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.

Using the protirelin test to distinguish mania from schizophrenia.

To explore the possible utility of the protirelin test in differentiating manic and schizophrenic patients, we gave a test dose of protirelin to 30 consecutive euthyroid inpatients who met Research Diagnostic Criteria for mania, 30 who met criteria for schizophrenia, undifferentiated subtype, and 20 normal volunteer controls. The mean maximal thyroid-stimulating hormone (TSH) response (delta TSH) to protirelin in the manic patients was lower than in the schizophrenic patients and in the controls. This mean difference was not attributable to differences in age, sex, baseline thyroid functioning, cortisol levels, or medication, but there was a considerable overlap of values in the patient groups. However, with a delta TSH less than or equal to 7.0 I microunits/mL to identify manic patients in the overall group, the sensitivity of the protirelin test was 60% and the specificity was 84%.

Thyroid abnormalities associated with rapid-cycling bipolar illness.

Bipolar patients taking lithium carbonate were classified as rapid-cycling or non-rapid-cycling based on whether they had ever experienced four or more affective episodes in a 12-month period. Overt hypothyroidism was found in 12 (50.7%) of the 24 rapid-cycling patients and in none of the 19 non-rapid-cycling patients. Elevated thyroid-stimulating hormone levels were present in 92% of the rapid-cycling group v 32% of the non-rapid-cycling group. Abnormalities of the hypothalamic-pituitary-thyroid axis, some of which may become apparent only during treatment with lithium carbonate, appear to interact with a predisposition to bipolar illness to produce rapid-cycling. These overt and covert abnormalities may help explain the reported efficacy of thyroid in treating "periodic catatonia" and rapid-cycling.

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.

Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites.

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.

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.

Cerebrospinal fluid probenecid studies: a reinterpretation.

Probenecid is used to block the transport of acid monoamine metabolites from cerebrospinal fluid (CSF), on the assumption that the resultant rise in CSF concentrations of the metabolites will reflect presynaptic "turnover" of the parent monoamine. However, CSF levels of probenecid correlate with CSF levels of the metabolite, suggesting that the blockade is incomplete at the probenecid levels obtained in human studies. This article reviews the literature on CSF probenecid-metabolite correlations and presents data demonstrating variations in the correlations across diagnostic groups. These cross-diagnostic variations may be due to group differences in membrane transport characteristics and and confound attempts to "correct for" CSF probenecid concentrations in studies of monoamine turnover.

Zimelidine and norzimelidine protein binding measured by equilibrium dialysis and cerebrospinal fluid.

Steady-state concentrations of a new antidepressant, zimelidine (ZIM), and its active metabolite, norzimelidine (NZIM), were measured in plasma and cerebrospinal fluid (CSF) in eight depressed patients. Free drug, as calculated from the ratio of CSF to plasma concentration, of ZIM was 8.4 +/- 1.8% and of NZIM was 18.3 +/- 2.8%. Equilibrium dialysis (ED) of plasma from the same patients on placebo yielded free fractions of 8.6 +/- 2.2% and 28.1 +/- 3.4% for the two compounds. alpha 1-Acid glycoprotein (alpha a-AG) was also measured in the same samples. Variation in free drug using either method was not great, but did modestly correlate with alpha 1-AG concentration in six of the eight patients in whom simultaneous placebo measures were available. Our results indicate that measurements in plasma or of free drug dependent on ED lead to erroneous conclusions regarding the proportion of free NZIM to ZIM. Considering the different potencies of the parent compound and active metabolite, this is an unusual problem.

Positive effects of carbamazepine on behavioral dyscontrol in borderline personality disorder.

In a double-blind crossover trial, carbamazepine, an anticonvulsant with primary effects on subcortical limbic structures, decreased the severity of behavioral dyscontrol in 11 women with borderline personality disorder significantly more than placebo. The authors emphasize the preliminary nature of their findings and discuss alternative hypotheses regarding mechanisms by which carbamazepine might influence behavioral dyscontrol.

Alprazolam-induced dyscontrol in borderline personality disorder.

The authors report a significant increase in dyscontrol in patients with borderline personality disorder who were taking alprazolam during a double-blind, placebo-controlled crossover study. They suggest that caution be used in prescribing alprazolam to patients with similar histories.

Dementia of bipolar illness: diagnosis and response to lithium.

The authors describe the misdiagnosis of an elderly patient with depressive dementia and suggest that lithium may be an effective treatment for some individuals with this disorder, particularly those with apparent bipolar illness.

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.

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.

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.

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.

Psychopharmacology of borderline personality disorder: a review.

Borderline personality disorder poses a significant treatment challenge to the clinician. The frequent presence of comorbid disorders and the occurrence of a wide array of possible target symptoms complicate clinical assessment. Limited data from controlled clinical trials suggest that neuroleptics, monoamine oxidase inhibitors, and the anticonvulsant carbamazepine produce statistically and clinically significant short-term symptom reduction and may be useful components of the treatment approach to borderline personality disorder. Further research is needed to identify subgroups of patients with borderline personality disorder who are particularly responsive to a given medication and to explore the possibility that specific symptom complexes (such as suspiciousness, anhedonia, affective lability, or behavioral dyscontrol) are preferentially responsive to specific agents.

Neuroendocrine effects of limbic activation by electrical, spontaneous, and pharmacological modes: relevance to the pathophysiology of affective dysregulation in psychiatric disorders.

1. Literature is reviewed that implicates various limbic structures (particularly amygdala and hippocampus) in the modulation of stress-associated neuroendocrine systems. 2. Procaine and related local anesthetics may show a selective proclivity for activating limbic structures. 3. Procaine stimulates ACTH-cortisol and prolactin, but not growth hormone secretion. This pattern is most comparable to that elicited by stimuli which act bilaterally on temporal lobe and limbic areas. 4. Procaine may be a useful agent for helping to elucidate the anatomic and physiologic basis for mood, endocrine, and cognitive dysregulation associated with stress and affective disorders. 5. The endocrine concomitants of limbic activation may have relevance to the course and symptom complex of affective disorders and related psychiatric conditions.

Suicidal and parasuicidal behavior in borderline personality disorder.

One of the most perplexing and dangerous aspects of borderline personality disorder is the wide array of suicidal and parasuicidal behaviors. Close phenomenologic evaluation of these behaviors reveals that they can be differentiated into various subcategories. Approaching these behaviors with a biologic perspective may prove helpful in elucidating the underlying etiologies and therapeutic approaches.

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.

Tricyclic-induced mania and MHPG excretion.

In order to evaluate the presumed involvement of altered noradrenergic receptor sensitivity in the switch process from depression into mania, we explored the relationship between pretreatment 3-methoxy-4-hydroxy-phenylglycol (MHPG) and tricyclic-induced mania or hypomania in bipolar depressed patients. Within the group of patients developing mania or hypomania on tricyclics, there was a strong positive correlation between pretreatment 24-hour urinary MHPG and the latency of onset of the episode. This finding is consistent with both the reported differences in MHPG excretion between unipolar and bipolar patients and the postulated noradrenergic involvement in the switch process.