethasone hypothalamic-pituitary-adrenocortical hyperactivity and postdexamethasone cortisol nonsuppression are not independently determined in endogenous depression.

Personality profiles and state aggressiveness in Finnish alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: Based on clinical observations in a series of studies on Finnish alcoholic, violent offenders, we asserted that the impulsive offenders represented an extreme group of type 2 alcoholics. We also observed that these subjects were vulnerable to hypoglycemia after the administration of oral glucose load. Furthermore, we believe that while being hypoglycemic, the impulsive offenders are particularly irritable and aggressive. In the present study, we addressed these issues by studying psychological trait and state variables in a new group of violent offenders and fire setters, and age- and sex-matched healthy volunteers. METHODS: Fifty-eight alcoholic, violent offenders and impulsive fire setters and 21 healthy volunteers were administered the Karolinska scales of personality and the Rosenzweig picture frustration test after an oral aspartame and glucose challenge. RESULTS: The psychological test results and the criminal histories of the offenders, together with biochemical measurements, suggest that a low 5-hydroxyindoleacetic acid concentration in cerebrospinal fluid in the alcoholic offenders is associated with irritability and impaired impulse control, and a high free testosterone concentration in cerebrospinal fluid is associated with increased aggressiveness, monotony avoidance, sensation seeking, suspiciousness, and reduced socialization. CONCLUSION: Finnish alcoholic, impulsive offenders have personality profiles characteristic of Scandinavian early-onset male alcoholics with antisocial traits, who have been also referred to as type 2 alcoholics.

CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers.

BACKGROUND: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover. METHODS: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors. RESULTS: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers. CONCLUSIONS: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.

Neonatal dexamethasone administration. I. Temporary delay of development of the circadian serum corticosterone rhythm in rats.

A series of experiments was undertaken to examine the effects of neonatal dexamethasone administration on the development of the circadian serum corticosterone rhythm in rats. Initial experiments showed that the rhythm began normally on postnatal day 18 in untreated animals. Then 1-day-old rats were injected sc with dexamethasone acetate (1, 10, or 100 microgram), dexamethasone phosphate (1, 3, or 5 microgram) beginning on day 1. Appropriate vehicle controls were included. At most doses and dosage regimens, rat pups were sacrificed at 0700 and 1900 h on postnatal days 16, 18, 20, and 22, but at the highest doses, they were sacrificed only on days 25 and 30. The single dexamethasone acetate injection (100 microgram) delayed the appearance of the corticosterone rhythm for 2 days compared to that in the vehicle-injected controls. Similarly, the 3 consecutive injections of dexamethasone phosphate (5 microgram) delayed the appearance of the rhythm for 4 days. All other dexamethasone dosage regimens were ineffective in altering the onset of the circadian corticosterone rhythm.

Neonatal dexamethasone administration. II. Persistent alteration of circadian serum anterior pituitary hormone rhythms in rats.

Newborn male rats were treated SC with dexamethasone phosphate (100 microgram) or dexamethasone acetate (100 microgram) on postnatal day 1, dexamethasone phosphate (5.0 microgram) opn postnatal days 1, 2, 3, or the corresponding drug vehicle. All animals were sacrificed 65-70 days later at previously determined daily trough and peak times of serum LH, TSH, and corticosterone: 0700 and 0100 h for LH, 0700 and 1300 h for TSH, and 0700 and 1900 h for corticosterone. None of the three dexamethasone treatment regimens affected the circadian variation of serum LH or corticosterone. Dexamethasone phosphate (100 microgram) altered the normal circadian rhythm of serum TSH in the adult animals, but the other two dexamethasone treatments did not affect the TSH rhythm. Basal 0700 h serum levels of FSH, PRL, and GH were also measured in these animals; none of the dexamethasone treatments altered the levels of these hormones compared to levels in the vehicle-injected controls.

Effect of thyroxine, testosterone, and corticosterone on nerve growth factor (NGF) and epidermal growth factor (EGF) concentrations in adult female mouse submaxillary gland: dissociation of NGF and EGF responses.

Testosterone propionate (TP) and corticosterone acetate (CA) were administered alone and in combination with T4 to assess the effect on submaxillary gland (SMG) nerve growth factor (NGF) and epidermal growth factor (EGF) concentrations in adult female mice. Mice were treated for 5 or 10 days. SMG NGF, and EGF concentrations were measured by specific RIA techniques. Mean SMG NGF (0.68 +/- 0.08 microgram/mg protein) and EGF (0.58 +/- 0.05 microgram/mg protein) concentrations were similar in control mice. T4 (0.4 microgram/g BW, sc, daily) significantly increased mean SMG NGF and EGF concentrations to 469% and 347%, respectively, of control values after 5 days and to 1190% and 568%, respectively, after 10 days of treatment. TP (25 microgram/g BW, sc, every 2 days) significantly increased mean SMG NGF and EGF concentrations to 734% and 767%, respectively, of control values at 5 days and to 1971% and 1953%, respectively, at 10 days. T4 and TP resulted in no further significant increases in either SMG NGF or EGF concentrations above the levels observed after TP alone. CA (25 microgram/g BW, sc, daily) increased mean SMG NGF, but not EGF, concentrations at both 5 and 10 days. Moreover, T4 and CA appeared to exert an additive effect on NGF. In contrast to the observations in adult female mice, T4 increased mean SMG NGF concentrations to 178% of control levels in adult male mice, but had no significant effect of SMG EGF concentrations. These data indicate that T4 and TP modulate SMG NGF and EGF concentrations in adult female mice. T4, however, appears to have a preferential effect on NGF on both male and female mice, unlike the equal effect on TP on both NGF and EGF. CA, like T4, also appears to increase NGF, but not EGF, concentrations in adult female SMG. The present results suggest separate regulatory mechanisms for T4, TP, and CA on SMG NGF and EGF biosyntheses.

Prolactin-related testosterone secretion in normal adult men.

The sleep-related increase of plasma testosterone (T) in adult men appears to be related not only to plasma luteinizing hormone (LH) levels but to prolactin (PRL) levels as well, suggesting that PRL may have a stimulatory influence on Leydig cell function. To further investigate the influence of PRL on T secretion, five young adult men were studied on three separate days one week apart. Blood samples were taken every 20 min between 0900 and 1800. At 1000 on each of the three days they received an intramuscular injection of saline, haloperidol 0.25 mg or haloperidol 0.50 mg, in a double-blind design. The blood samples were analyzed for LH, follicle stimulating hormone (FSH), PRL and T. It was hypothesized that there would be a dose-related increase in both PRL and T following drug administration. Mean PRL levels rose promptly and significantly in a dose-related manner in response to the haloperidol, which has strong dopamine blocking effects. By 1600, PRL had returned to control values. In contrast to the PRL response, neither LH nor FSH levels were affected by haloperidol. On the saline control day mean T levels showed the normal decline during daytime hours. After 0.25 mg haloperidol, mean T levels were maintained for several hours, and after 0.50 mg haloperidol, T levels were increased for several hours. These alterations in the normal diurnal pattern of T were statistically significant. They began about 60 min after the corresponding drug-induced increases in PRL levels. This delay between increased PRL and increased T is consistent with the similar delay between the increases of these two hormones that occur at night during sleep. The results of this study lend further support to the hypothesis that PRL is another pituitary hormone that stimulates T secretion in adult men.

Dose-dependent effects of scopolamine on nocturnal growth hormone secretion in normal adult men: relation to delta-sleep changes.

To explore the sensitivity of nocturnal GH secretion to different degrees of cholinergic blockade, we investigated the effects of two doses of the muscarinic receptor antagonist scopolamine (SCOP; 3.0 and 6.0 micrograms/kg, im) and placebo, administered in a randomized fashion at 2300 h on three nights to eight normal male volunteers. Both doses of SCOP produced significant reductions in mean nocturnal GH concentration compared to the effects of the placebo; the higher dose of SCOP reduced GH to a greater degree than the lower dose, but this difference was not statistically significant (mean, 2.3 micrograms/L after 6 micrograms/kg vs. 3.0 micrograms/L after 3 micrograms/kg). Both SCOP doses significantly shifted GH secretion into later portions of the night, with a significantly greater delay observed after the larger dose. Similarly, a significant delay in the time of the GH rise was produced by SCOP. In contrast, the effects of both doses of SCOP on delta-sleep or sleep onset were small. These data confirm earlier reports demonstrating that cholinergic muscarinic input represents a potentially important source of regulation of nocturnal GH release and suggest that the magnitude of the reduction in GH and the extent of delay in the GH rise time may reflect quantitative differences in the degree of cholinergic blockade. These data are in agreement with recent studies suggesting that the timing of GH release need not be associated with delta-sleep per se.

Nocturnal increase of plasma testosterone in men: relation to gonadotropins and prolactin.

The nocturnal increase of plasma testosterone (T) in adult men has been well established. Luteinizing hormone (LH) does not show a similar increase throughout the night, whereas prolactin (PRL) does, suggesting the possibility of other hormone influence on T secretion. To investigate this possibility, 8 young adult men were studied for 4 consecutive nights in the sleep laboratory (2 nights adaptation, 2 nights blood sampling), by blood samples taken every 30 min during the 8-h sleep period, for measurement of LH, follicle stimulating hormone (FSH), PRL, and T. LH and FSH were secreted episodically, with little or no change in baseline levels during the night. PRL and T also were secreted episodically, but their baseline levels increased as the night progressed. Both LH and PRL had maximum within-subject correlations (averages equal +0.35 and +0.48 respectively) with T when they led T by 60 min. Within-subject correlations done on first differences (to remove the effect of slow trends) were near zero. LH and PRL had larger correlations with T than did FSH, for both calculations. These data suggest that both LH and PRL levels precede T levels by about 60 min. PRL thus may participate in the regulation of nocturnal T secretion in adult men.

Influence of methyl-TRH-induced prolactin increase on serum testosterone levels in normal adult men.

Our previous studies suggest that increased serum PRL, secondary to haloperidol-induced dopamine blockade, augments serum testosterone (T) levels in normal men. To rule out a direct effect of haloperidol on the testis, serum samples from a methyl-TRH study in normal men, in whom serum PRL levels were increased by a stimulus other than dopamine blockade, were analyzed for T. Fourteen subjects received both a low dose (6.25-12.5 micrograms) and a high dose (100-500 micrograms) of methyl-TRH on separate days; blood sampling was done for 15 min before and for 4 h after drug infusion. Compared to a saline control group of 14 normal men, who showed a diurnal decline of serum T levels, the methyl-TRH treated subjects had statistically significant increases in serum T after both low and high doses. These data provide further support for the concept that PRL is a pituitary hormone capable of augmenting serum T levels in normal adult men.

Effects of prolactin and prolactin plus luteinizing hormone on plasma testosterone levels in normal adult men.

In an earlier study, normal adult men were shown to have increased plasma testosterone (T) levels over a several-hour period after haloperidol-induced increases in plasma PRL levels. The present study was designed both to replicate our first study and to examine the potential synergism of PRL and LH in influencing T levels on a short term basis in normal men. Eight volunteers received on 4 separate days an in injection of saline or 0.5 mg haloperidol at 1000 h and an iv injection of saline or 88 IU human LH (hLH) at 1100 h in a double blind randomized block design arranged to augment plasma levels of PRL, LH, and PRL and LH together on the different test days as well as to afford a saline control day. Only five of the eight subjects had prompt PRL responses to haloperidol equivalent to those of our earlier study. As the purpose of this study was to examine the effect of increased PRL on plasma T levels, these five subjects were used for the determination of changes in plasma T. After haloperidol administration, their PRL levels rose an average of 19 ng/ml, to the high-normal range, and after the hLH infusions, their LH levels rose an average of 71 ng/ml. On the saline control day, mean T levels showed the normal diurnal decline. After 0.5 mg haloperidol, T levels were maintained for several hours, and after 88 IU hLH, T levels were increased for several hours. Increased PRL levels concomitant with hLH administration did not produce a T response greater than that caused by hLH alone. The results of this study replicate the effect of drug-induced PRL augmentation on plasma T levels found in our earlier study, but they fail to demonstrate a synergistic effect of acutely increased PRL on LH-stimulated T secretion. PRL thus seems to be another pituitary hormone capable of increasing plasma T in adult men, but it clearly is a weaker stimulus than LH.

Intravenous infusion of beta-endorphin increases serum prolactin, but not growth hormone or cortisol, in depressed subjects and withdrawing methadone addicts.

In a randomized, double blind, cross-over study, human beta-endorphin or saline was infused iv over 30 min into six depressed psychiatric patients and four methadone addicts. All depressed subjects showed prompt, 2- to 4-fold increases in serum PRL levels, which lasted at least 2 h. The addicts, who were undergoing acute methadone withdrawal, showed similar PRL increases, which were dose dependent. beta-Endorphin did not increase serum levels of cortisol or GH in either group of subjects. These results suggest that iv beta-endorphin has potent but selective neuroendocrine effects in depressed patients and subjects withdrawing from methadone.

Analysis of the CYP2D6 gene polymorphism and enzyme activity in African-Americans in southern California.

Despite its importance in drug metabolism and disease susceptibility, CYP2D6 activity and genetic polymorphism have rarely been investigated in African-American populations. In order to bridge this gap, we examined the genotype and phenotype of the enzyme in 154 African-American (AA) and 143 Caucasian (C) normal volunteers. AAs are significantly more likely to possess *17 and *5, but less likely to have *4. Overall, the two groups were similar in their CYP2D6 activity as measured with dextromethorphan as the probe (metabolic ratio 2.21 +/- 0.78 for AAs; 2.11 +/- 0.86 for Cs; t = 1.02, NS). Two of four AAs and six of seven Cs were classified as poor metabolizers and have two nonfunctioning alleles. CYP2D6 activity is determined by *17, *4, *5 and age in AAs (r2 = 0.33, f = 18.8, P < 0.001) and by *4 and *XN in Cs (r2 = 0.14, f = 10.8, P < 0.001). These results support previous findings demonstrating the importance of *17 in determining CYP2D6 activity in AAs.

Dissociation between plasma bioactive and immunoactive ACTH concentrations in depressed patients.

Previous studies have reported dissociations between plasma cortisol and immunoactive adrenocorticotropic hormone (ACTH) concentrations in both normal controls and in patients with major depression. In order to investigate this issue further, placebo and dexamethasone (DEX) were administered to normal controls and depressed patients at 11 PM, and plasma cortisol and ACTH were measured the following morning at 7 AM. Plasma ACTH concentrations were quantitated by both immunoassay (I-ACTH) and by bioassay (B-ACTH). In 10 normal controls, DEX (0.25, 0.5, and 1.0 mg, PO, elixir) produced a dose-related suppression of cortisol, I-ACTH and B-ACTH, with all three hormones significantly suppressed by DEX (0.5 and 1.0 mg) (p < or = 0.01). In 20 depressed patients, 7 AM plasma ACTH and cortisol concentrations were assessed following a single dose of DEX (0.5 mg). Fifteen patients were classified as suppressors and five as escapers, as reflected by mean (+/- SEM) cortisol concentration of 19.9 +/- 3.0 ng/ml and 81.2 +/- 7.0 ng/ml, respectively. Mean I-ACTH concentrations were comparable in both the escapers (8.6 +/- 1.6 pg/ml) and in the suppressors (7.0 +/- 1.0 pg/ml). In contrast, the mean B-ACTH concentration was more than two-fold higher in the escapers (4.5 +/- 0.5 pg/ml) than in the suppressors (2.2 +/- 0.3 pg/ml) (p < or = 0.001). Eleven of the 20 patients received both placebo and DEX (0.5 mg) on two separate occasions. Although DEX significantly suppressed both cortisol (p < or = 0.0001) and B-ACTH (p < or = 0.01) concentrations, I-ACTH was not significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuroendocrine aspects of primary endogenous depression. X: Serum growth hormone measures in patients and matched control subjects.

To determine the extent of dysregulation of growth hormone (GH) secretion in endogenous depression, we measured nocturnal serum GH concentrations and GH responses to thyrotropin-releasing hormone (TRH, gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared with their controls, the patients showed no difference in basal nocturnal GH concentrations or in GH responses to TRH or LHRH. The GH measures were not significantly related to the other endocrine measures reported previously, including dexamethasone suppression test status. None of the diagnostic schemes for endogenous/melancholic depression which we studied was significantly related to the GH measures in the patients. Of the other subject and symptom variables, the mood depression factor of the Hamilton depression scale and the performance difficulty factor of the Beck depression inventory were moderately negatively correlated with the nocturnal GH measures. These findings suggest that, in contrast to the previously reported hypothalamopituitary-adrenal cortical and thyroid axis abnormalities in our patients, GH secretion was relatively normal. Patients with more severe depressed mood and greater difficulty accomplishing tasks did have moderately lower nocturnal GH values.

Serum dexamethasone concentrations in endogenous depressives before, during, and after treatment: preliminary observations.

The 1.0-mg Dexamethasone (DEX) Suppression Test (DST) was performed in 10 endogenous depressives prior to treatment, during treatment, and again when the patients were medication- and symptom-free. Five of the 10 patients were DST escapers prior to treatment, and all 10 patients were DST suppressors following treatment. During treatment, 6 patients were DST escapers, 2 of them having been suppressors initially. There were no significant differences in serum DEX concentrations before, during, and after treatment in either the 5 DST escapers or the 5 DST suppressors. These results lend further support to the concept that reduced serum DEX concentrations are not the major factor underlying DST nonsuppression.

Sleep electroencephalographic abnormalities in adolescent depressives: effects of scopolamine.

In contrast to sleep studies of adult depressives that have consistently demonstrated abnormalities of sleep continuity, slow-wave sleep, and REM sleep, existing studies of depressed children and adolescents have been conflicting. Furthermore, only one study has explored the cholinergic regulation of sleep in early-onset depressives. In the present study, the electroencephalographic sleep of 20 adolescent outpatients with major depressive episodes and 13 normal control adolescents was obtained on two separate 2-night sessions, 1 night incorporating challenge with scopolamine. Depressed adolescents showed increased baseline phasic REM sleep measures, increased arousals, a trend toward reduced slow-wave sleep, and a greater difference in the change of first REM period density on the scopolamine night versus placebo night compared to controls. These findings support the continuity of some sleep abnormalities of depression into adolescence, and suggest that adolescent depression may be associated with alterations of cholinergic neurotransmission in some patients.

Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression.

Scopolamine (SCOP) (3.0 mu/kg and 6.0 micrograms/kg) and saline were administered intramuscularly at 11:00 PM to eight normal male volunteers in a randomized design, and the effects on the sleep electroencephalogram (EEG) and nocturnal cortisol secretion (via blood sampling every 15 min) were evaluated. Compared to saline, SCOP produced a significant dose-related delay in rapid eye movement (REM) latency. In contrast, neither dose of SCOP significantly affected nocturnal plasma cortisol concentrations. These results suggest that the central cholinergic system that regulates the onset of REM sleep is more sensitive to dysregulation than the cholinergic system that controls the degree of nocturnal cortisol secretion. If central cholinergic overactivity is responsible for both the REM sleep latency and cortisol abnormalities in depressed patients, then our findings with SCOP might help explain why the incidences of these abnormalities are different.

Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects.

To ascertain the extent of dysregulation of prolactin (PRL) secretion in endogenous depression, we determined nocturnal serum PRL concentrations and PRL responses to thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria (RDC) primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared to their matched controls, the patients showed no difference in basal nocturnal PRL concentrations, a marginally significant 20%-25% increase in the PRL response to TRH, and no differences in post-LHRH or postdexamethasone PRL concentrations. In the patients, there was a weak, negative correlation between age and PRL (r = -0.30), but none of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the PRL measures. The PRL measures also were unrelated to pre- and postdexamethasone cortisol concentrations and to the thyrotropin (TSH) responses to TRH in both groups of subjects. In contrast to the previously reported hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities in these patients, our findings suggest that PRL secretion was relatively normal.