Effects of local anesthetics on experiential, physiologic and endocrine measures in healthy humans and on rat hypothalamic corticotropin-releasing hormone release in vitro: clinical and psychobiologic implications.

Local anesthetics, given i.v. to treat cardiac arrhythmias and for regional anesthesia, exert prominent central nervous system side effects, such as sensory distortions and mood changes. In experimental animals, these drugs activate limbic structures, such as the amygdala, that may coordinately regulate sensory processing, mood and pituitary hormone secretion during stress. Clinically relevant i.v. doses of the short-acting local anesthetic procaine were administered to 17 healthy volunteers and topographic electroencephalographic (EEG) spectra, stress-responsive neuroendocrine and cardiovascular parameters and sensory-cognitive and mood changes were examined. Because corticotropin-releasing hormone (CRH) mimics the behavioral and physiologic responses to stress and activates limbic structures in experimental animals, the effects of procaine and lidocaine on immunoreactive CRH release from rat hypothalami in vitro were also explored. Procaine administration produced a dose-related increase in fast (21-50 Hz) EEG activity, a significant decrease in alpha EEG activity and dose-dependent increases in heart rate, systolic blood pressure and plasma adrenocorticotropic hormone, cortisol and prolactin secretion. Dose-dependent increases in sensory distortions involved virtually all modalities, particularly auditory, visual and somatosensory. Mood changes occurred in most subjects, including anxiety, euphoria and arousal. In vitro, procaine and lidocaine both produced significant dose-related increases in immunoreactive CRH release from rat hypothalami, maximal at 10(-6) M, that were blocked by carbamazepine, a limbic anticonvulsant used in the management of mood disorders. The electrophysiologic effects of procaine in these volunteers were analogous to local anesthetic effects in experimental animals and consistent with the activation of subcortical structures localized within the temporal lobe, such as the amygdala. The effects of procaine on stress-responsive neurohormones were similar to those of amygdala stimulation both in experimental animals and human subjects. The in vitro data suggested that procaine-induced pituitary-adrenal activation involves stimulation of hypothalamic CRH, although additional (e.g., limbic-hypothalamic) mechanisms may contribute in vivo. These data were compatible with a direct action of local anesthetics on limbic structures that might account for many of the central effects seen with the systemic use of these agents in clinical practice.

Evaluating change: a simple technique for determining the statistical significance of proportional criteria.

A simple method to calculate statistically significant differences between proportions is presented to evaluate changes in quality assessment and utilization data. The authors believe that this calculation could be a valuable analytic method for evaluating changes in monitored criteria, particularly in the assessment of criteria measuring high-volume events.

Mood variability: a study of four groups.

OBJECTIVE: The authors' goal was to determine whether self-rated patterns of mood regulation differed among patients with major depression, patients with borderline personality disorder, patients with premenstrual syndrome (PMS), and normal subjects. METHOD: Fourteen days of morning and evening mood self-ratings on a visual analog scale were analyzed for 65 female subjects (10 with major depression, 16 with borderline personality disorder, 15 with PMS, and 24 without psychiatric diagnoses). For each individual, the mean and standard deviation of morning and evening ratings, the mean absolute change in mood from one day to the next, and the change from morning to evening were determined. RESULTS: The four groups differed significantly on every measure of mood and mood variability except diurnal variation. As expected, the group with major depression had the lowest global ratings and a low degree of variability. The group with borderline personality disorder was less depressed than the group with major depression and showed a high degree of mood variability. Autocorrelation analysis suggested that mood ratings in borderline personality disorder vary randomly from one day to the next. The mood variability over the 14 days of the patients with PMS was significantly greater than that of normal subjects. CONCLUSIONS: The visual analog scale can capture patterns of mood and mood variability thought to be typical of these diagnostic groups. Mood disorders differ not only in the degree of abnormal mood but also in the pattern of mood variability, suggesting that mechanisms regulating mood stability may differ from those regulating overall mood state.

Self-ratings of anger and hostility in borderline personality disorder.

Forty-six patients with borderline personality disorder with and without major depression and 27 normal volunteers completed the Buss-Durkee Hostility Inventory, a self-rating scale of anger and hostility. The patients with borderline personality had significantly higher scores than the normal volunteers. The scores of the patients with borderline personality disorders were not related to gender, treatment or research setting, the degree of acute distress, or the presence of major depression. These findings suggest that a proneness to anger and hostility are enduring characteristics of borderline personality disorder and that anger and depression may represent independent clinical conditions with independent biological mechanisms regulating these two affective states.

Neuropsychological testing of patients with borderline personality disorder.

OBJECTIVE AND METHOD: This study examined whether a battery of neuropsychological tests could detect cognitive deficits--particularly in the areas of perception, learning, and memory--in patients with borderline personality disorder. The test battery was completed by 16 research outpatients with borderline personality disorder, typified by behavioral dyscontrol and diagnosed according to DSM-III-R criteria and the Diagnostic Interview for Borderline Patients. A comparison group of 16 normal volunteers also completed the test battery. RESULTS: The performance of the borderline patients was significantly impaired in comparison with that of the normal group on memory tests requiring uncued recall of complex, recently learned material. Cues given on an auditory memory task partially corrected that deficit. The patients' performance was also significantly impaired on several visual perceptual tests. These deficits do not appear to have been attributable to attentional problems, psychomotor impairment, current major depression, or history of alcohol abuse. CONCLUSIONS: The observed difficulties in separating essential from extraneous visual information and in recalling complex material may be relevant in understanding some of the clinical features of borderline personality disorder. The observed memory improvement resulting from cueing suggests specific strategies that may be used to aid patients' recall of complex material.

CSF metabolites in borderline personality disorder compared with normal controls.

Cerebrospinal metabolites were measured in 17 patients with borderline personality disorder and 17 normal controls. There were no significant differences between the two groups in levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylglycol (MHPG). Within the borderline group, lower levels of CSF 5-HIAA were significantly associated with a history of genuine suicide attempts, but were not associated with violence, self-mutilation, or with the presence of major depression. Thus, CSF 5-HIAA levels are not distinctively low in a diagnostic group characterized by impulsivity and suicidal behavior, but within that group may be associated with genuine suicide attempts.

Dysphoric mania. Clinical and biological correlates.

Patients studied at peak severity of a manic episode showed substantial degrees of depression (dysphoria) and anxiety. Compared with nondysphoric manics (n = 26), the dysphoric manics (n = 22) had a significantly greater number of previous hospitalizations, and they displayed less rapid cycling both in the year before and during the index hospitalization admission. The severity of manic dysphoria tended to correlate with the number of previous hospitalizations, a finding that was highly significant in women (n = 27). Medication-free manic patients (n = 22) had significant elevations in cerebrospinal fluid norepinephrine concentrations compared with depressed and euthymic patients and normal volunteers, and the degree of elevation correlated significantly with the degree of manic dysphoria, anger, and anxiety rated at the time of the lumbar puncture. Patients with dysphoric mania, recognized by Kraepelin to have poor prognoses, have been reported to respond poorly to lithium carbonate but may be among those who respond to carbamazepine. Clinical, biologic, and pharmacologic response characteristics of manic subgroups, particularly those with extreme dysphoric components to their illness, appear to be clinically meaningful and deserving of further investigation.

Cerebral structure in borderline personality disorder.

Computed tomographic (CT) scans of brains of patients with borderline personality disorder and normal volunteers were analyzed for ventricle-brain ratios, third ventricular size, and evidence of frontal lobe atrophy. There were no significant differences between the two groups on any of these measures except for a narrower third ventricle in borderline patients, which could be accounted for by the narrower third ventricle observed in female subjects overall. While borderline patients may show signs of subtle neurological dysfunction, they do not show evidence of structural brain pathology.

Pharmacotherapy of borderline personality disorder: a review.

Pharmacotherapy has emerged as a beneficial adjunct to psychotherapy in the overall treatment regimen for patients with borderline personality disorder. The authors review controlled and uncontrolled studies of neuroleptics, antidepressants, anxiolytics, anticonvulsants, and lithium carbonate in the treatment of this disorder. Although no one medication has emerged as the treatment of choice, patterns of response can be identified. These patterns may be helpful in guiding clinical choice of pharmacotherapy as well as directing research to an understanding of the etiological mechanisms underlying this complex disorder.

Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output.

The effects of antidepressant treatment on noradrenergic function were studied in 27 patients with a major affective disorder. Twenty-four-hour urinary excretion of 6-hydroxymelatonin and "whole-body norepinephrine (NE) turnover," ie, 24-hour urinary output of NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol, vanillylmandelic acid, and normetanephrine, were measured before and after treatment with the tricyclic desipramine hydrochloride, the aminoketone bupropion hydrochloride, the nonselective monoamine oxidase (MAO) inhibitor tranylcypromine sulfate, and the specific MAO type A inhibitor clorgiline. 6-Hydroxymelatonin excretion increased following antidepressant treatment, while at the same time whole-body NE turnover was reduced. These findings support the hypothesis that antidepressant therapy increases noradrenergic "efficiency," in that functional output, as measured by 6-hydroxymelatonin, is maintained while total NE production is decreased.

Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients.

For 51 patients with rapid cycling affective disorder, clinical and family history data indicated that the illness was phenotypically and genetically related to more typical forms of affective disorder, was characterized by a bipolar course (100%), and was more common in women (92%). Manic-depressive cycles were separate from menstrual cycles. At the time of onset of rapid cycling, 73% of the patients were taking antidepressant drugs; the continuation of rapid cycling was associated with antidepressant drug therapy in 51% of the patients. Although most patients had been referred to a research ward because they were considered to be refractory to treatment, 37% attained essentially complete remissions, usually during treatment with lithium and/or monoamine oxidase inhibitors.

Pharmacotherapy of borderline personality disorder. Alprazolam, carbamazepine, trifluoperazine, and tranylcypromine.

Sixteen female outpatients with borderline personality disorder and prominent behavioral dyscontrol, but without a current episode of major depression, were studied in a double-blind, crossover trial of placebo and the following four active medications: alprazolam (average dose, 4.7 mg/d); carbamazepine (average dose, 820 mg/d); trifluoperazine hydrochloride (average dose, 7.8 mg/d); and tranylcypromine sulfate (average dose, 40 mg/d). Each trial was designed to last six weeks. Tranylcypromine and carbamazepine trials had the highest completion rates. Physicians rated patients as significantly improved relative to placebo while receiving tranylcypromine and carbamazepine. Patients rated themselves as significantly improved relative to placebo only while receiving tranylcypromine. Patients who tolerated a full trial of trifluoperazine showed improvement, those receiving carbamazepine demonstrated a marked decrease in the severity of behavioral dyscontrol, and those receiving alprazolam had an increase in the severity of the episodes of serious dyscontrol. As an adjunct to psychotherapy, pharmacotherapy can produce modest but clinically important improvement in the mood and behavior of patients with borderline personality disorder. As a research tool, patterns of pharmacological response may provide clues to biological mechanisms underlying dysphoria and behavioral dyscontrol.

Dysphoria associated with methylphenidate infusion in borderline personality disorder.

Two patients with borderline personality disorder experienced dramatic dysphoric episodes after acute administration of intravenous methylphenidate in a double-blind manner. These dysphoric episodes were similar to those which occurred spontaneously under conditions of psychological stress. Case histories and the behavioral and cardiovascular effects of the infusions are described. The pharmacology of methylphenidate is discussed in order to elucidate possible mechanisms mediating the observed responses to this drug.

Intravenous procaine as a probe of limbic system activity in psychiatric patients and normal controls.

Evidence from animal and human studies suggests that procaine hydrochloride may selectively activate limbic system structures and suppress neocortical structures. We administered a series of intravenous bolus doses of procaine hydrochloride to 31 subjects (7 with affective disorders, 17 with borderline personality disorder, and 7 healthy normal volunteers). Dose-related cognitive and sensory distortions and illusions were observed; affective experiences ranged widely from euphoric to dysphoric. Topographic electroencephalogram (EEG) analysis indicated selective increases in fast activity (26-45 Hz) over the temporal lobes; the degree of increase in this activity correlated with degree of dysphoria experienced. Procaine was associated with increases in secretion of cortisol, adrenocorticotrophic hormone (ACTH), and prolactin, but not with growth hormone. These preliminary data are consistent with the possibility that procaine might serve as a clinically useful probe of psychosensory, affective, electrophysiological, and endocrine effects referable to the limbic system.