Robert T. Rubin

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.

Pharmacoendocrinology of major depression

SummaryMajor depressives often have abnormalities in the secretion patterns of their anterior pituitary hormones and target endocrine gland hormones. There are changes in both basal hormone secretion and the responses of these hormones to perturbation tests. Considerable work has been done attempting to develop a clinical application for some of these changes as biological state markers of endogenous depression. Prominent among the changes is an overactivity of the hypothalamo-pituitary-adrenocortical (HPA) axis. The dexamethasone suppression test (DST), as a reflection of HPA axis activity, has been the most thoroughly investigated “biological test” in psychiatry to date. Considerably fewer studies have addressed more fundamental issues of HPA axis regulation in depression, such as the relationship between pre-DST cortisol hypersecretion and DST outcome. The next most widely investigated endocrine axis in depression has been the hypothalamo-pituitary-thyroid (HPT) axis. Most studies have dealt with the TSH response to exogenously administered thyrotropin releasing hormone. While blunted TSH responses have been found in depressives compared with normal controls, the frequency of blunted responses in other types of psychiatric patients has made this test marginally useful for differential diagnosis. The reported changes in other hormone axes, for example the blunted growth hormone response to several challenges noted in depressed patients, have not been investigated sufficiently thoroughly to support their general clinical use at present. Because the same putative central nervous system (CNS) neurotransmitters appear to be involved in both the modulation of affects and the regulation of the hypothalamic releasing and inhibiting factors, it is tempting to suggest that a common CNS neurotransmitter dysfunction underlies both the depressive state and the aforementioned altered endocrine dynamics. However, proposing this hypothesis has been considerably easier than demonstrating it.

Neuroendocrine aspects of primary endogenous depression III. Cortisol secretion in relation to diagnosis and symptom patterns

In order to ascertain the extent of hypothalamo-pituitary-adrenal cortical (HPA) hyperactivity in endogenous depression, we determined circadian serum cortisol patterns, cortisol responses to dexamethasone (DEX) administration, and urine free cortisol excretion before and after DEX administration in 40 definite endogenous depressives diagnosed with the Research Diagnostic Criteria. The cortisol measures ranged from normal to clearly elevated. To elucidate the clinical correlates of these hormone measures in the patients, we examined the relationships of the pre- and post-DEX cortisol measures to the diagnosis of endogenous/melancholic depression by different systems and to the overall severity and specific dimensions of depressive symptomatology. In this group of endogenous depressives, none of the diagnostic schemes for endogenous/melancholic depression which we studied was significantly related to the pre- or post-DEX cortisol measures. Of the other subject and symptom variables, only age and the agitation/anxiety factor of the Hamilton depression scale shown consistent relationships with the cortisol measures. Both were positively correlated, to a moderate degree, with the hormone measures, and they were not correlated with each other. Together they explained approximately 20% of the variance in the cortisol measures. Thus, within a group of moderately to severely ill endogenous depressives, the older and the more agitated anxious patients have a significantly greater likelihood of showing increased HPA activity. These findings indicate that age should be controlled in studies of the HPA axis and that the subjective experience of anxiety may contribute to HPA hyperactivity in endogenous depression.

The neuroendocrinology of human sleep

Abstract Sleep consists of several distinct patterns of CNS activation, including synchronized or slow wave of sleep and desynchronized or rapid eye movement sleep. Specific areas of the brain as well as specific biogenic amine neurotransmitters appear to be responsible for the periodic shifts between sleep stages. Hypothalamic regulation of the anterior pituitary gland also is influenced by the same biogenic amine neurotransmitters, and the episodic release patterns of the anterior pituitary hormones suggest prominent CNS influences. This review considers the relationship of these hormone release patterns to the circadian sleep-wake cycle and to sleep staging within the sleep period itself.

Specificity of the salivary cortisol dexamethasone suppression test across psychiatric diagnoses

One hundred forty-eight psychiatric inpatients, 12 outpatients, and 17 normal controls were given the 1.0-mg overnight Dexamethasone Suppression Test (DST), with salivary cortisol concentrations being measured as the dependent variable. Based on the Structured Clinical Interview for DSM-III, the patients were diagnosed as having major depression with melancholia (n = 21), nonmelancholic major depression (n = 50), mania (n = 15), schizophrenia (n = 32), dementia (n = 6), substance dependence/abuse n = 18), and miscellaneous (n = 18). Neither the melancholic major depressives nor the entire group of major depressives had significantly higher salivary cortisol pre- or postdexamethasone as compared with all the other patients combined, nor did the melancholic patients have significantly higher cortisol than the nonmelancholic depressives. The inpatients as a group had significantly higher pre- and postdexamethasone cortisol values than the normal controls; cortisol values for the outpatients were intermediate between these two groups. Illness severity (in the depressives), length of time in hospital before the DST, and medication regimen were all unrelated to DST outcome. Thus, in this study, the salivary cortisol DST showed little clinical utility in discriminating major depressives with and without melancholia from other patients with a broad range of psychiatric diagnoses. The test did distinguish between hospitalized psychiatric patients and normal control subjects and between depressed inpatients and depressed outpatients, indicating that hospitalization-related variables contributed to DST outcome.

Secondary depression in panic disorder and agoraphobia. II. Dimensions of depressive symptomatology and their response to treatment

Secondary depressive symptomatology in 435 subjects with panic disorder and phobic avoidance was studied before and after alprazolam treatment. No subject who had a primary affective disorder was included. Calculation of Hamilton Depression Rating Scale factor scores revealed that the agitation/anxiety, sleep disturbance, and somatization factors accounted for approximately 75% of the HAM-D total score; these all showed significant improvement with alprazolam treatment. There were few differences in dimensions of depressive symptomatology between those subjects with and those without major depression; the main difference was in the overall intensity of the depression.

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.

Basal and haloperidol-stimulated prolactin in neuroleptic-free men with schizophrenia defined by 11 diagnostic systems

Forty-four male, neuroleptic-free, acutely psychotic patients with at least one diagnosis of schizophrenia among 11 diagnostic systems, and 28 healthy controls, underwent measurement of prolactin (PRL) concentrations before and after intravenous administration of haloperidol (0.5 mg). Basal PRL concentrations were lower in the patients with Research Diagnostic Criteria (RDC) DSM-III, Cloninger, and Taylor and Abrams schizophrenias than in controls. Compared with the controls, the PRL response to haloperidol was lower in the patients with schizophrenia defined by all diagnostic systems except those of Schneider and M. Bleuler. Neither basal nor stimulated PRL concentrations were correlated with positive symptoms, but basal PRL was correlated with the Brief Psychiatric Rating Scale (BPRS) depression-related subscore. This study lends further support for the presence of dopaminergic dysfunction in schizophrenia, and demonstrates the advantages and problems in the use of multidiagnostic psychopathological evaluation to categorize a disorder where there is major disagreement among diagnostic systems.

Differences in asymmetry of facial expression between left- and right-handed children

Abstract Ten left-handed children unselected for cerebral dominance and ten right-handed children, 8–10 yr old, posed for facial photographs while mimicking several emotional expressions. Left side and right side facial composites were prepared and shown to 30 raters. The majority of right-handed children were judged to be left facial dominant, while the left-handers were judged to be mainly indeterminate and right facial dominant. These findings indicate a difference in hemifacial emotional expression between left- and right-handed children.

DSM-III Melancholia: Do the criteria accurately and reliably distinguish endogenous pattern depression?

The Structured Clinical Interview for DSM-III (SCID), Newcastle Endogenous/Reactive Index, Feinberg-Carroll Discriminant Index, and Hamilton Depression Scale were used to assess 70 depressed patients in order to determine similarities and differences in symptom structure and severity in those patients with and without endogenous/melancholic depression. All patients with melancholia according to DSM-III had definite endogenous major depression by the Research Diagnostic Criteria (RDC), but only 20 out of 35 patients with RDC definite endogenous depression were DSM-III melancholic. There was a greater difference in symptom pattern between those patients with definite endogenous depression and those with probable or non-endogenous depression than there was between the melancholic and non-melancholic definite endogenous depressives. A prerequisite for the valid delineation of a nosological category is the establishment of good reliability for diagnostic criteria. Using SCID ratings of audiotaped interviews of 9 patients (5 with major depression), the 8 raters in this study achieved a kappa coefficient of 0.79, suggesting that the use of a structured interview can improve the reliability of DSM-III diagnoses. Interrater reliabilities for most of the individual DSM-III major depressive episode and melancholia items were reasonable, but some were low. The low reliabilities could be improved by redefinition of the items to reduce ambiguity and by development of a SCID glossary.