Choline acetyltransferase activity of spinal cord cell cultures increased by co-culture with muscle and by muscle-conditioned medium.

Activity of the enzyme choline acetyltransferase (CAT), which mediates the synthesis of the neurotransmitter, acetylcholine, was increased up to 20- fold in spinal cord (SC) cells grown in culture with muscle cells for 2 wk. This increase was directly related to the duration of co-culture as well as to the cell density of both the SC and muscle involved and was not affected by the presence of the acetylcholine receptor blocking agent, alpha-bungarotoxin. Glutamic acid decarboxylase (GAD) activity was often markedly decreased in SC-muscle cultures while the activities of acetylcholinesterase and several other enzymes were little changed. Increased CAT activity was also observed when SC cultures were maintained in medium which had been conditioned by muscle cells or by undifferentiated cells from embryonic muscle. Muscle-conditioned medium (CM) did not affect the activities of SC cell GAD or acetylcholinesterase. Dilution or concentration of the CM directly affected its ability to increase SC CAT activity , as did the duration and timing of exposure of the SC cells to the CM. The medium could be conditioned by muscle cells in the presence or absence of serum, and remained effective after dialysis or heating to 58 degrees C. Membrane filtration data were consistent with the conclusion that the active material(s) in CM had a molecular weight in excess of 50,000 daltons. We conclude that large molecular weight material that is released by muscle cells is capable of producing a specific increase in CAT activity of SC cells.

Choline acetyltransferase activity is increased in combined cultures of spinal cord and muscle cells from mice.

The activity of choline acetyltransferase was more than tenfold greater in combined cultures of spinal cord and muscle cells than in cultures of spinal cord cells alone. This increase was associated with the formation of functional neuromuscular junctions in culture. Counts of silver-stained cells and determinations of other enzyme activities indicated that the increased choline acetyltransferase activity was not due to nonspecific neuronal survival but reflected greater activity in the surviving neurons. Hence, muscle had a marked, highly specific trophic effect on the cholinergic neurons that innervated it.

Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder.

BACKGROUND: Our previous studies have suggested that combat veterans with posttraumatic stress disorder (PTSD) have alterations in hypothalamic-pituitary-adrenal axis functioning that are different from the well-documented biological changes observed in major depressive disorder and following exposure to stress. METHODS: In the present study, we examined cortisol and lymphocyte glucocorticoid receptor number before and after the administration of 0.50 and 0.25 mg of dexamethasone in 14 combat veterans with PTSD, 12 combat veterans without PTSD, and 14 nonpsychiatric healthy men. All subjects were medication free at the time of testing and none met diagnostic criteria for major depression or substance dependence. RESULTS: Combat veterans with PTSD suppressed cortisol to a greater extent than did combat veterans without PTSD and normal controls in response to both doses of dexamethasone. Differences in cortisol suppression could not be attributed to substance dependence history or differences in dexamethasone bioavailability. Combat veterans with PTSD showed a larger number of baseline glucocorticoid receptors compared with normal men. Combat veterans without PTSD also had a larger number of baseline glucocorticoid receptors compared with normal men and in fact were comparable to combat veterans with PTSD on this measure. However, only veterans with PTSD showed a decrease in lymphocyte glucocorticoid receptor number following dexamethasone administration. CONCLUSION: The data support the hypothesis of an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal axis in PTSD.

Possible subtypes of affective disorder suggested by differences in cerebral laterality and testosterone. A preliminary report.

Two language-related dichotic listening tests of cerebral laterality were used to divide a group of 18 hospitalized patients with affective disorder into two subgroups of nine. The groups proved to differ in serum testosterone levels at the time of admission and in mean serum testosterone levels throughout hospitalization. Moreover, there was a positive correlation between testosterone level and symptom severity in one of the laterality-defined subgroups and a negative correlation in the other. These data (1) provide new evidence of pathophysiological heterogeneity within a single general diagnostic group; (2) suggest that noninvasive, inexpensive, and easily administered dichotic listening tests may be able to define pathophysiologically meaningful subgroups; and (3) suggest a role for testosterone-related alterations in left hemisphere function in the pathogeneses of some affective disorders.

An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology.

Isocarboxazid and placebo were evaluated in 130 anxious depressives. Drug was superior to placebo on depression, anxiety, interpersonal sensitivity, and global measures, and on symptoms of hostility, anxiety, obsessiveness, and psychological-cognitive components of depression. There were no significant differences between treatment effects on psychomotor and typical vegetative symptoms. Isocarboxazid was more effective than placebo in major, but not in minor, depression. It was significantly more effective in depression classified as endogenous depression or melancholia by various diagnostic criteria. Drug was more effective than placebo in atypical depression with vegetative reversal and in Brief Psychiatric Rating Scale (BPRS)-derived profiles of anxious and hostile depression; there were no drug-placebo differences in atypical depression without vegetative reversal, or in BPRS retarded and agitated/excited depression. Interpersonal sensitivity emerged as an important drug-responsive dimension.

Cerebral laterality, symptoms, and diagnosis in psychotic patients.

A dichotic nonsense test and a dichotic word test were used to assess cerebral laterality in 100 acutely symptomatic inpatients. Schizophrenic patients had significantly lower right ear advantages (REAs) than healthy controls, depressed patients, or schizoaffective patients. Manic patients did not differ from any other group, but manics with lower REAs were likely to have more symptoms of thought disorder than of mood disturbance while the reverse was likely to be true for manic patients with higher REAs. A subset of patients tested after symptom remission showed recovery-related increases in REA on the nonsense test and decreases on the word test, replicating previous findings. Those schizophrenics with evidence of greater disease-related decreases in REA on the nonsense than on the word test had predominantly negative symptoms whereas those with similar changes on the two tests had predominantly positive symptoms. These observations suggest the hypothesis that positive symptoms are related to overactivation of a dysfunctional left hemisphere by right hemisphere input while negative symptoms reflect a left hemisphere deficit state.

Serum thyroxine change and clinical recovery in psychiatric inpatients.

Serum free thyroxine (FT4), total thyroxine (TT4), and Brief Psychiatric Rating Scale (BPRS) measurements were obtained following hospital admission and at 2-week intervals during hospitalization in 80 male psychiatric inpatients with a variety of major psychotic and affective disorders. A strong correlation between the range values for BPRS sum and for FT4 (p less than 0.005) and TT4 (p less than 0.001) levels indicated that change in overall symptom severity was linked to change in thyroxine levels during clinical recovery. We found the relationship not to be a simple one, but to require definition of criteria for three patient subgroups for each hormone, taking into account the initial absolute thyroxine level, as well as the direction and magnitude of hormonal change during recovery. The hormonally defined "good recovery" subgroup included patients with high initial thyroxine levels that then fell substantially, patients with low initial thyroxine levels that then rose substantially, and patients with initial thyroxine levels in the middle range that subsequently changed substantially. The hormonally defined "poor recovery" subgroup included those patients not meeting these criteria. The degree of clinical improvement in the hormonally defined good recovery group was significantly greater by almost twofold than the poor recovery group both for FT4 (p less than 0.04) and TT4 (p less than 0.02). These findings suggest that a "normalizing" principle underlies the relationship between clinical recovery and thyroxine levels and that both FT4 and TT4 levels within the normal range appear to have clinical significance in either reflecting or contributing to the course of a variety of psychiatric disorders and possibly having a role in pathogenesis.

Serum testosterone differences between patients with schizophrenia and those with affective disorder.

Serum testosterone levels (ng/dl) were measured at 2-week intervals during the course of hospitalization in 35 male inpatients in the following four diagnostic groups: undifferentiated schizophrenia, paranoid schizophrenia, bipolar I disorder-manic, and major depressive disorder (endogenous type). The mean (+/- SE) testosterone levels during hospitalization were significantly higher (p less than 0.001) in the schizophrenic patients (510 +/- 38) than in the affective disorder patients (347 +/- 25). This difference persisted throughout hospitalization, being present in the first sample following admission (p less than 0.03) and the final sample before discharge (p less than 0.01). The above group differences were largely due to high testosterone levels in the paranoid schizophrenic subgroup (mean +/- SE level of 559 +/- 41). A longitudinal, as well as cross-sectional, view of the hormonal and clinical data suggests that the testosterone system is linked to both state and trait psychological factors, and this issue is discussed in the light of prior basic psychoendocrine research on this system. The potential application of these findings for new approaches to the development of biological criteria for psychiatric diagnosis is discussed.

Prolactin response to low-dose dexamethasone challenge in combat-exposed veterans with and without posttraumatic stress disorder and normal controls.

The prolactin and cortisol responses to dexamethasone (0.5 mg) were studied in combat veterans with (n = 18) and without (n = 12) posttraumatic stress disorder (PTSD) and normal controls (n = 18). Both veteran groups demonstrated greater prolactin suppression than the normals. In contrast, only veterans with PTSD showed an enhanced cortisol suppression in response to dexamethasone. These findings suggest that the prolactin response to dexamethasone may reflect a feature of combat exposure rather than PTSD per se.

Multidimensional hormonal discrimination of paranoid schizophrenic from bipolar manic patients.

The search for biological markers of psychiatric disorders has traditionally involved univariate approaches, usually focusing upon one measure at a time, and to date has been primarily directed towards the assessment of depressive rather than psychotic illnesses. The present study explores a multidimensional psychoendocrine strategy, using a profile of five hormones, including cortisol, epinephrine, norepinephrine, testosterone, and free thyroxine, and is directed at the differentiation of two major psychotic illnesses, bipolar manic disorder and paranoid schizophrenia. When the levels of these hormones were assessed at admission and biweekly during hospitalization, the mean values for all five hormones were found to differ markedly between the two diagnostic groups. There was, however, always a zone of overlap in levels between the two groups when each of the five hormones were viewed individually, so that at best only about 70% of patients were correctly separated by diagnostic group using any single hormone alone. By contrast, multivariate approaches combining mean values of three or more hormones, using either stepwise discriminant analysis or multidimensional scaling, yielded 95% correct classification of the two diagnostic groups. Similar but not quite as great accuracy of classification was achieved with only the initial hormone sample obtained at the time of hospital admission. These preliminary findings provide encouragement for further exploration of multidimensional hormonal strategies in the search for useful biological criteria to assist in the diagnosis of psychiatric disorders.

Glucocorticoid receptor number and cortisol excretion in mood, anxiety, and psychotic disorders.

In the present study, we measured cytosolic lymphocyte glucocorticoid receptor and 24-hour urinary cortisol excretion in patients with major depressive disorder, bipolar mania, posttraumatic stress disorder, panic disorder, and schizophrenia. Patients with major depression had the smallest, and posttraumatic stress disordered patients the largest, mean number of glucocorticoid receptors per cell compared to patients in the other groups. Bipolar manic and panic patients did not differ from each other in regard to the number of lymphocyte glucocorticoid receptors. Bipolar manic and panic patients did have significantly more glucocorticoid receptors/cell than schizophrenic patients. The mean 24-hour urinary cortisol excretion was significantly higher in patients with major depression and bipolar mania than in those in the other diagnostic groups. Lymphocyte glucocorticoid receptor number and cortisol excretion tended to be inversely related, when the entire sample was considered as a whole, but this effect did not reach statistical significance. It is concluded that lymphocyte glucocorticoid receptors may be modulated by multiple influences, not just ambient cortisol levels. These preliminary data suggest that the assessment of lymphocyte glucocorticoid receptor number in tandem with cortisol levels may provide a more meaningful estimate of hypothalamic-pituitary-adrenal axis activity than is achieved using cortisol alone.

Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder.

Neuroendocrine studies examining the hypothalamic-pituitary-adrenal (HPA) axis under baseline conditions and in response to neuroendocrine challenges have supported the hypothesis of altered HPA functioning in posttraumatic stress disorder (PTSD). However, to date, there is much debate concerning the nature of HPA changes in PTSD. Furthermore, in studies showing parallel findings in PTSD and major depressive disorder there is controversy regarding whether the HPA alterations suggest a specific pathophysiology of PTSD, or, rather, reflect comorbid major depressive disorder. This review summarizes findings of HPA axis dysfunction in both PTSD and major depressive disorder, and shows distinct patterns of HPA changes, which are probably due to different mechanisms of action for cortisol and its regulatory factors.

Characterization of depression in war-related posttraumatic stress disorder.

OBJECTIVE: Many patients with posttraumatic stress disorder (PTSD) have symptoms of depression, but operationalized psychological constructs related to depression have not been used extensively in characterizing affective symptoms of PTSD. The authors' objective is to better characterize the affective component of PTSD. METHOD: The subjects were 45 male psychiatric inpatients at a Veterans Administration medical center; 28 met DSM-III-R criteria for PTSD and 17 met Research Diagnostic Criteria (RDC) for major depressive disorder. All of the subjects with PTSD were Vietnam veterans. The 21-item Hamilton Rating Scale for Depression was used to assess state measures of symptom severity, and the Depressive Experiences Questionnaire was used to measure dimensions of dependency, self-criticism, and self-efficacy. RESULTS: The mean total Hamilton scale score of the patients with PTSD was nonsignificantly higher than that of the patients with major depressive disorder; patients with PTSD had higher scores on almost all individual Hamilton symptoms, particularly insomnia, somatic anxiety, and diurnal variation. Patients with PTSD had significantly higher scores on the self-criticism scale but not on the dependency and self-efficacy scales of the Depressive Experiences Questionnaire. The scores of patients with PTSD on the dependency and self-criticism scales were negatively correlated. No significant differences between patients with PTSD with and without concurrent major depressive disorder were observed. CONCLUSIONS: Characterization of such depressive dimensions of PTSD as dependency and self-criticism may have important clinical implications.

Exposure to atrocities and severity of chronic posttraumatic stress disorder in Vietnam combat veterans.

OBJECTIVE: The authors' objective was to explore aspects of trauma associated with severity of posttraumatic stress disorder (PTSD) in Vietnam veterans. METHOD: Several ratings of stress exposure and symptom severity were administered to 40 patients with combat-related PTSD. RESULTS: A significant relationship was observed between exposure to atrocities and the impact of PTSD on veterans' lives, as measured by the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder. Exposure to atrocities was also significantly correlated with current symptom severity. In contrast, combat exposure alone was not significantly associated with overall symptom severity. Both atrocity and combat exposure, however, were significantly related to reexperiencing symptoms. CONCLUSIONS: The data suggest that the enduring effect and severity of PTSD symptoms on an individual are associated more with exposure to brutal human death and suffering than the threat of death associated with combat.

Personality disorders in treatment-seeking combat veterans with posttraumatic stress disorder.

OBJECTIVE: Many patients with posttraumatic stress disorder (PTSD) appear to have co-occurring symptoms of character pathology; however, to date there have been no empirical studies of comorbid clinician-rated axis II personality disorders in war veterans with chronic PTSD. The authors' objective was to assess DSM-III-R personality disorders in treatment-seeking combat veterans with PTSD. METHOD: They used the Personality Disorder Examination, a standardized diagnostic interview for DSM-III-R axis II disorders, to assess DSM-III-R personality disorders in 34 patients with PTSD; 18 of the subjects were inpatients and 16 were outpatients. RESULTS: A high rate of character pathology was observed in both inpatient and outpatient groups. The most frequent disorders for which criteria were met were borderline, obsessive-compulsive, avoidant, and paranoid personality disorders. Inpatients had a higher rate of nearly every personality disorder than did outpatients. Inpatients were significantly more likely to meet diagnostic criteria for paranoid, schizotypal, avoidant, and self-defeating personality disorders. CONCLUSIONS: War-related PTSD in treatment-seeking Vietnam veterans is often accompanied by diffuse, debilitating, and enduring impairments in character. Subtyping patients with PTSD on the basis of specific axis II profiles may aid in the selection of more specific and effective treatments.

Psychological dimensions of depression in borderline personality disorder.

OBJECTIVE: The authors' goal was to test empirically a commonly held assumption that the depression in borderline personality disorder is primarily anaclitic. METHOD: The Depressive Experiences Questionnaire and the Hamilton Rating Scale for Depression were administered to 26 patients with borderline personality disorder (16 of whom were depressed) and 12 depressed patients without borderline personality disorder. RESULTS: Patients with borderline personality disorder showed more self-criticism but did not endorse more anaclitic items than depressed patients without borderline personality disorder. CONCLUSIONS: These findings suggest that self-criticism is an underemphasized characteristic of depression in borderline personality disorder.

Altered platelet alpha 2-adrenergic receptor binding sites in borderline personality disorder.

The authors found significantly fewer total platelet alpha 2-adrenergic receptor binding sites in 13 nonmedicated patients with borderline personality disorder than in 11 patients with borderline personality disorder who were receiving low doses of benzodiazepines and 18 nonpsychiatric control subjects. The two patient groups showed comparable degrees of depression as assessed by the Hamilton Rating Scale for Depression. However, nonmedicated borderline patients were considerably more anxious than medicated patients, raising the possibility that lower alpha 2-adrenergic receptor binding in borderline personality disorder is related to anxiety.

A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder.

In a double-blind, randomized clinical trial, the efficacy of imipramine and of phenelzine was compared with that of placebo in 34 male veterans with posttraumatic stress disorder (PTSD). Both medications reduced PTSD symptoms.

Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder.

OBJECTIVE: The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). METHOD: They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects. RESULTS: Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety. CONCLUSIONS: These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.

Impact of cumulative lifetime trauma and recent stress on current posttraumatic stress disorder symptoms in holocaust survivors.

OBJECTIVE: The purpose of this study was to examine the relationships among cumulative lifetime trauma, recent stressful events, and presence and severity of current posttraumatic stress disorder (PTSD) symptoms in Holocaust survivors and nonexposed comparison subjects. METHOD: Lifetime trauma, recent stressful events, and presence and severity of PTSD were assessed in Holocaust survivors (N=72) and comparison subjects ( N=19). RESULTS: Survivors with PTSD (N =40) reported significantly greater cumulative trauma and recent stress than survivors without PTSD (N=32) and comparison subjects. Severity of PTSD symptoms, cumulative trauma, and recent stress were significantly associated. CONCLUSIONS: The presence and severity of current PTSD were related to having experienced stressful events in addition to the Holocaust.