Jeffrey L. Rausch

A kinetic analysis and replication of decreased platelet serotonin uptake in depressed patients

Platelet serotonin uptake was kinetically measured in 32 psychiatric inpatients and 32 age- and sex-matched controls. Patients were categorized into four groups: depressed patients, manic bipolars, other affective disorders, and nonaffective psychiatric disorders. A randomized block factorial analysis of variance indicated that the depressed patients had a significantly lower maximal velocity (Vmax) of serotonin uptake in comparison to matched controls, without a statistically significant difference in Km. No statistically significant difference was found for any of the other diagnostic groups in comparison to controls for Vmax or Km. These results are compared with previous studies of platelet serotonin transport in clinically depressed patients and in physostigmine-induced depression.

Physostigmine effects on serotonin uptake in human blood platelets

Platelet serotonin (5HT) uptake was measured in 18 subjects administered physostigmine salicylate in a double-blind, placebo crossover design. In comparison to placebo, the drug caused a significant transient depression in mood, as measured by self- and observer-rated depression scores. In addition, physostigmine significantly increased platelet counts while independently decreasing the maximum velocity (Vmax) of platelet serotonin uptake. Physostigmine administration did not significantly affect the affinity constant (Km) for platelet serotonin uptake. The data are interpreted as being consistent with the postulate that platelet serotonin uptake may be decreased in depressed patients via cholinergic mechanisms.

Biochemical hypotheses of premenstrual tension syndrome.

As information has evolved concerning the incidence of cyclical emotional changes preceding theonset of menses, th e premenstrual tension syndrome (PMT) has gained increased attention in boththe lay and professional literature. Although there has been some disagreement as to the exact nature,the time of occurrence, or even the existence of PMT (Koeske, 1981), ther ies considerable consensusthat the PMT syndrome indeed exists (Janowsky al. et 1966, 1967, 1969, 1973). Steine al.r et (1980)and Halbreich & Endicott (1982) have now operationalized psychodiagnostic criteria for PMT whichcan allow separate studies to attain diagnostic consensus more accurately.Several methodological problems in PMT research have limited exploration ho owf premenstrualphysiology might influence mood. A major problem has been the strong reliance on the use ofcorrelative techniques. Man hormones,y electrolytes, , neurotransmitters and somatic parameterschange within the menstrual cycle, and a tradition has existed for assuming the aetiologicalimportance of a favourite correlate which changes premenstrually. Although such correlations area reasonable place to start, it may be naive to believe that temporal correlations necessarily implyaetiology.Another problem in PMT research is the general assumption that circulating ovarian-linkedhormones as such are of fundamental significance in triggering and sustaining premenstrualemotional symptoms. It is equally possible that central neurotransmitters, neuromodulators, andneuroendocrine mechanisms control the onset and intensity of PMT, and that peripheral ovarianand other hormonal changes are merely simultaneous epiphenomena, and/or are driven by the abovecentral influences, but do not actually exert behavioural effects.The use of retrospective reports in PMT research has caused additional problems, withexaggerated incidences being reported, probably due to societal expectations (Koeske 1981, Parlee; ,1973; Sommer, 1978). In contrast, the incidence of PMT symptoms reported usually is relativelylow in prospective PMT studies. Thus, many subjects who report PMT do not show symptoms inactual experiments. Also, since the intensity of PMT may vary from month to month (Green, 1982),such variation may introduce serious inconsistencies and variance problems into research studies.One recent step forward in this area has been the administration of repeated mood and behaviouralratings to prospective subjects over several cycles to screen for and document cyclic emotionalchanges before a given subject is used in a specific PMT study.Also, there is some evidence that the stress of the experimental method itself may influence andconfound studies exploring menstrual cycle-behavioural relationships (Koeske 1981, ; Parlee , 1982).Conversely, a major impediment to understanding and treating PMT has been its remarkablesensitivity to treatment by placebo. Many promising aetiological hypotheses have been based onobserved ameliorative effects in uncontrolled studies of compounds which have specific centralbiochemical effects. Subsequent controlled studies have shown these treatments to be no moreeffective than placebo.There have been several hormonal hypotheses proposed to explain the aetiology of premenstrualtension. The most obvious o thesf e involves an aetiological role for fluctuations in ovarian steroids.The oestrogen withdrawal hypothesis suggests that PMT is due to premenstrual oestrogenwithdrawal. The observation that high levels of oestrogen have antidepressant effects (Klaiber etal. 1979) lends support to this possibility. However, the premenstrual fall in oestrogen is not the

Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients ☆

The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirones effects on cortisol may occur after chronic gepirone administration.

Effect of nicotine on human blood platelet serotonin uptake and efflux.

1. Physostigmine administration has been previously shown to decrease the uptake of serotonin in human platelets. In order to test whether uptake could be inhibited as a nicotinic-cholinergic effect, the in vitro effects of nicotine on platelet 5HT uptake and efflux were examined. 2. Nicotine stimulated release of serotonin from human blood platelets, and competitively inhibited human platelet serotonin uptake in a concentration-dependent fashion at in vitro concentrations as low as 20 microM for uptake. 3. The kinetics of the nicotine effects on uptake were different from those of physostigmine. Unlike the effects of physostigmine, nicotine produced different kinetic changes, with an increase in Km and no consistent change in Vmax. 4. The efflux and inhibition of uptake paralleled that previously reported in rat brain in vitro, and was likewise similar to concentrations found previously to augment extracellular amine in other tissue preparations. However, the effects of nicotine in human platelets were not reversible by nicotinic antagonism with hexamethonium. 5. The results distinguish human platelet from rat brain with respect to nicotinic antagonism, and suggest that, at similar concentrations, nicotine may increase extracellular serotonin through differing mechanisms.

Atenolol treatment of late luteal phase dysphoric disorder

Activation of the renin-angiotensin-aldosterone system has been hypothesized as a potential pathophysiological factor in premenstrual tension syndrome (PMS). Atenolol is a predominate beta 1-blocker which can decrease plasma renin activity and inhibit the urinary excretion of aldosterone. Sixteen women meeting provisional diagnoses of late luteal phase dysphoric disorder were treated for symptoms of PMS with atenolol (50 mg once daily) in a randomized placebo-crossover double-blind design. The data indicated significant improvements on the irritability, vigor, elation, and friendliness scores in response to atenolol compared to placebo. Significant changes were not found for several other ratings scales, indicating that atenolol improved only selected symptoms in the group as a whole. However, the women who had premenstrual tension symptoms for more than 5 years (n = 8) were improved on most of the rating scales. Atenolol decreased premenstrual plasma aldosterone to a limited extent. There was also a trend in the data toward higher luteal progesterone levels during the month subjects took atenolol. Plasma renin activity and aldosterone correlated with estrogen and progesterone levels during the placebo month but not during the active month.

Correlated cholinomimetic-stimulated beta-endorphin and prolactin release in humans

Previous studies, both in animals and humans, have demonstrated that the intravenous or intraventricular administration of endogenous opioids and opiates produce dose dependent increases in plasma concentrations of prolactin. Notably, in humans, intravenous infusion of centrally active cholinomimetic drugs, such as physostigmine or arecoline, may produce significant increases in plasma concentrations of prolactin and beta-endorphin immunoreactivity. In three separate studies, conducted collaboratively between the National Institute of Mental Health and the University of California at San Diego, physostigmine and arecoline associated increases in plasma concentrations of beta-endorphin immunoreactivity were highly correlated with increases in plasma prolactin concentrations. These results are of interest because centrally active cholinomimetic drugs have been variously reported either to have no effect, to increase, or to inhibit anterior pituitary prolactin release. We propose that cholinergic stimulation of hypothalamic beta-endorphin may represent an interesting example of peptidergic modulation of primary neurochemical effects on hypothalamic-pituitary hormonal regulation.

Platelet serotonin transport after a single ECT

Platelet 5-HT uptake was examined in six depressed patients before and after a single electroconvulsive treatment and compared with six age- and sex-matched controls. The depressed patients had a significantly (P<0.05) lower Vmax of platelet 5-HT uptake prior to ECT (22.9±7.6 pm/2×10 platelets) than did control subjects (37.5±9.1 SEM). After a single ECT treatment, the Vmax significantly (P<0.05) increased to levels (34.6±10.1) no longer significantly different from control. The results are compared with recent data from depressed patients indicating that low baseline levels of platelet imipramine binding increase after ECT treatment.

Kinetic effects of desmethylimipramine treatment on platelet serotonin uptake in depressed patients: A comparison with imipramine

The kinetic effects of desmethylimipramine (DMI) on platelet serotonin (5HT) uptake were compared to those of imipramine (IMI) in eight DMI-treated depressed patients and seven IMI-treated depressed patients, and compared to values after patients were off drug for 19 (+/- 8 SD) and 33 (+/- 15) days. As expected, IMI was a stronger inhibitor of 5HT uptake than DMI during treatment, with the mean apparent Km in treated patients being elevated nearly threefold over that of the drug-free condition. In DMI-treated patients, the mean Km was elevated nearly twofold over that of the drug-free condition. Although DMI is considered a preferential norepinephrine uptake inhibitor, the results suggest the following: (1) Significant decreases in the apparent platelet 5HT affinity are achieved with DMI; (2) the inhibition kinetics in depressed patients are competitive; (3) there was a significant relationship between Km change and depression outcome with DMI discontinuation; and (4) DMI, as a metabolite, appears to contribute to the 5HT uptake inhibition of IMI in vivo.

Measurement of ACTH and prolactin in the Dexamethasone Suppression Test

ABSTRACT— Plasma concentrations of ACTH and prolactin were measured in psychiatric inpatients at 8 a.m. and 4 p.m. before and after the standard 1 mg overnight Dexamethasone Suppression Test (DST). Plasma concentrations of cortisol were measured at 8 a.m. and 4 p.m., and 11 p.m. before and after 1 mg dexamethasone. Dexamethasone suppressed plasma concentrations of ACTH, prolactin and cortisol in the subject group as a whole. “Cut Points” obtained using Fishers Exact Test identified plasma ACTH values at 8 a.m. baseline, 4 p.m. baseline and 8 a.m. post‐dexamethasone and plasma prolactin values at all four times that significantly differentiated patients with bipolar depressive disorder and major depressive disorder from other psychiatric patients. There were no cut points found at any of the six times for plasma levels of cortisol that significantly differentiated between these two diagnostic groups. Of interest in this subject population, basal (pre‐dexamethasone) plasma concentrations were of more diagnostic information than post‐dexamethasone values. These pilot findings suggest that monitoring plasma prolactin and ACTH concentrations before and after dexamethasone might increase the sensitivity and specificity of this laboratory test for depression.