Dennis L. Murphy

Age-related changes in sleep in depressed and normal subjects

All-night electroencephalographic (EEG) sleep data were examined a function of age in normal control subjects and hospitalized, unmedicated depressed patients with primary affective illness. By analysis of variance, Total Sleep time, Delta Sleep, Sleep Efficiency, Rapid Eye Movement (REM) Sleep, and REM Latency decreased as a function of age, whereas Early Morning Awake time and Intermittent Awake time increased. Compared with normal controls, after the effects of age were covaried out, depressed patients had a greater Sleep Latency, Early Morning Awake time, Intermittent Awake time, Duration and REM Density of the first REM period, and average REM Density for the night, as well as less Sleep Efficiency, less Delta Sleep, and shorter REM Latency, Early Morning Awake time increased with age in depressives but not in normals.

Growth hormone response to clonidine as a probe of noradrenergic receptor responsiveness in affective disorder patients and controls

The growth hormone (GH) response to the alpha-adrenergic agonist clinidine was blunted in 19 depressed patients compared to 20 controls. The difference remained significant when age- and sex-matches pairs of patients and controls were compared from this sample, either including or excluding subjects with elevated GH baseline levels. Plasma levels of free 3-methoxy-4-hydroxyphenyl-glycol (MHPG) were assayed in blood samples drawn just before the clonidine infusion. A modest negative correlation was found between the plasma MHPG values and the magnitude of the GH responses to clonidine, although baseline plasma MHPG levels were not significantly different between patients and controls. The diminished GH response to clonidine observed suggests that many depressed patients may have decreased alpha-adrenoreceptor responsiveness. Decreased responsiveness may in some cases be associated with relatively increased indices of presynaptic noradrenergic availability. Such a model might have implications for understanding the functional status of the noradrenergic neurotransmitter system in depressed patients and the possible subtyping of affective disorder patients.

The dexamethasone suppression test in patients with primary obsessive-compulsive disorder

The dexamethasone suppression test (DST) was administered to 16 obsessive-compulsive disorder (OCD) patients. Six of these patients (37.5%) had an abnormal DST response. There was a trend for patients with the DST abnormality to have higher depression rating scale scores and a higher incidence of family history of affective illness compared to DST suppressors. Although 7 of the 16 OCD patients met DSM-III criteria for major depressive disorder, in every case the affective symptoms were secondary to the primary obsessional illness. The relationship of the DST to the specificity of psychiatric diagnoses is discussed.

Presnyaptic noradrenergic regulation during depression and antidepressant drug treatment

A specific testable hypothesis in which supersensitive alpha-2-adrenoreceptors play an important role in the etiology and maintenance of affective illness is presented based on the following observations: (1) published findings of changes in adrenergic receptors in the periphery and brains of rats in response to antidepressant regimens; (2) new studies of the monoamine oxidase type A-inhibiting antidepressant clorgyline, specifically relating to adaptation in the alpha-adrenergic presynaptic negative feedback system; (3) human peripheral alpha-adrenergic receptor changes from studies of patients with affective illness; and (4) observations from animals and humans experiencing stress and withdrawal from chronic amphetamine and opiate administration, suggesting that the development of supersensitive alpha-2-adrenoreceptors may lead to affective illness in vulnerable individuals. Old and new pharmacologic treatments are then discussed in terms of their capacity to specifically alter adrenergic receptor state.

Physostigmine induction of depressive symptomatology in normal human subjects.

Nine normal volunteers, screened for the absence of a personal or family history of affective disorders and free of concurrent marijuana usage, received intravenous infusions of high dose physostigmine or saline in a randomized, double-blind, counterbalanced paradigm. Self-rating and observer ratings both demonstrated a statistically significant, physostigmine associated increase in depressive-type symptoms in the group as a whole, particularly pronounced in certain individuals. These results are the first report of physostigmine associated depressive symptomatology in normal subjects. While our findings are discrepant with two previous studies, our use of multiple self-ratings, and some differences in physostigmine dosage and infusion times might have contributed to this difference. These findings suggest that high dose physostigmine may represent a pharmacological model of depression in normal subjects, or alternatively may be diagnostic of vulnerability to affective disorder in certain subjects free of a previous history of affective disturbances.

Possible subsensitization of alpha2-adrenergic receptors by chronic monoamine oxidase inhibitor treatment in psychiatric patients

Clonidine was administered to nine psychiatric patients before and after chronic treatment (3 to 4 weeks) with clorgyline, a selective monoamine oxidase type A inhibitor with antidepressant efficacy. The hypotensive response to clonidine, believed to be mediated by brain alpha 2-adrenergic receptors, was significantly attenuated by chronic but not acute (2 to 3 days) clorgyline treatment, with a time course similar to the onset of its clinical efficacy. This study supports the hypothesis that subsensitization of alpha 2-adrenergic receptors plays an important role in clorgylines antidepressant effects and may constitute a key contribution to the mode of action of other antidepressant treatments as well.

Plasma catecholamines and their metabolites in obsessive-compulsive disorder

Plasma catecholamines and their metabolites were sampled in 13 medication-free patients with obsessive-compulsive disorder (OCD) and 29 normal controls. In addition to severe OCD symptoms, the patients had significantly higher anxiety, tension, and resting pulse rates than the controls. Nonetheless, mean plasma concentrations of norepinephrine (NE) and epinephrine (E), the catecholamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA), and the stress-related hormone cortisol did not differ between OCD patients and normal controls. When the patients and control populations were combined and average plasma NE and E levels calculated over 35 min, subjects with a higher mean NE output (greater than 1.1 pm/ml) had higher Profile of Mood States depression scores than subjects with a low NE output (less than 1.1 pm/ml). Altogether, these results indicate that elevated plasma catecholamine measures are not likely to be associated with the pathophysiology of OCD.

INHIBITION OF T LYMPHOCYTE ACTIVATION BY A NOVEL P56LCK TYROSINE KINASE INHIBITOR

A new p56lck tyrosine kinase inhibitor WIN 61651 [1,4-dihydro-7-(4-methyl-1-piperizinyl)-1-(4-(4-methyl-1-piperi zinyl))phenyl- 4-oxo-3-quinolinecarboxamide) is described. WIN 61651, which is competitive with ATP, demonstrates selectivity for the lymphoid restricted tyrosine kinase p56lck over serine/threonine kinases, such as protein kinase C and protein kinase A, and over some other tyrosine kinases, including erbB2, epidermal growth factor receptor, and insulin receptor; however, it is equipotent for inhibition of p56lck and the platelet derived growth factor receptor tyrosine kinases. WIN 61651 inhibits p56lck activity in cell-free assays, tyrosine kinase activity in a T lymphocytic cell line, and T cell activation, as measured by IL-2 production by purified CD4 positive peripheral blood T lymphocytes and the mixed lymphocyte reaction. WIN 61651 constitutes a new tool for studies on the role for tyrosine kinases in lymphocyte function.

Phenylethylamine excretion in depression

Urinary phenylethylamine (PEA) excretion was evaluated in two populations of depressed hospitalized patients. Seven of 53 patients had PEA values exceeding three times the highest value found in 16 normal controls. The patients with high PEA excretion were all females. They were not, however, otherwise clinically distinguishable from depressed patients with low PEA. In a subsample of 31 patients and 10 controls, PEA excretion was not correlated with phenylacetic acid (PAA) excretion. These results suggest that depression is not associated with a generalized PEA deficit and that PAA reductions, previously reported in a depressed patient population, may not reflect a PEA abnormality.

Indices of noradrenergic output in depression

Concentrations of plasma norepinephrine (NE) and plasma-3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure, and heart rate were measured on 2 days in 25 depressed patients and 25 controls. Comparisons were made between patients and controls, and also between days for both groups, to determine the short-term stability of these measures. The means of the plasma and urinary noradrenergic metabolite measures were not significantly different between groups. The variance of plasma MHPG, plasma NE, and mean blood pressure was greater in the depressed patients than in controls. Blood pressure, plasma MHPG, and plasma NE were relatively stable as suggested by the significant correlations between the 2 days for each of these variables. Plasma NE, plasma MHPG, and the sum of the deaminated urinary metabolites (MHPG and vanillylmandelic acid) were significantly intercorrelated. These results support other data in suggesting that plasma concentrations of NE and MHPG may be useful measures of noradrenergic activity, but may not consistently distinguish depressed patients from controls.