Paul H. Soloff

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.

Impulsivity and prefrontal hypometabolism in borderline personality disorder.

Prefrontal hypoperfusion and decreased glucose uptake in the prefrontal cortex (PFC) are found in violent criminal offenders, murderers and aggressive psychiatric patients. These abnormalities may be independent of diagnosis and associated with impulsive-aggression as a personality trait. Impulsive-aggression is a clinical characteristic of borderline personality disorder (BPD) where it is associated with assaultive and suicidal behaviors. We conducted FDG-PET studies in 13 non-depressed, impulsive female subjects with BPD and 9 healthy controls to look for abnormalities in glucose metabolism in areas of the PFC associated with regulation of impulsive behavior. Statistical Parametric Mapping-99 (SPM99) was used to analyze the PET data with Hamilton depression scores as covariate. Significant reductions in FDG uptake in BPD subjects relative to healthy controls were found bilaterally in medial orbital frontal cortex, including Brodmanns areas 9, 10 and 11. There were no significant areas of increased uptake in BPD subjects compared to control subjects. Covarying for measures of impulsivity or impulsive-aggression rendered insignificant the differences between groups. Decreased glucose uptake in medial orbital frontal cortex may be associated with diminished regulation of impulsive behavior in BPD.

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.

Structural brain abnormalities in borderline personality disorder: A voxel-based morphometry study

Imaging studies using region-of-interest morphometry and positron emission tomography have contributed to our understanding of structural and functional abnormalities in borderline personality disorder (BPD); however, both methods have practical limitations to their usefulness for exploratory studies of brain-behavior relationships. We used voxel-based morphometry (VBM) in 34 subjects with BPD and 30 healthy control (HC) subjects to study effects of diagnosis, gender, childhood sexual abuse, depressed mood, impulsivity and aggression on group differences. VBM is a computer-based method for whole brain analysis that combines the advantages of a functional study with a structural method. The BPD subjects, diagnosed with the Diagnostic Interview for Borderline Patients and the International Personality Disorders Examination, were compared with 30 HC subjects, with age and gender covaried. Analyses were repeated separately by gender and, in women, by histories of childhood sexual abuse. Depressed mood, impulsivity, and aggression were covaried in separate analyses. Compared with HC, BPD subjects had significant bilateral reductions in gray matter concentrations in ventral cingulate gyrus and several regions of the medial temporal lobe, including the hippocampus, amygdala, parahippocampal gyrus, and uncus. BPD women (and abused BPD women), but not BPD men, had significant reductions in medial temporal lobe, including the amygdala. BPD men, but not BPD women, showed diminished gray matter concentrations in the anterior cingulate gyrus compared with findings in HC subjects. Covarying for depressed mood rendered group differences non-significant in the ventral cingulate but had little effect on differences in medial temporal cortex. Covarying for aggression (LHA) had relatively little effect on group differences, while covarying for impulsivity, as determined by the Barratt Impulsiveness Scale, rendered all previously noted voxel-level group differences non-significant. Diminished gray matter in the prefrontal cortex and the medial temporal cortex may mediate the dysregulation of impulse and affect in BPD. Group differences varied greatly by gender, levels of depression, and impulsivity. VBM is an efficient method for exploratory study of brain-behavior relationships.

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.

Impulsivity, gender, and response to fenfluramine challenge in borderline personality disorder ☆

Behavioral impulsivity in borderline personality disorder (BPD) is associated with indices of diminished central serotonergic function, independent of suicidal behavior, depression or alcohol use disorder. Many of these studies have been conducted among males in specialized settings. Studies of BPD females, who constitute the majority of BPD patients, are generally conducted in community settings and report inconsistent findings. We studied gender differences in behavioral impulsivity and the prolactin response to D,L-fenfluramine (FEN) in BPD subjects in a community setting. A FEN challenge study was conducted with 64 BPD subjects (20 male, 44 female), and 57 controls (36 male, 21 female). Axis I and II disorders, including BPD, and suicidal histories were assessed by structured interviews. Controls were free of Axis I and II disorders. Impulsivity and aggression were assessed by the Buss-Durkee Hostility Inventory, Barratt Impulsiveness Scale, Minnesota Multiphasic Personality Inventory-Psychopathic Deviate subscale, and the Brown-Goodwin Lifetime History of Aggression. Male, but not female, BPD subjects had significantly diminished prolactin responses compared to controls. Impulsivity and aggression each predicted prolactin responses. A significant effect of BPD diagnosis on prolactin response was eliminated when impulsivity was co-varied. Impulsivity and aggression were inversely related to delta-prolactin and peak-prolactin responses among male but not female subjects. Gender differences in central serotonergic function may contribute to variations in impulsivity in BPD.

Developmental histories of borderline patients

Abstract The developmental histories of 45 borderline inpatients, as defined by Gunderson-Singer criteria and the Diagnostic Interview for Borderlines, were compared to 42 schizophrenic and 32 depressed controls defined by RDC. Three currently popular hypotheses for borderline personality development were systematically studied: a neurobehavioral model, a separation hypothesis, and a family-dynamic theory. A neurobehavioral survey revealed some complications of pregnancy; prematurity, persistent rocking, and temper tantrums in borderline patients but no increased incidence of hyperactivity, clumsiness, or learning difficulties compared to controls. Borderline patients experienced more early life parental loss and had greater difficulties with normal developmental separations. Their relationships with parents were negative and conflictual, with over-involved mothers and under-involved (or absent) fathers. While supporting the importance of separation trauma and a pathologic family structure, our data do not provide consistent support for a neurobehavioral origin of borderline development.

5HT2A Receptor Binding is Increased in Borderline Personality Disorder

BACKGROUND Postmortem studies in suicide victims demonstrate an increase in the number of post-synaptic 5-HT(2A) receptor binding sites in ventral lateral and orbital frontal cortex. Diminished metabolic responses to serotonergic activation are noted in these areas in impulsive subjects with borderline personality disorder (BPD), a group at high risk for suicidal behaviors. We examined 5HT(2A) receptor binding potential (BP) in impulsive subjects with BPD, with positron emission tomography neuroimaging with [(18)F] altanserin. METHODS Fourteen female subjects with BPD were assessed for Axis I comorbidity, depressed mood, impulsivity, aggression, suicidality, childhood abuse, and compared with 11 healthy female control subjects. The 5HT(2A) receptor binding was evaluated in prefrontal cortex, anterior cingulate, hippocampus, temporal lobe, occipital cortex, and thalamus. Data were analyzed with Logan graphical analysis and a four-compartment (4C) model. RESULTS Hippocampal 5HT(2A) receptor binding was significantly increased in BPD subjects compared with control subjects in both Logan and 4C analyses, covarying for age. Hippocampal BP values were related to comorbid major depressive episode, with highest values found in non-depressed BPD subjects and lowest in healthy control subjects. The BP values were not related to depressed mood, impulsivity, aggression, suicidality, or childhood abuse. CONCLUSIONS 5HT(2A) receptor binding is increased in the hippocampus of BPD subjects independent of depressed mood, impulsivity, aggression, suicidality, or childhood abuse. Dysregulation of serotonergic function in hippocampus might contribute to affective and behavioral symptoms in BPD.

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.

Prospective predictors of suicidal behavior in borderline personality disorder at 6-year follow-up.

OBJECTIVE Recurrent suicidal behavior is a defining characteristic of borderline personality disorder. Although most patients achieve remission of suicidal behavior over time, as many as 10% die by suicide, raising the question of whether there is a high-risk suicidal subtype. The authors conducted a longitudinal study of suicidal behavior in borderline personality disorder patients to identify prospective predictors of suicide attempts and to characterize those patients at highest risk for suicide completion. METHOD Demographic and diagnostic characteristics and clinical and psychosocial risk factors assessed at baseline were examined for predictive association with medically significant suicide attempts using Cox proportional hazards models. The authors defined prospective predictors for participants who completed 6 or more years in the study and compared the data to those of earlier intervals. RESULTS Among 90 participants, 25 (27.8%) made at least one suicide attempt in the interval, and most attempts occurred in the first 2 years. The risk of suicide attempt was increased by low socioeconomic status, poor psychosocial adjustment, family history of suicide, previous psychiatric hospitalization, and absence of any outpatient treatment before the attempt. Higher global functioning scores at baseline decreased this risk. CONCLUSIONS Risk factors predictive of suicide attempt change over time. Acute stressors such as major depressive disorder were predictive only in the short term (12 months), while poor psychosocial functioning had persistent and long-term effects on suicide risk. Half of borderline patients have poor psychosocial outcomes despite symptomatic improvement. A social and vocational rehabilitation model of treatment is needed to decrease suicide risk and optimize long-term outcomes.