Seasonal patterns in platelet ligand binding are related to membrane proteins.

A seasonal pattern of platelet [3H]imipramine (3H-IMI) binding was explained by a similar but inverted pattern in membrane protein levels in repeated measures of 20 normal volunteers. No seasonal pattern was evident when 3H-IMI binding was expressed on the basis of surface area rather than membrane protein. Platelet Bmax levels in 50 depressed patients were lower than those of controls when values were expressed in terms of platelet surface area. The results support previous reports of low Bmax values in unipolar major depression, but indicate that seasonal changes in 3H-IMI binding are due to fluctuations in membrane protein and not to changes in the number of receptive sites. The present findings also have similar implications for other platelet measures expressed in terms of membrane protein.

Seasonal rhythm of platelet 3H-imipramine binding in normal controls.

The densities of platelet 3H-imipramine sites were determined by repetitive measures of 11 normal controls over the course of 1 year. A significant seasonal variation was found, with a circannual peak on February 17 and a nadir on August 18. The estimated amplitude of this rhythm was +/- 599.54 fmol/mg, which fluctuated about a yearly mean of 2647.5 fmol/mg. The present results underscore the importance of including seasonally matched controls in the evaluation of potential patient differences in platelet binding.

Changes in platelet 3H-imipramine binding with chronic imipramine treatment are not state-dependent.

One month of imipramine treatment increased both the Kd and Bmax of platelet 3H-imipramine binding in 11 endogenous unipolar depressed patients. Continued treatment (13 weeks) of 5 patients subsequently lowered the Bmax values of 2 patients who had initially shown the largest increases, so that binding was no longer significantly elevated after 13 weeks. The observed changes in Kd but not in Bmax, could be explained by the carryover of tightly bound drug to the binding assay, although neither of the measures were correlated with plasma imipramine levels. Posttreatment Bmax (4 weeks) values were inversely related to plasma cortisol levels, although a weak but positive correlation was found before treatment. No significant change was found in plasma cortisol with treatment. Clinical responses were not related to cortisol or Bmax changes, although optimal improvement was associated with extreme values (high and low) of pretreatment Bmax. The present results, obtained with imipramine, and similar results obtained after nortriptyline and electroconvulsive shock by others, suggest that at least some antidepressants may induce transient changes in the Bmax of platelet binding that are independent of affective state.

Decreased seasonal mesor of platelet 3H-imipramine binding in depression.

Seasonal cycles of platelet 3H-imipramine binding were compared in 49 endogenous unipolar depressed patients and 20 normal volunteers. A significant sinusoidal component was detected in the Bmax of binding in both patients and controls with similar amplitudes and seasonal peaks. However, the yearly average (mesor) of the patient group was significantly lower (20.0%) than that of the normal controls. The results support earlier claims of a diminished platelet binding in endogenous depression and indicate that this decrease was still evident in the presence of a 48.2% (controls) to 65.8% (patients) seasonal variation. Control Bmax values were normally distributed about a best-fit mean (cosinor fit). In contrast, patient values appeared to be bimodally distributed with one mode that was similar to controls and one mode that was substantially lower. In general, psychiatric symptoms failed to distinguish between patients with high and low platelet binding and no correlation was found between Bmax and severity of illness (HAM-D).

Adrenal androgens and cortisol in major depression.

Nine depressed subjects and nine comparison subjects completed a study of abnormalities in adrenal androgen and cortisol metabolism. Serum levels of cortisol and dehydroepiandrosterone (DHA) at 8:00 a.m. and 4:00 p.m. revealed hypercortisolemia and loss of diurnal DHA variation but not cortisol variation in the depressed group. These findings suggest that in depression, adrenal androgens, in contrast to cortisol, are partially regulated by mechanisms independent of ACTH.

A controlled trial of desipramine in 18 men with posttraumatic stress disorder.

Eighteen male U.S. veterans meeting DSM-III criteria for posttraumatic stress disorder (PTSD) completed a 4-week double-blind, crossover study comparing administration of 200 mg/day of desipramine with placebo. Response was measured by using the Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and the Impact of Event Scale. Overall, the only apparent response to desipramine was in some symptoms of depression; there were no changes in anxiety and other PTSD symptoms.

Maternal stress, HPA activity, and fetal/infant outcome.

Preliminary conclusions from our research include the possibility that each of the HPA products evaluated, even though correlated (e.g., ACTH and beta E), may be linked to unique and specific outcomes. Maternal stress during the 28-30 weeks of gestation is associated with birth outcome. Increased levels of psychosocial stress were significantly related to gestational age at birth and infant birth weight. Maternal stress during the third trimester was associated with increased maternal plasma levels of ACTH and cortisol. This finding is consistent with possible mechanisms whereby psychosocial stress influences birth outcome. CRH controls the timing of labor and delivery. Precocious elevation of CRH is related to the risk of preterm delivery. This system may be "stress-sensitive." Even though pregnant women may be immunized from stress, the stress signal that is transmitted (release of ACTH and cortisol) is amplified by the placental release of CRH. This possibility has at least two consequences: (1) influencing the timing of delivery and (2) desensitization of hypophyseal corticotrophs and further "protection" of the pregnant women from the results of stress (i.e., release of ACTH and beta E). Beta E appears to influence fetal learning and perhaps the developing nervous system.

Corticotrophin-releasing hormone and fetal responses in human pregnancy.

During human pregnancy, maternal and fetal compartments of the human placenta produce and release corticotrophic-releasing hormone (CRH). Elevations of placental CRH are associated with decreased gestational length (including preterm delivery). The effects of elevated placental CRH on human fetal neurological development are not known. Pregnant women in the 31st and 32nd week of gestation consented to procedures for collection of blood and measurement of fetal heart rate (FHR) in response to a series of 40 vibro-acoustic stimuli (VAS). Measures of habituation and dishabituation were calculated from the FHR. All subjects were followed to delivery. Fetuses (N = 33) of women with highly elevated CRH were least responsive (p < .03) to stimulation after presentation of a novel (dishabituating) stimulus with control for parity, fetal gender, medical (antepartum) risk, and gestational length at term. In a larger sample (N = 156) a polynomial model predicted the pattern of FHR reactivity for the first 15 trials. Placental CRH concentration significantly predicted FHR reactivity after controlling for the effects of trial number, baseline FHR, inter-trial interval, and presence of uterine contractions. Increased maternal CRH levels were significantly related to the length of gestation after controlling for the effects of fetal gender, parity, and medical risk (p = .05). The relationship between length of gestation and FHR was not significant suggesting separate actions of CRH on these events. Elevated placental CRH appears to accelerate certain developmental events (gestational length) and may influence the fetal nervous system. The impaired fetal responses to novelty and increased arousal observed in this study suggest that neurological systems may be targets for placental CRH during sensitive developmental periods.

Acidosis stimulates beta-endorphin release during exercise.

Elevated blood levels of beta-endorphin have been associated with high-intensity exertion, but the stimulus for beta-endorphin release is unknown. Some studies of exercise have associated beta-endorphin release with increased exertion levels, but other evidence suggests that acidosis may stimulate the release of beta-endorphin. This study examines acidosis as a possible stimulus for beta-endorphin release by examining the effects of arterial blood gases, whole blood lactate, and respiratory changes on beta-endorphin levels and by examining the effects of buffering during exercise on these levels. Initially, seven healthy adult males were evaluated during incremental exercise. During incremental exertion, indicators of acidosis correlated with endorphin levels: pH (r = -0.94), PCO2 (r = -0.85), HCO3- (r = -0.88), base excess (r = -0.94), and lactate (r = 0.89). A multivariate model showed that beta-endorphin levels were predicted best by the change in base excess. A time course analysis showed that beta-endorphin responses peaked postexercise and paralleled blood acid levels. Subsequently, subjects were compared after alkali loading and placebo during constant-intensity exercise at 85% of maximal exertion to determine whether acidosis is necessary for endorphin release. Treatment with a buffer, which effectively maintained pH above 7.40, significantly suppressed endorphin release (F = 3.07; P < 0.0001). The results of this study indicate that acidosis rather than any other physiological change associated with high-intensity exertion is the primary stimulus for beta-endorphin release.

Uncoupling of proopiomelanocortin (POMC) fragments is related to self-injury.

Proopiomelanocortin (POMC) contains several interesting, behaviorally active peptides. Release patterns of these fragments have been related to bizarre episodes of self-injurious behavior (SIB) among autistic individuals. Moreover, elevation in beta-endorphin (betaE) but not ACTH levels was associated with a positive response to an acutely administered, centrally acting opioid blocker among autistic individuals exhibiting SIB. In the present study, POMC fragments were measured in 12 self-injurious patients before and after long term (3 month) treatment with an opiate blocker naltrexone (NTX). POMC fragments were sampled from blood collected at the beginning of the baseline and placebo-controlled treatment phases of the study. Results indicated that the co-release (coupling) of POMC fragments were stable over time and the profile of POMC fragments in plasma predicted the effectiveness of a CNS acting drug in autistic subjects who self-injure.

Third trimester POMC disregulation predicts use of anesthesia at vaginal delivery.

In a prospective study, third trimester plasma levels of BE and ACTH were determined in 58 women who delivered vaginally. Peptide regulation was compared between subjects who used conduction anesthesia at delivery and subjects who did not. Third trimester levels of maternal BE and ACTH were significantly related; however, the relationship was significant only in subjects who did not receive conduction anesthesia (n = 24) at delivery. The normal co-release pattern between BE and ACTH in subjects receiving conduction anesthesia (n = 34) during birth was uncoupled. The use of conduction analgesia during vaginal delivery was significantly related to a disregulation index created to quantify the BE-ACTH release pattern. Uncoupled ACTH and BE patterns may result from modified control of pro-opiomelanocortin (POMC) expression during pregnancy or unique proteolytic processing of POMC, and may alter pain tolerance during delivery.

Platelet monoamine oxidase activity and evoked response as predictors of anxiety and depression derived from the content analysis of speech.

Platelet MAO activity has been reported by several investigators to differentiate schizophrenia, schizophrenia related depressive disorders, alcoholism, unipolar and bipolar depression from normal controls. Evoked potentials likewise have differentiated schizophrenic and affective patients. However, the precise relationship between MAO activity, evoked potentials (EP), and psychiatric illness has not been clarified. A possible association between psychopathology and high MAO activity/EP reducing and low MAO activity/EP augmenting has been reported. Such a bidirectionality further confounds results. This study was undertaken to determine the association of psychopathological dimensions found in a group of subjects whose platelet MAO activity and evoked responses were obtained two years earlier. Utilizing the Gottschalk-Gleser verbal behavior scales of Anxiety, Depression, Social Alienation-Personal Disorganization and Cognitive Impairment a significant correlation was revealed between low platelet MAO activity and high Total Anxiety scale and Shame Anxiety subscale scores. Additionally, a significant correlation was demonstrated between reducing evoked potentials and elevated Death Anxiety, Somatic Concerns, and Total Death and Mutilation Depression subscales scores, combined and separately. Furthermore, a significant positive correlation was found between augmenting evoked potentials and Overt Hostility Outward scores. No significant correlations were demonstrated between platelet MAO activity or evoked potentials and Social Alienation-Personal Disorganization or Cognitive Impairment scores. These findings lend support to the position that biological markers may predict predispositions to anxiety and depression.

Influence of protein concentration on platelet 3H-imipramine binding.

1. The effects of protein concentration in the assay mixture on platelet 3H-imipramine binding were studied in normal controls. 2. Increasing protein concentrations (76-926 micrograms/ml) were found to alter estimates of binding affinity (Kd) but not the number of binding sites (Bmax). 3. Increasing Kd estimates were protein dependent at concentrations in excess of ca. 200 micrograms/ml but were not protein dependent at lower concentrations. 4. A comparison of the present results with previous reports suggests that widespread interlaboratory differences in reported Bmax values for normal controls cannot be attributed to differences in the protein content of incubated samples. Rather these differences may be due to the inclusion of non-membrane protein in the assayed material.

Relationship between seasonal patterns of platelet serotonin uptake and 3H-imipramine binding in depressed patients and normal controls.

1. Significant seasonal variations were found in the velocity of serotonin (Vmax) uptake and the density of 3H-imipramine binding sites (Bmax) in blood platelets from normal controls. 2. Peak 3H-imipramine (3H-IMI) binding was found in February whereas peak serotonin (5HT) uptake was found in June and these measures were not correlated in paired comparisons. 3. Both Vmax and Bmax values of depressed patients deviated from the normal seasonal pattern with lower uptake and binding in the patient group. 4. A comparison of Vmax and Bmax deviations from the normal patterns of uptake and binding revealed a significant correlation between these measures such that patients with low Vmax values were the same as those with low Bmax values. 5. The results support previous claims that the 3H-IMI binding site may be closely associated with, or identical to, a 5HT transport carrier. 6. A significant correlation between uptake and binding further suggests that a common defect may be responsible for observed decreases in Vmax and Bmax values of depressed patients.

Relationship between 3H-imipramine binding, 14C-serotonin uptake, and the surface area of blood platelets.

1. The relationship between 14C-serotonin uptake, 3H-imipramine binding and surface area was studied in blood platelets. 2. Platelet rich plasma from 5 normal subjects was divided into 5 size subfractions by differential centrifugation and the total surface areas computed from platelet size profiles. 3. Linear relationships were found between both uptake and binding as a function of surface area regardless of platelet size. 4. The results suggest that platelet heterogeneity may contribute to the variability of uptake measurements which are commonly expressed on a per platelet basis. In contrast, the importance of heterogeneity to binding measurements, which are expressed per unit protein, may have been previously overestimated.

Apomorphine induced alteration in corneofundal potentials in depression.

1. The role of dopamine (DA) in mood regulation remains controversial. 2. Previous studies have examined DA sensitivity by measuring neuroendocrine responses following an agonist challenge. For the most part the results of such tests have failed to provide convincing evidence of a DA abnormality in affective disorders. 3. Neuroendocrine responses, however, are subject to complex regulatory influences and respond to DA systems which differ from those thought to modulate mood. 4. Recent animal and human studies suggest that light-dark adaptive electrical responses of the retinal pigment epithelium may serve as a better model of dopaminergic function. 5. The present study reports neuroendocrine and ocular results prior to, and following, an apomorphine (APO; 0.75 mg sc) challenge in 12 depressed patients and 12 normal controls. 6. Apomorphine administration increased both light and dark retinal potentials in patients whereas those of controls decreased and this group difference was significant (p < 0.002). 7. No group differences were detected in any measure at baseline, or in prolactin, or growth hormone levels after the APO challenge. 8. The results indicate that the retina may serve as a more sensitive indicator of dopamine abnormalities in depressive illness.

REM latency, dexamethasone suppression test, and thyroid releasing hormone stimulation test in posttraumatic stress disorder.

1. Twenty-one patients with post-traumatic stress disorder (PTSD) were included in a study utilizing baseline rapid eye movement (REM) latency measurements, the dexamethasone suppression test (DST), and the protirelin (thyroid releasing hormone; TRH) stimulation test. The DST and TRH stimulation test were repeated after double blind treatment with desipramine. 2. A high number of patients (75%) exhibited a REM latency of 60 min or less and blunted thyroid stimulating hormone (TSH) response to TRH (61.9%) on baseline tests while only one patient showed cortisol escape from dexamethasone suppression. 3. After four weeks of desipramine treatment, significant improvements were reported in the Hamilton Rating Scale for depression, but not for anxiety symptoms, PTSD symptoms, or self-rated depressive symptoms. 4. Desipramine treatment did not affect hormonal responses to TRH. 5. The findings of shortened REM latency and altered TRH stimulation test suggest PTSD and depression may share some pathophysiological abnormalities.

Sleep deprivation therapy in depressive illness and Parkinson's disease.

1. Sleep deprivation is commonly associated with feelings of fatigue and cognitive impairment. 2. Patients with depressive illness, however, often experience mood improvements under these same conditions. 3. Other studies now show that tremor and rigidity, in patients with Parkinson's disease, are also improved by sleep depression therapy. 4. The neural substrates which underlie these effects are unclear. Some recent evidence, however, suggests that sleep deprivation may activate mechanisms which are otherwise typical of conditions of metabolic stress. 5. A common feature of these mechanisms is the suppression of cholinergic activity which is thought to be excessive, in relation to monoamine transmission, in both depression and Parkinson's disease.

Subclasses of platelet 3H-imipramine binding sites.

The possible presence of multiple high affinity 3H-imipramine (3H-IMI) binding sites on blood platelets was studied using trypsin digestion and cyanoimipramine (CNIMI), a pseudo-irreversible inhibitor of 3H-IMI binding and serotonin uptake. Increasing concentrations of CNIMI resulted in a discontinuous curve with a plateau at intermediate concentrations (0.05-0.35 nM). CNIMI sensitive (0.25 nM) sites accounted for approximately half of total high affinity 3H-IMI binding as defined by displacement with 100 microM desipramine. Similar results were obtained when platelet membranes were pretreated with trypsin (0.21-0.84 mg/ml), and no additional inhibition was evident with a combination of both treatments. The present results suggest that 3H-IMI may bind to two separate types of high affinity sites. One subclass is apparently proteinaceous and sensitive to low concentrations of CNIMI, whereas the other is apparently nonproteinaceous and is CNIMI resistant.

Platelet MAO activity in personality disorders and normal controls.

Platelet monoamine oxidase (MAO) activity has been related to several psychiatric disorders and personality dimensions. The purpose of this study was to measure platelet MAO activity in personality disorders and determine its relationship to symptoms analogous to sensation seeking. Twenty-eight males admitted to a psychiatric unit with a DSM-III-R diagnosis of personality disorder were compared to normal controls. Patients with Axis I diagnoses other than adjustment disorder were excluded. There was no difference in MAO activity between patients and normals, although it was lower in borderline patients. MAO activity was inversely correlated with sensation seeking, especially in the patient group, as predicted. The results are consistent with the view that platelet MAO activity is a marker of general psychopathology.