Progress in pharmacotherapy of borderline disorders. A double-blind study of amitriptyline, haloperidol, and placebo.

In symptomatic patients with borderline disorder, we conducted a double-blind, placebo-controlled trial of haloperidol and amitriptyline hydrochloride to test the differential efficacy of medication against the affective and schizotypal symptoms that characterize the disorder. Sixty-one patients, diagnosed by the Diagnostic Interview for Borderline of Gunderson et al, completed randomized trials of haloperidol (n = 21), amitriptyline (n = 20), and placebo (n = 20). Medications were given in dose ranges of 4 to 16 mg for haloperidol (mean, 7.24 mg) and 100 to 175 mg for amitriptyline hydrochloride (mean, 147.62 mg) for five-week periods, with weekly self-rated and observer-rated measures of mood, schizotypal symptoms, and global functioning. Haloperidol was superior to both amitriptyline and placebo on a composite measure of overall symptom severity, with no difference between amitriptyline and placebo. Haloperidol produced significant improvement on a broad spectrum of symptom patterns, including depression, anxiety, hostility, paranoid ideation, and psychoticism. In contrast, amitriptyline was minimally effective, with small gains limited to some areas of depressive content. The magnitude of change tended to be modest and was more apparent in self-rated than observer-rated measures.

Phototherapy in individuals with and without subsyndromal seasonal affective disorder.

Antidepressant and energizing effects of bright light exposure (phototherapy) have been widely reported to occur in patients with seasonal affective disorder. We have attempted to evaluate whether other segments of the population might benefit from phototherapy, most notably individuals with subsyndromal seasonal affective disorder, as well as healthy individuals with no winter difficulties (controls). We have studied 20 subjects in each of these two categories and have found that bright artificial light did not alter mood and behavior in controls. In contrast, individuals with subsyndromal seasonal affective disorder responded favorably to treatment with bright environmental light. A dose of 5 hours of bright light exposure, divided between morning and evening, was more effective than 2 hours of exposure. This finding may have practical implications for establishing optimal environmental lighting conditions for those individuals whose winter difficulties do not meet criteria for seasonal affective disorder.

Borderline and schizotypal personality disorders treated with low-dose thiothixene vs placebo.

Fifty outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene (Navane) or placebo treatment that was continued for 12 weeks. The mean daily dosage of thiothixene hydrochloride in the final week of the study was 8.7 mg, a lower dosage than is used in outpatient schizophrenics. Significant drug-placebo differences were found, regardless of diagnosis, on "illusions," "ideas of reference," "psychoticism," "obsessive-compulsive symptoms," and "phobic anxiety," but not on "depression." Thiothixene seems to have more than an antipsychotic effect. Since response to treatment studies are a means for reformulating diagnostic concepts, we suggest a subdiagnosis defined by those symptoms that are drug-responsive, some of which are not included in current diagnostic criteria. Patients with borderline and schizotypal disorder without the foregoing symptoms probably would not profit from thiothixene and might needlessly be placed at risk for adverse drug effects.

Restricted antigenic variability of the epitope recognized by the neutralizing gp41 antibody 2F5.

OBJECTIVE: To investigate whether variations of the conserved gp41 amino-acid sequence ELDKWA affect its binding or neutralization by monoclonal antibody (MAb) 2F5. DESIGN AND METHODS: Neutralization assays were performed with primary isolates from different HIV-1 subtypes and the sequences corresponding to the 2F5 epitope region were analysed. Studies of MAb 2F5 peptide reactivity were performed by spot analysis, using peptides immobilized on cellulose. The frequency of emergence of neutralization-resistant virus variants was determined by immune selection experiments in the presence of MAb 2F5. RESULTS: Primary isolates from clades A, B and E were neutralized by MAb 2F5. Neutralization sensitivity correlated with the presence of the LDKW motif. A K-to-N change in the core sequence was identified in a neutralization-resistant patient isolate. Neutralization resistant virus variants that were selected in the presence of MAb 2F5 were found to contain D-to-N, D-to-E, or K-to-N changes within the LDKW sequence. Neither in natural isolates nor in variants obtained under immune selection conditions in the laboratory were changes in the L and W positions observed. Studies of MAb 2F5 binding to variations of the ELDKWA peptide confirmed that the changes at the first and last positions did not significantly reduce binding capacity, whereas amino-acid changes from D to N, D to E, and K to N almost completely abrogated binding of MAb 2F5. CONCLUSION: Sequence analysis of a variety of primary isolates suggests that the major determinant of MAb 2F5 binding corresponds to the amino-acid sequence LDKW. Naturally occurring and in vitro selected neutralization-resistant viruses contained changes in the D and K positions of the ELDKWA motif.

The amphetamine challenge test in patients with borderline disorder.

The authors used amphetamine as a psychopharmacological probe to investigate the hypothesis that patients with borderline personality disorder are prone to psychosis following ingestion of a dopamine agonist. Sixteen patients with borderline personality disorder participated in the study. Significant increases in the mean total Brief Psychiatric Rating Scale scores and in activation and thought disturbance factors after amphetamine administration were noted in the sample. Patients with diagnoses of both schizotypal and borderline personality disorders worsened transiently with amphetamine administration, but patients with only the borderline diagnosis improved. These results indicate the usefulness of pharmacological probes to further understand DSM-III axis II disorders.

Paradoxical effects of amitriptyline on borderline patients.

A paradoxical increase in suicide threats, paranoid ideation, and demanding and assaultive behavior occurred among 15 borderline inpatients receiving amitriptyline in a double-blind study. This pattern differed significantly from that of 14 nonresponding patients receiving placebo.

Cerebral glucose metabolism in patients with summer seasonal affective disorder.

Positron emission tomography scans of nine patients diagnosed with summer seasonal affective disorder (SSAD) were compared with scans of 45 normal control subjects to investigate differences in brain glucose metabolism. All subjects performed an auditory discrimination task beginning several minutes before injection of F-18-deoxyglucose and continuing for 30 minutes after injection. Regional glucose metabolic rates were extracted from 60 rectangular regions of interest measured in five planes selected as atlas matches from 28 total slices. Statistically significant differences between patients with SSAD and normal control subjects were found in cerebral glucose metabolic rate and also in normalized regional glucose metabolic rates in the orbital frontal cortex and in the left inferior parietal lobule.

Characterizing depression in borderline patients.

The comorbidity of depression and borderline disorder was studied in 39 symptomatic borderline inpatients defined by the Diagnostic Interview for Borderlines using three independent methods for assessing depression and three definitions of depression. Evaluations were conducted by the Schedule for Affective Disorders and Schizophrenia interviews for Research Diagnostic Criteria (RDC) depressive disorders, by clinical ratings for atypical depressive disorder, and by self-rated questionnaires for hysteroid dysphoria. Diagnoses of an RDC depression were made in 25 (64.1%), atypical depressive disorder in 16 (41%), and hysteroid dysphoria in 25 (64.1%) of the borderline patients. Two depressive diagnoses were present in 64.1% of patients, while 17.9% of patients met criteria for all three depressive disorders. No one method accurately characterized depression in borderline patients.

Patient and family attitudes about schizophrenia: implications for genetic counseling.

Psychiatrists are giving increased attention to genetic counseling for mental illness. However, the burden of these illnesses are perceived by families and the degree to which families feel a need for genetic counseling have yet to be established. Attitudes and perceptions measured in this study focus on etiology, familial risk, and socioeconomic burden of schizophrenia, as well as childbearing plans and the acceptability of genetic counseling. Members of 17 families, each with a child diagnosed schizophrenic, were studied using the Family Attitudes Questionnaire. The results demonstrate that the well family members view schizophrenia as a severe and debilitating illness. The results also show that there is a disparity between the attitudes of well family members and patients: 92 percent of parents compared to 25 percent of patients identified schizophrenia as a disorder associated with extreme burden. Regarding childbearing decisions, 29 percent of parents compared to 66 percent of patients say they would have children (in hindsight or in future) based on what they now know about schizophrenia in their family. This result corroborates reports from genetic counselors for other illnesses: the wish for children appears to override considerations of risk and burden for those potentially genetically affected persons who have not reached their desired family size.

Contrasts between symptoms of summer depression and winter depression.

Epidemiological studies and studies of clinical populations suggest that there are primarily two opposite patterns of seasonally recurring depressions: summer depression and winter depression. In addition, there is preliminary evidence that the two seasonal types of depression may have opposite types of vegetative symptoms. In the present study, we prospectively monitored symptoms of depression in 30 patients with recurrent summer depression and 30 sex-matched patients with recurrent winter depression and compared the symptom profiles of the two groups. Consistent with predictions based on the earlier reports, we found that winter depressives were more likely to have atypical vegetative symptoms, with increased appetite, carbohydrate craving, weight gain and hypersomnia, and that summer depressives were more likely to have endogenous vegetative symptoms, with decreased appetite and insomnia. A cluster analysis performed on the patients' symptom profiles without reference to season of occurrence of their episodes separated 78% of the summer depressives and winter depressives from each other on the basis of their symptoms (chi 2 = 19.29, P less than 0.001).

Alprazolam versus imipramine in depressed out-patients with neurovegetative signs.

The purpose of this study was to compare the safety and efficacy of a relatively new antidepressant drug, alprazolam (a triazolobenzodiazepine) with imipramine in the treatment of 60 depressed symptomatic volunteers. Eligible patients were randomly assigned after a 1-week washout to one of the medications and followed for 6 treatment weeks. Contrary to the earlier report of Feighner et al. (1983), who found alprazolam superior to imipramine and placebo, but consistent with Rush et al. (1985) we find imipramine superior in efficacy to alprazolam on a variety of symptoms. Both the present study and Rush's study employed patients with signs indicative of response to tricyclics. Feighner's patients may have been the type who tend to be less responsive to tricyclics but may be more responsive to alprazolam. Some of our data also show that alprazolam may have a more advantageous effect in the early weeks of treatment but is overtaken in subsequent treatment weeks by imipramine.

Bovine whey fractionation based on cation-exchange chromatography.

Bovine whey proteins have potential applications in veterinary medicine, food industry and as supplements for cell culture media. A fractionation scheme for the economically interesting proteins, such as IgG, lactoferrin and lactoperoxidase, based on cation exchangers was the goal of our investigations. A chromatographic process was developed where alpha-lactalbumin passes through the column and separation of the desired proteins is achieved. Four different cation-exchange media (S-HyperD-F, S-Sepharose FF, Fractogel EMD SO3- 650 (S) and Macro-Prep High S Support) were compared in regard to their dynamic binding capacity for IgG and their different elution behaviours when sequential step gradients with NaCl buffers were applied. Peak fractions were analyzed by size-exclusion chromatography and sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Lactoperoxidase activity was monitored by the oxidation of o-phenylenediamine. In order to explain the different resolution behaviours, isocratic runs with pure standards of whey proteins were performed. The k' values were calculated and plotted against salt concentration. Fractogel EMD had the highest binding capacity for IgG, 3.7 mg/ml gel at a linear flow-rate of 100 cm/h, but the resolution was low compared to that with the other three media. S-Hyper D and S-Sepharose FF showed lower capacities, 3.3 and 3.2 mg/ml gel, respectively, but exhibited better protein resolution. These effects could be partially explained by the k' versus salt concentration plots. The binding capacity of Macro-Prep S was considerably lower compared to that of the other resins investigated because its selectivity for whey proteins was completely different. S-Sepharose FF and S-Hyper D combine relatively high dynamic capacity for IgG and good resolution. Compared to studies with standard proteins, such as 100 mg/ml bovine serum albumin for S-Hyper D, their binding capacities were very low. Even after removal of low-molecular-mass compounds, the capacity could not be improved significantly. The running conditions (low pH) were responsible for the low protein binding capacity, since low-molecular-mass compounds in the feed do not compete with the adsorption of whey protein. The dynamic capacity did not decrease to a large extent within the range of flow-rates (100-600 cm/h) investigated. The dynamic capacity of HyperD and Fractogel was at least five times higher when pure bovine IgG was used for determination. In conclusion, S-Sepharose FF, S-Hyper D-F and Fractogel EMD SO3- 650 (S) are considered as successful candidates for the large-scale purification of bovine whey proteins.

Amphetamine response in borderline patients.

The behavioral and biological responses to d-amphetamine have been studied extensively in patients with schizophrenia and depression, and to a lesser degree in bipolar affective disorders. Because of theories linking borderline personality disorder to those illnesses, amphetamine, 30 mg, p.o., was administered to eight borderline patients in a double-blind, placebo-controlled study and the results were compared to the responses of normal subjects under identical conditions. Amphetamine led to symptoms of psychosis in four out of eight (50%) borderline patients. No normal subject became psychotic during the procedure. Global ratings of well-being were significantly elevated in the borderline group compared to the normal group. In addition the global response was highly inversely correlated with the patient's score on the Diagnostic Interview for Borderlines. Borderline patients had a nonsignificantly decreased growth hormone response following amphetamine compared to normals. Thus, borderline patients appear to be pharmacodynamically separable from normals.

Borderline personality disorder: replication of MMPI profiles.

The purpose of this study was to determine whether a particular MMPI profile is associated with borderline personality disorder (BPD). Forty-seven symptomatic volunteers who satisfied DSM-III criteria for borderline and/or schizotypal personality disorder were given the full MMPI. Concordance of MMPI profile for BDP confirmed the findings of four previous studies. Elevations were noted on F, D, PD, PA, PT, and SC. A subject's profile with this pattern is interpreted from item content as generally neurotic, dysthymic, socially withdrawn, suspicious, apathetic toward the future, affectively erratic, unable to anticipate the consequences of his or her own behavior, and unable to judge the social desirability of his or her own behavior. Correlations of the foregoing scales with a total BPD score ranged from .44 to .77, with a multiple R of .80 and a cross validity of .77. The accuracy of predicting actual BPD and non-BPD cases was 89%. Accordingly, the MMPI could be used as a coarse screen for BPD casefinding in that patients with the MMPI profiles above should be selected for more thorough diagnostic workup. In the future, the MMPI might be linked to other variables, such as drug response, to understand further the pathophysiology of BPD.

Phototherapy in subsyndromal seasonal affective disorder (S-SAD) and "diagnosed" controls.

Antidepressant and energizing effects of bright light exposure have been widely reported to occur in patients with seasonal affective disorder (SAD). In order to evaluate whether other segments of the population might also benefit from this treatment, we studied 20 normal individuals with mild SAD-like symptoms (subsyndromal SAD, S-SAD) and 20 with no reported seasonal difficulties (non-S-SAD). Whereas S-SAD individuals benefited from phototherapy, non-S-SAD normals did not. This finding raises the questions of whether a history of seasonal problems might be a marker of vulnerability to affective episodes and if S-SAD individuals might be considered as a high risk population in this regard.

Diagnoses of the relatives of schizotypal outpatients.

Relatives of 22 schizotypal probands were evaluated for lifetime psychiatric diagnoses. Forty-four (N = 44) of the 97 available relatives were interviewed directly using the Diagnostic Interview Schedule. The rates of psychiatric diagnoses were compared with those of sixty-six (N = 66) of 140 relatives of 30 depressed patients. Family history of mental illness was ascertained by the informant method on the remainder of relatives of both proband groups. The rate of depression found in the relatives of schizotypal patients was 52% in those directly interviewed and 25.7% when informants' reports on unavailable relatives are pooled with direct interview data. These rates were not significantly higher than those found for the relatives of depressed probands (34.8% by direct interview and 21% including reports from informants). The high rates of depression in the relatives of schizotypal probands may indicate that schizotypal personality is associated with affective disorder and not only with schizophrenia. However, the high rates may be due to the presence of depressive character traits in relatives, which inflate the rates of dysthymic disorder and other chronic depressive disorders in the relatives of borderline patients.

Amitriptyline versus haloperidol in borderlines: final outcomes and predictors of response.

The authors report the final results of a 4-year study of amitriptyline and haloperidol in 90 symptomatic borderline inpatients. Medication trials were double-blind and placebo controlled and lasted 5 weeks. Haloperidol (4-16 mg/day) produced significant improvement over placebo in global functioning, depression, hostility, schizotypal symptoms, and impulsive behavior. Significant effects of amitriptyline (100-175 mg/day) were generally limited to measures of depression. Factor analysis identified three symptom change patterns: a global depression, hostile depression, and schizotypal symptom pattern. Medication effects favoring haloperidol were most prominent for hostile depression. Variables predicting favorable response to haloperidol included severity of schizotypal symptoms, hostility, and suspiciousness. Schizotypal symptoms and paranoia predicted poor outcome on both depression patterns with amitriptyline. Placebo effects were most prominent on acute state symptoms, with severe character traits predicting poor response.