Stress and hippocampal abnormalities in psychiatric disorders.

The hippocampus plays a main role in regulating stress response in humans, but is itself highly sensitive to neurotoxic effects of repeated stressful episodes. Hippocampal atrophy related to experimental stress has been reported in laboratory studies in animals. Several controlled brain imaging studies have also shown hippocampal abnormalities in psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and borderline personality disorder (BPD). This paper reviews the physiological role of the hippocampus in stress circuitry and the effects of stress on cognitive functions mediated by the hippocampus. We also review brain imaging studies investigating hippocampus in PTSD, MDD, and BPD. This literature suggests that individuals with PTSD, MDD, and BPD may suffer hippocampal atrophy as a result of stressors associated with these disorders. Prospective, longitudinal studies will be needed in high-risk offspring and first-episode subjects to explore the relationship between stress and hippocampal atrophy in these neuropsychiatric illnesses.

Serotonin, impulsivity, and alcohol use disorders in the older adolescent: a psychobiological study.

BACKGROUND: Alcohol use disorders (AUDs) among adolescents are associated with a high prevalence of conduct disorder (CD), much as type II alcoholism in adults is associated with impulsive-aggressive behavior and antisocial personality traits. Adults with impulsive personality disorders and AUD demonstrate diminished central serotonergic responsiveness to serotonergic agonists. Dysregulation of central serotonergic function may contribute to a vulnerability to impulsive-aggressive behavior, CD, and AUD. We studied older adolescents, both male and female, to examine the relationships between sex, dispositional impulsivity, aggressivity, CD, and responsiveness to serotonergic challenge with d,l fenfluramine (FEN) early in the development of AUD. METHODS: Thirty-six adolescents between the ages of 16 and 21 years were assessed for DSM-IV AUD and other Axis I disorders by using the Psychoactive Substance Use Disorders section of the Structured Clinical Interview for DSM III-R, the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, and CD interviews. Impulsivity and aggressivity were assessed by the Barratt Impulsiveness Scale, Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Eysenck Impulsiveness Questionnaire, Youth Self Report, and Multidimensional Personality Questionnaires. FEN was administered as 0.8 mg/kg to a maximum of 60 mg, and blood was sampled at fixed intervals for prolactin, cortisol, fenfluramine, and norfenfluramine levels. RESULTS: Eighteen adolescents (12 male, 6 female) with AUD scored significantly higher on all measures of impulsivity and aggressivity compared with 18 healthy controls (12 male, 6 female). There were no significant differences between groups in peak prolactin or cortisol responses (minus baseline), or area-under-the-curve determinations (AUC); however, 9 subjects with AUD and comorbid CD had significantly elevated cortisol AUC levels compared with subjects with AUD and no CD or with normal controls. In the total sample, cortisol AUC was associated positively with measures of aggression. CONCLUSIONS: Adolescents with early-onset AUD are characterized by impulsivity and aggressivity compared with healthy peers but do not demonstrate the diminished prolactin or cortisol responses to FEN characteristic of adult alcoholics with impulsive-aggression.

Hippocampal volume in adolescent-onset alcohol use disorders.

OBJECTIVE: Alcohol use disorders (defined as DSM-IV alcohol dependence or abuse) are prevalent and serious problems among adolescents. As adolescence is marked by progressive hippocampal development, this brain region may be particularly susceptible to the adverse effects of adolescent alcohol use disorders. This study compared the hippocampal volumes of adolescents and young adults with adolescent-onset alcohol use disorders to those of healthy matched comparison subjects. METHOD: Magnetic resonance imaging was used to measure the hippocampal volumes and volumes of comparison brain regions in 12 subjects with alcohol use disorders and 24 comparison subjects matched on age, sex, and handedness. RESULTS: Both left and right hippocampal volumes were significantly smaller in subjects with alcohol use disorders than in comparison subjects. Total hippocampal volume correlated positively with the age at onset and negatively with the duration of the alcohol use disorder. Intracranial, cerebral, and cortical gray and white matter volumes and measures of the mid-sagittal area of the corpus callosum did not differ between groups. CONCLUSIONS: In the mature brain, chronic alcohol use disorders are associated with graded global brain dysmorphology. Although the etiology, neuropsychological consequences, and permanence of these hippocampal findings need to be further examined, these findings suggest that, during adolescence, the hippocampus may be particularly susceptible to the adverse effects of alcohol.

A fenfluramine-activated FDG-PET study of borderline personality disorder.

BACKGROUND: Impulsive aggression in patients with personality disorders is associated with diminished levels of cerebrospinal fluid (CSF) 5-HIAA, blunted neuroendocrine responses to serotonergic agonists, and decreased glucose utilization in the prefrontal cortex. We tested the hypothesis that impulsive aggression in borderline personality disorder (BPD) may be associated with diminished serotonergic regulation in the prefrontal cortex, using positron-emission tomography (PET) neuroimaging during pharmacologic challenge with d,l fenfluramine (FEN). METHODS: A 2-day, single-blind, placebo-controlled FEN challenge study was conducted in five patients with BPD (and no Axis I MDD) and eight healthy control participants. On Day 1, 4 mCi [(18)F]-fluorodeoxyglucose (FDG) was injected 3 hours after ingestion of placebo; on Day 2, FDG was injected 3 hours after ingestion of.8 mg/kg to 60 mg of d,l fenfluramine. After 30 min, a 45-min emission scan was acquired on the Siemans/CTI 951r/31 scanner. PET data were aligned to MR images and analyzed by Statistical Parametric Mapping (SPM96). RESULTS: In response to placebo, uptake of FDG was greater in control participants than patients in large areas of the prefrontal cortex including medial and orbital regions bilaterally (BA 10-11), left superior temporal gyrus, and right insular cortex. There were no areas in which patients had greater relative regional uptake than control participants. In response to FEN, relative regional uptake of FDG (relative to placebo) was greater in control participants compared to patients in medial and orbital regions of right prefrontal cortex (BA 10), left middle and superior temporal gyri (BA 22-23), left parietal lobe (BA 40), and left caudate body. CONCLUSIONS: Patients with BPD have diminished response to serotonergic stimulation in areas of prefrontal cortex associated with regulation of impulsive behavior.

Psychopharmacology of borderline personality disorder.

Pharmacotherapy for patients with borderline personality disorder is directed against the psychobiology of cognitive-perceptual, affective, and impulsive-behavioral symptoms. A symptom-specific method using current empiric evidence for drug efficacy in each symptom domain is proposed. Drugs in each medication class have some potential utility against specific symptoms in patients with borderline personality disorder.

Characteristics of suicide attempts of patients with major depressive episode and borderline personality disorder: a comparative study.

OBJECTIVE: Suicidal behavior is highly prevalent in borderline personality disorder and major depressive episode, although the characteristics of suicide attempts in the two disorders are believed to differ. Comorbidity of borderline personality disorder and major depressive episode may obscure characteristics of suicide attempts that are uniquely related to the psychopathology of each disorder. We compared suicidal behavior in patients with borderline personality disorder, major depressive episode, and borderline personality disorder plus major depressive episode to determine whether characteristics of suicide attempts differed between groups and if aspects of core psychopathology predicted specific attempt characteristics. METHOD: Eighty-one inpatients with borderline personality disorder, including 49 patients with borderline personality disorder plus major depressive episode, were compared to 77 inpatients with major depressive episode alone on measures of depressed mood, hopelessness, impulsive aggression, and suicidal behavior, including lifetime number of attempts, degree of lethal intent, objective planning, medical damage, and degree of violence of suicide methods. RESULTS: No significant differences were found in the characteristics of suicide attempts between patients with borderline personality disorder and those with major depressive episode. However, patients with both disorders had the greatest number of suicide attempts and the highest level of objective planning. An increase in either impulsive aggression or hopelessness or a diagnosis of borderline personality disorder predicted a greater number of attempts. Hopelessness predicted lethal intent in all three groups and predicted objective planning in the group with both disorders. Medical damage resulting from the most serious lifetime suicide attempt was predicted by number of attempts. CONCLUSIONS: Comorbidity of borderline personality disorder with major depressive episode increases the number and seriousness of suicide attempts. Hopelessness and impulsive aggression independently increase the risk of suicidal behavior in patients with borderline personality disorder and in patients with major depressive episode.

Recent life events, social adjustment, and suicide attempts in patients with major depression and borderline personality disorder.

This study investigated the impact of recent life events and social adjustment on suicide attempter status in 34 patients with major depression, 24 patients with borderline personality disorder, and 22 patients with co-morbid major depression and borderline personality disorder. Suicide attempters reported more recent life events and scored lower on a measure of social adjustment in their families and overall social adjustment, compared with non-attempters. Borderline disordered and borderline or depressed patients were more likely to have attempted suicide than patients with major depression only. Recent life events did not predict attempter status. Lower social adjustment in the immediate family and lower overall social adjustment were predictive of suicide attempter classification, regardless of diagnosis. Borderline disordered patients low on overall social adjustment were over 16 times more likely to have attempted suicide than patients diagnosed with major depression only. Recent life events may elevate suicide risk in groups already at high risk for suicide completion, whereas high levels of social adjustment may be protective against stress-related suicidal behavior.

Algorithms for pharmacological treatment of personality dimensions: symptom-specific treatments for cognitive-perceptual, affective, and impulsive-behavioral dysregulation.

A pharmacological approach to treating patients with personality disorders (PD) is based on evidence that some dimensions of personality are mediated by variations in neurotransmitter physiology and are responsive to medication effects. Target symptoms for pharmacotherapy in the PD patient are derived from expressions of cognitive-perceptual, affective, and impulsive-behavioral dysregulation of central neurotransmitter functions. Pharmacotherapy is directed at state symptoms during periods of acute decompensation and at trait vulnerabilities, which represent the diathesis to future episodes. A basic assumption of this approach is that neurotransmitter biology transcends Axis I and Axis II definitions and that closely related symptoms may share a common pathophysiology, independent of categorical definition. A common pathophysiology implies the possibility of shared responsiveness to medication. Using a dimensional definition of symptom domains, the author has developed treatment algorithms for cognitive-perceptual symptoms, affective dysregulation, and impulsive-behavioral dyscontrol in personality disorder patients.

Exploring AIDS-related knowledge, attitudes, and behaviors of female Mexican migrant workers.

AIDS-related knowledge, attitudes, and behaviors were assessed in female Mexican migrant laborers. Thirty-two women were administered a modified version of the Hispanic Condom Questionnaire. Respondents were knowledgeable about the major modes of HIV transmission, but one-third to one-half of the women believed that they could contract AIDS from unlikely casual sources. Although respondents reported few negative beliefs about condom use, actual condom use with sex partners was low and knowledge of proper condom use was problematic. Consequently, 75 percent reported never carrying condoms. Implications of these findings for future research and provision of services for female Mexican migrants are discussed.

PIP: According to US Department of Health and Human Services data for 1990, there are approximately 4.1 million migrant workers in the US, mainly of Mexican background. Half of all Mexican immigrants over the past 2 decades have been women. Findings are presented from a December 1992 assessment of AIDS-related knowledge, attitudes, and behaviors among a sample of female Mexican migrant laborers in Jalisco, Mexico, a small agricultural sending community 210 km from Guadalajara. The 32 women administered a modified version of the Hispanic Condom Questionnaire were of mean age 34.2 years and had lived and worked in the US since 1982. Women currently living in the US were visiting Jalisco for the Christmas holiday. Although the surveyed women were knowledgeable about the major modes of HIV transmission, 33-50% believed that they could contract AIDS from unlikely casual sources. Respondents reported few negative beliefs about condom use, but actual condom use with sex partners was low and knowledge of proper condom use was inadequate. 42% reported ever using a condom and 75% reported almost never carrying condoms. The implications of these findings are discussed with regard to future research and the provision of services to female Mexican migrants.

Special feature: psychobiologic perspectives on treatment of personality disorders.

The neurobiology of personality dimensions provides a theoretical framework for the design of pharmacologic treatment and studies in the PD patient. Neurotransmitter mediation of specific dimensions, such as novelty seeking, impulsivity, or schizotypy, suggests the usefulness of highly selective medications as clinical treatment and, simultaneously, as confirmatory dimensions. For example, the efficacy of SSRI antidepressants against impulsivity suggests both a clinical treatment and confirmation of the role diminished serotonergic function in impulse dysregulation. Similarly, the efficacy of neuroleptics against schizotypal symptoms supports the hypothesized role in the personality disorders lies in a better understanding of neurotransmitter and receptor function, using sophisticated PET neuroimaging techniques and receptor-specific radioligands to define the biologic basis of specific dimensions. As the focus of study gets smaller, we will no longer treat whole personalities, or even dimensions as we currently view them, but receptor-related functions. The challenge for the pharmacotherapist is to discriminate interpersonal from biologic pathologies, i.e., not to "biologize" all behavior.

Risk factors for suicidal behavior in borderline personality disorder.

OBJECTIVE: This study identified potential risk factors for suicidal behavior in patients with borderline personality disorder defined by the Diagnostic Interview for Borderline Patients and by DSM-III-R criteria for patients who did and did not attempt suicide. METHOD: Histories of suicide attempts and attempt characteristics were obtained by Schedule for Affective Disorders and Schizophrenia interviews from 84 patients with borderline personality disorder and were related to severity of borderline pathology, diagnostic comorbidity, and state and trait symptoms. RESULTS: There were 61 patients with a lifetime history of suicide attempts (72.6%), with an average of 3.39 (SD = 2.87) attempts per patient. Attempters were significantly older than nonattempters, with more impulse actions, antisocial personality disorder comorbidity, and state depression. State depression was significantly less severe in patients who had attempted suicide in the present episode (or past year) than in patients who had attempted suicide only in the past. A comorbid diagnosis of major depression, alcoholism, or drug use disorder did not distinguish attempters from nonattempters. Suicide attempt in the present episode was best predicted by the number of prior lifetime attempts. A highly serious intent to commit suicide was predicted by the number of lifetime attempts and subjective depression, while a low intent was predicted by a mixed subtype of borderline personality disorder plus schizotypal personality disorder and paranoid ideation. A high degree of medical lethality was predicted by number of lifetime attempts, older age, and hysteroid dysphoria, while low lethality attempts were associated with high degrees of anger. CONCLUSIONS: Risk factors for suicidal behavior in patients with borderline personality disorder include older age, prior suicide attempts, antisocial personality, impulsive actions, and depressive moods but not comorbid affective disorder, alcoholism, or drug use disorders.

Is there any drug treatment of choice for the borderline patient?

Psychotropic medication is used extensively in the borderline patient in an effort to treat the cognitive, affective, impulsive-behavioral and anxious-fearful symptoms which comprise the state symptoms and trait vulnerabilities of BPD. This paper reviews the efficacy of neuroleptics, antidepressants (TCA, MAOI and SSRI), lithium carbonate, carbamazepine and benzodiazepines against these 4 symptom domains. There is currently no single drug treatment of choice in BPD. Current research supports acute treatment. Maintenance trials are generally lacking or show limited efficacy. A dimensional approach is recommended for clinical practice and future research trials, targeting specific symptom domains with selective medication. Pharmacotherapy should be viewed as a useful adjunct to psychotherapy in the long-term treatment of the borderline patient.

Continuation pharmacotherapy of borderline personality disorder with haloperidol and phenelzine.

OBJECTIVE: The aim of this study was to assess the effectiveness of low-dose neuroleptic medication and monoamine oxidase inhibitor (MAOI) antidepressant medication in continuation pharmacotherapy of patients with borderline personality disorder. METHOD: The authors conducted a double-blind, placebo-controlled study comparing continuation therapy with a neuroleptic (up to 6 mg/day of haloperidol), an MAOI antidepressant (up to 90 mg/day of phenelzine), and placebo in 14 men and 40 women with borderline personality disorder. Continuation medication trials lasted 16 weeks, following 5 weeks of acute therapy. RESULTS: Continuing haloperidol demonstrated efficacy only for the treatment of irritability. Higher levels of depression, hypersomnia, and leaden paralysis were noted in the patients who received haloperidol than in those who received phenelzine and those who received placebo. The dropout rate during the first 8 weeks of the continuation study was significantly higher for the patients receiving haloperidol (64%) than for those receiving placebo (28%). Continued phenelzine demonstrated only modest efficacy for the treatment of depression and irritability. An activating effect of phenelzine was shown on measures of excitement and reactivity. CONCLUSIONS: No evidence of efficacy was found for continuation therapy with haloperidol in the treatment of borderline personality disorder other than in the treatment of irritability. Little evidence of efficacy was found for continuation therapy with phenelzine for borderline personality disorder other than modest improvements in irritability and depressive symptoms. There is currently no clear pharmacological treatment of choice for the continuation therapy of borderline personality disorder.

Efficacy of phenelzine and haloperidol in borderline personality disorder.

OBJECTIVE: To compare the efficacy of a neuroleptic (haloperidol) to a monoamine oxidase inhibitor antidepressant (phenelzine sulfate) against the affective, cognitive, and impulsive-aggressive symptoms of criteria-defined borderline inpatients in an effort to dissect apart affective and schizotypal symptom patterns or subtypes using medication response. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Inpatient unit of a tertiary care university psychiatric hospital serving a large public catchment area. PATIENTS: One hundred eight consecutively admitted borderline inpatients defined by Gunderson's Diagnostic Interview for Borderline Patients and DSM-III-R criteria, randomly assigned to 38 phenelzine, 36 haloperidol, and 34 placebo trials. INTERVENTIONS: Following 1 week free of medication, haloperidol (average dose, 4 mg/d), phenelzine sulfate (average dose, 60 mg/d), or placebo were given for 5 weeks with weekly symptom ratings and plasma drug level determinations. MAIN OUTCOME MEASURES: Efficacy was measured on depression (Hamilton Rating Scale, Beck Depression Inventory), global severity (Global Assessment Scale, Symptom Checklist-90 items [SCL-90]), anxiety, anger-hostility (SCL-90, Inpatient Multidimensional Psychiatric Scale [IMPS], Buss-Durkee Hostility Inventory), psychoticism (Schizotypal Symptom Inventory, SCL-90, IMPS), impulsivity (Ward Scale, Barratt Impulsiveness Scale, Self-Report Test of Impulse Control), and borderline psychotherapy (Borderline Syndrome Index). RESULTS: Three-way comparisons between groups indicated superior efficacy for phenelzine, followed by placebo and haloperidol on measures of depression, borderline psychopathologic symptoms, and anxiety. Pairwise comparisons between medication and placebo revealed significant efficacy for phenelzine against anger and hostility but no efficacy against atypical depression or hysteroid dysphoria. We were unable to replicate prior reports of efficacy for the neuroleptic. CONCLUSIONS: Pharmacologic dissection of borderline personality disorder patients into affective and schizotypal subtypes could not be demonstrated.

Haloperidol vs. phenelzine in continuation therapy of borderline disorder.

We report the first double-blind, placebo-controlled continuation study comparison of a neuroleptic (haloperidol < or = 6 mg), monoamine oxidase inhibitor (MAOI) antidepressant (phenelzine < or = 90 mg), and placebo in 54 patients with borderline personality disorder. Continuation medication trials of 16 weeks followed 5 weeks of acute therapy. Haloperidol continued to be effective beyond the acute phase only for the treatment of irritability. Higher levels of depression, hypersomnia, and leaden paralysis were noted in the haloperidol group than in the phenelzine and placebo groups. The dropout rate during the first half (8 weeks) of the continuation study was significantly higher for the haloperidol group (64%) than for the placebo group (28%) (p < .05). Phenelzine demonstrated very modest efficacy beyond that noted in the acute phase for the treatment of depression and irritability. Phenelzine was shown to have an activating effect on measures of excitement and reactivity.

A preliminary trial of fluoxetine in refractory borderline patients.

Borderline personality disorder is characterized by many of the symptoms associated with serotonin dysregulation, including affective lability, suicidal behaviors, and impulsive aggression. These provide an ideal clinical model for studying the treatment of these serious symptom presentations. The recent development of selective serotonin reuptake inhibitors such as fluoxetine makes it possible to study the role of serotonin in the etiology of affective and behavioral dyscontrol in borderline personality disorder. In this preliminary medication trial, 5 borderline personality disorder patients with severe symptoms resistant to phenelzine and neuroleptics were treated openly with fluoxetine 20 to 40 mg for 8 weeks, with weekly ratings of symptoms. The findings from this work suggested efficacy for fluoxetine in treating the depressive and impulsive symptoms of refractory patients with borderline personality disorder.

The depressed borderline: one disorder or two?

Depression in the borderline patient may present as a reactive mood state, an expression of character, or an independent comorbid affective disorder. The symptom picture is most often heterogeneous, "atypical," and chronic. Pharmacologic trials with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) produce modest improvement on a variety of symptoms, though not always on depression. Medication effects on depressed mood in borderline personality disorder (BPD) are independent of comorbid diagnoses of major depression, atypical depression, or hysteroid dysphoria. Residual symptoms are the rule. A literature review, including studies of comorbidity, longitudinal followup, family history, and laboratory and pharmacotherapy studies, suggests that the borderline patient has both a core biologic affective dysregulation and a pathologic personality organization. The combination of constitutional and psychodynamic etiologies for borderline pathology requires consideration of both pharmacotherapy and psychotherapy in any comprehensive treatment.

Fluoxetine trial in borderline personality disorder.

Borderline personality disorder (BPD) is defined by many of the symptoms associated with serotonin dysregulation, including affective lability, suicidal behaviors, and impulsive aggression, providing an ideal clinical model for studying the treatment of these serious disorders. The recent development of selective serotonin re-uptake inhibitors such as fluoxetine makes it possible to study the role of serotonin in the etiology of affective and behavioral dyscontrol in BPD. In this preliminary medication trial, 5 patients with BPD were treated openly with 20 mg to 40 mg of fluoxetine for 8 weeks, with weekly ratings of symptoms. The findings from this work suggested efficacy for fluoxetine in treating the depressive and impulsive symptoms of patients with BPD. The findings were mixed concerning the efficacy of fluoxetine in treating the hostility and psychotic symptoms of BPD. No evidence for effectiveness was found in the treatment of the anxiety, phobic anxiety, or interpersonal sensitivity of BPD.

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.