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Larry J Siever

Publications and source records attributed to Larry J Siever.

At least 37 records · Page 2Linked to original sources
PubMed2004

Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression.

RATIONALE: Impulsive aggressive personality disordered patients have been shown to have decreased relative glucose metabolism in orbito-frontal cortex and anterior cingulate gyrus compared with normal subjects. In addition, patients with impulsive aggression have an attenuation of symptoms with selective serotonin reuptake inhibitor (SSRI) treatment. OBJECTIVES: The goals of the present study were to attempt to replicate the finding of improvement in impulsive aggression in borderline personality disorder with SSRIs and to investigate the specific cortical areas modified by medication, which might underlie the observed clinical improvement using (18)FDG-PET. METHODS: Ten impulsive aggressive patients with borderline personality disorder were imaged with (18)F-deoxyglucose positron emission tomography at baseline and after receiving fluoxetine at 20 mg/day for 12 weeks. Anatomical MRIs were coregistered to PET and relative metabolic rates were obtained in 39 Brodmann areas. RESULTS: Brodmann areas 11 and 12 in the orbito-frontal cortex showed significant increases in relative metabolic rate. Significant clinical improvement was also observed as assessed by the Overt Aggression Scale-Modified. CONCLUSIONS: These changes are consistent with a normalizing effect of fluoxetine on prefrontal cortex metabolism in impulsive aggressive disorder.

Adult↗
PubMed2004

Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide.

BACKGROUND: Previous imaging studies demonstrated that schizophrenia is associated with increased amphetamine-induced dopamine (DA) release in the striatum, most pronounced during episodes of illness exacerbation. Schizotypal personality disorder (SPD) is a schizophrenia spectrum disorder, genetically related to schizophrenia. The goal of this study was to investigate striatal DA function in patients with SPD. METHODS: In our study, 13 SPD patients and 13 matched healthy control subjects underwent single photon emission computed tomography (SPECT) scan during bolus plus constant infusion of the D2/3 radiotracer [123I]iodobenzamide (IBZM). Striatal specific to nonspecific equilibrium partition coefficient (V(3)") was measured at baseline and following amphetamine administration (.3 mg/kg). RESULTS: No significant differences were observed in baseline V(3)" between groups. Amphetamine induced a larger decrease in [123I]IBZM V(3)" in SPD patients (-12 +/- 5%) compared with control subjects (-7 +/- 5%, p =.03). CONCLUSIONS: The reduction in [123I]IBZM V(3)" induced by amphetamine in SPD was similar to that observed in remitted schizophrenia patients (-10 +/- 9%, n = 17), but significantly lower than that observed during illness exacerbation (-24 +/- 13%, n = 17). This suggests that DA dysregulation in schizophrenia spectrum disorders might have a trait component, present in remitted patients with schizophrenia and in SPD, and a state component, associated with psychotic exacerbations but not SPD.

Adult↗
PubMed2004

Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction.

BACKGROUND AND RATIONALE: Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D(1) receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D(1) stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia. OBJECTIVES: This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D(1) signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function. RESULTS AND CONCLUSIONS: Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D(1) receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D(1) receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.

Animals↗
PubMed2004

Context-processing deficits in schizotypal personality disorder.

Research suggests that schizotypal personality disorder (SPD) is a part of the spectrum of schizophrenia-related illnesses. This article hypothesizes that a deficit in the representation and maintenance of context is a core cognitive disturbance in schizophrenia and that SPD individuals should demonstrate context-processing deficits. To test this hypothesis, the authors administered 3 versions of their AX-CPT task, designed to assess context processing, to 35 healthy controls and 26 individuals with DSM-IV SPD. They also administered working memory and selective attention tasks. SPD individuals displayed context representation deficits similar to those found in schizophrenia but did not show the same additional deficits in context maintenance. Context processing was strongly associated with working memory and selective attention performance in the SPD individuals.

Adult↗
PubMed2004

The pathophysiology of schizophrenia disorders: perspectives from the spectrum.

OBJECTIVE: This overview focuses on neurobiological abnormalities found in subjects with schizotypal personality disorder, the prototype of the schizophrenia spectrum disorders, and chronic schizophrenia in the context of common vulnerabilities shared by schizotypal personality disorder and schizophrenia, as well as the factors that protect against the severe cognitive/social deficits and frank psychosis of chronic schizophrenia. A pathophysiological model of the relationship between schizotypal personality disorder and schizophrenia was developed based on this data. METHOD: The authors provide a selective review of major findings regarding the pathophysiology of schizotypal personality disorder and integrate these results in conjunction with preclinical studies into a model of the pathophysiology of the spectrum. RESULTS: People with schizotypal personality disorder share phenomenological, genetic, and cognitive abnormalities with people with chronic schizophrenia. While temporal volume reductions appear to be common to both groups, there may be preservation of frontal lobe volume in schizotypal personality disorder compared to schizophrenia. Findings to date regarding striatal volume, metabolic rate, and dopamine release in subjects with schizotypal personality disorder compared to subjects with chronic schizophrenia are consistent with hypotheses of reduced striatal dopaminergic activity in schizotypal personality disorder compared to schizophrenia. CONCLUSIONS: Genetic or environmental factors that promote greater frontal capacity and reduced striatal dopaminergic reactivity might contribute to sparing people with schizotypal personality disorder from the psychosis and severe social and cognitive deterioration of chronic schizophrenia. Further research is required to test these hypotheses more definitively.

Atrophy↗
PubMed2003

Neurobiologic function and temperament in subjects with personality disorders.

BACKGROUND: Personality traits have been hypothesized to involve specific neurotransmitter systems. In order to test this model, the relationship between the responses to serotonergic and noradrenergic probes, central cerebrospinal fluid (CSF) measures of monoamine neurotransmitters and the Tridimensional Personality Questionnaire (TPQ) were evaluated in a cohort of personality disorder subjects. METHODS: A total of 142 patients meeting at least one personality disorder (meeting Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised criteria) participated in these studies. The prolactin response to fenfluramine (a measure of serotonin function) was obtained for 110 subjects; growth hormone response to clonidine (a measure of noradrenergic function) was obtained for 77 subjects, while homovanillic acid (HVA) at baseline, an index of dopaminergic function, was available for 103 subjects. Measures of central neurotransmitter function (dopaminergic, serotonergic, and noradrenergic: HVA, 5-hydroxyindolacetic acid, and 3-methoxy-4-hydroxyphenylglycol, respectively) were available for 36 subjects. Separate regression analyses utilizing each of the hypothesized associations, where the TPQ total scores were used as the dependent measures and the biologic indices were the independent measures were conducted. Exploratory correlational analyses between these biologic measures and the four dimensions of the TPQ (and its subscales) were also conducted. (Correlations are reported if they would remain significant at P<.01 level after Bonferroni correction for multiple comparisons across the six neuroendocrine measures). RESULTS: In the regression analyses, there was a trend association between CSF and plasma HVA in predicting novelty-seeking (P<.07). No other significant associations were found in the other three measures. Regarding the individual correlational analyses, the persistence scale of the TPQ was significantly positively correlated with the growth hormone response to clonidine (r=.30, P<.008). The sentimentality subscale (reward dependence) was positively correlated with CSF 5-hydroxyindolacetic acid (r=0.45, P<.001), while the attachment subscale (also reward dependence) was correlated with CSF 3-methoxy-4-hydroxyphenylglycol (r=0.49, P<.002). CONCLUSION: Limited support was provided for a relationship between monoamines, particularly dopamine and novelty-seeking as well as norepinephrine and reward dependence but other hypothesized relationships were not supported by these measures.

Brain↗
PubMed2003

Abuse and neglect in childhood: relationship to personality disorder diagnoses.

BACKGROUND: Childhood history of abuse and neglect has been associated with personality disorders and has been observed in subjects with lifetime histories of suicidality and self-injury. Most of these findings have been generated from inpatient clinical samples. METHODS: This study evaluated self-rated indices of sustained childhood abuse and neglect in an outpatient sample of well-characterized personality disorder subjects (n=182) to determine the relative associations of childhood trauma indices to specific personality disorder diagnoses or clusters and to lifetime history of suicide attempts or gestures. Subjects met criteria for ~2.5 Axis II diagnoses and 24% reported past suicide attempts. The Childhood Trauma Questionnaire was administered to assess five dimensions of childhood trauma exposure (emotional, physical, and sexual abuse, and emotional and physical neglect). Logistic regression was employed to evaluate salient predictors among the trauma measures for each cluster, personality disorder, and history of attempted suicide and self-harm. All analyses controlled for gender distribution. RESULTS: Seventy-eight percent of subjects met dichotomous criteria for some form of childhood trauma; a majority reported emotional abuse and neglect. The dichotomized criterion for global trauma severity was predictive of cluster B, borderline, and antisocial personality disorder diagnoses. Trauma scores were positively associated with cluster A, negatively with cluster C, but were not significantly associated with cluster B diagnoses. Among the specific diagnoses comprising cluster A, paranoid disorder alone was predicted by sexual, physical, and emotional abuse. Within cluster B, only antisocial personality disorder showed significant associations with trauma scores, with specific prediction by sexual and physical abuse. For borderline personality disorder, there were gender interactions for individual predictors, with emotional abuse being the only significant trauma predictor, and only in men. History of suicide gestures was associated with emotional abuse in the entire sample and in women only; self-mutilatory behavior was associated with emotional abuse in men. CONCLUSION: These results suggest that childhood emotional abuse and neglect are broadly represented among personality disorders, and associated with indices of clinical severity among patients with borderline personality disorder. Childhood sexual and physical abuse are highlighted as predictors of both paranoid and antisocial personality disorders. These results help qualify prior observations of the association of childhood sexual abuse with borderline personality disorder.

Adult↗
PubMed2003

The role of childhood trauma in differences in affective instability in those with personality disorders.

BACKGROUND: This study examined the relationship of self-reported histories of childhood trauma to measures of affective instability in a sample of unmedicated outpatients with various personality disorders (n=174). METHODS: Childhood trauma was measured by the Childhood Trauma Questionnaire. Affective instability comprises at least two dimensions: affective lability, assessed using the Affective Lability Scale, and affective intensity, assessed using the Affective Intensity Measure. RESULTS: A history of emotional abuse was the only trauma variable that significantly correlated with the affect measures in the total sample (r=.21-.30). More fine-grained analyses revealed that the relationship of emotional abuse and affective instability measures varied as a function of both gender and personality disorder type. In subjects with borderline personality disorder, the correlation for emotional abuse was greatly attenuated for both Affective Lability Scale (r=.10) and Affective Intensity Measure (r=.15) total scores. CONCLUSION: This suggests that nontrauma-related factors may be more predominant in affective dyscontrol in individuals with borderline personality disorder.

Adolescent↗
PubMed2003

RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia.

Serotonin 2C receptor (5-HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5-HT2CR mRNA undergoes adenosine-to-inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5-HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5-HT2CR-tr) which encodes a non-functional serotonin receptor. 5-HT2CR mRNA editing efficiencies and the expression of the full-length and the truncated 5-HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5-HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5-HT2CR and 5-HT2CR-tr mRNA variants revealed that the expression of 5-HT2CR-tr was approximately 50% of that observed for the full-length isoform.

Adenosine↗
PubMed2003

Reduced processing resource availability in schizotypal personality disorder: evidence from a dual-task CPT study.

Performance on a dual-task information processing task was investigated in 23 schizotypal personality disorder patients (SPD), 29 patients with other noncluster A personality disorders (OPD) and 8 non-psychiatric healthy controls (NC). All participants were assessed using a computer-based visual continuous performance test (CPT) and an auditory CPT individually, and administered again simultaneously in a dual-task condition. The SPD group showed a greater increase in the number of errors of omission than the OPD group or normal controls on the CPT tasks in the dual-task conditions. Performance operating characteristics indicated that the SPD patients did not allocate their attention in a manner different from the healthy controls, suggesting that poorer performance was due to resource limitations in the dual task condition and not strategic failures. These results are similar to previous studies of patients with schizophrenia, where performance deficits on information processing tests have been shown to be related to resource limitations more than failures in effective allocation of attention.

Acoustic Stimulation↗
PubMed2003

Growth hormone response to guanfacine in boys with attention deficit hyperactivity disorder: a preliminary study.

OBJECTIVE: This preliminary study evaluated a method for assessing central noradrenergic function in children via the growth hormone response to a single dose of the alpha-2 adrenergic receptor agonist guanfacine and examined whether this measure distinguishes between attention deficit hyperactivity disorder (ADHD) boys with and without reading disabilities (RD). METHODS: Plasma growth hormone was assessed before and after the oral administration of guanfacine and placebo in boys with ADHD who were divided into subgroups based on the presence (n = 3) or absence (n = 5) of RD. RESULTS: Guanfacine and placebo conditions did not differ at baseline, but peak growth hormone was significantly higher following guanfacine. The increase in growth hormone following guanfacine was significantly greater in boys without RD as compared to those with RD, with no overlap between the groups. CONCLUSIONS: Consistent with findings using peripheral measures of noradrenergic function, these preliminary data suggest that ADHD boys with and without RD may differ in central noradrenergic function.

Adrenergic alpha-Agonists↗
PubMed2003

The relationship of borderline personality disorder to posttraumatic stress disorder and traumatic events.

OBJECTIVE: The authors examined the relationship of borderline personality disorder to posttraumatic stress disorder (PTSD) with respect to the role of trauma and its timing. METHOD: The Trauma History Questionnaire and the PTSD module of the Structured Clinical Interview for DSM-III-R were administered to 180 male and female outpatients with a diagnosis of one or more DSM-III-R personality disorders. Path analysis was used to evaluate the relationship between borderline personality disorder and PTSD. RESULTS: High rates of early and lifetime trauma were found for the subject group as a whole. Compared to subjects without borderline personality disorder, subjects with borderline personality disorder had significantly higher rates of childhood/adolescent physical abuse (52.8% versus 34.3%) and were twice as likely to develop PTSD. In the path analysis of the relationship between borderline personality disorder and PTSD, none of the different types of paths (direct path, indirect paths through adulthood traumas, paths sharing the antecedent of childhood abuse) was significant. The associations with both trauma and PTSD were not unique to borderline personality disorder; paranoid personality disorder subjects had an even higher rate of comorbid PTSD than subjects without paranoid personality disorder, as well as elevated rates of physical abuse and assault in childhood/adolescence and adulthood. CONCLUSIONS: The associations of personality disorder with early trauma and PTSD were evident, but modest, in borderline personality disorder and were not unique to this type of personality disorder. The results do not appear substantial or distinct enough to support singling out borderline personality disorder from the other personality disorders as a trauma-spectrum disorder or variant of PTSD.

Adolescent↗
PubMed2003

Deficient attentional modulation of the startle response in patients with schizotypal personality disorder.

OBJECTIVE: Attentional deficits have been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. The purpose of this study was to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated subjects with schizotypal personality disorder. METHOD: Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed in an acoustic attention-to-prepulse paradigm. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval. RESULTS: The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response. In contrast, the subjects with schizotypal personality disorder failed to show this pattern. CONCLUSIONS: Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.

Acoustic Stimulation↗
PubMed2003

Risperidone in the treatment of schizotypal personality disorder.

OBJECTIVE: Schizotypal personality disorder (SPD) has many phenomenological, genetic, physiologic, and neuroanatomical commonalities with schizophrenia. Patients with the disorder often suffer from marked social and occupational impairment, yet they have been difficult to treat with medications because of their unusual sensitivity to side effects. This study was designed to determine whether low-dose risperidone treatment is acceptable to SPD patients and can reduce characteristic schizotypal symptoms. In addition, if SPD patients respond to an antipsychotic medication, this will provide support for the notion of a commonality in treatment response between SPD and schizophrenia. METHOD: Twenty-five patients with DSM-IV-defined SPD were entered into a 9-week randomized, double-blind, placebo-controlled study of low-dose risperidone (starting dose of 0.25 mg/day, titrated upward to 2 mg/day) in the treatment of SPD. Patients were rated with the Positive and Negative Syndrome Scale (PANSS), the Schizotypal Personality Disorder Questionnaire, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions scale. Data were collected from 1995 to 2001. RESULTS: The subjects had a low incidence of depression and of comorbid borderline personality disorder. Patients receiving active medication had significantly (p <.05) lower scores on the PANSS negative and general symptom scales by week 3 and on the PANSS positive symptom scale by week 7 compared with patients receiving placebo. Side effects were generally well tolerated, and there was no group difference in dropout rate for side effects. CONCLUSION: Low-dose risperidone appears to be effective in reducing symptom severity in SPD and is generally well tolerated.

Adolescent↗
PubMed2002

Neuropsychological performance in schizotypal personality disorder: evidence regarding diagnostic specificity.

BACKGROUND: Individuals with schizotypal personality disorder (SPD) share cognitive deficits with schizophrenic patients, suggesting that these deficits represent a core feature of the schizophrenia spectrum. We investigated the neuropsychological profile in SPD patients compared with two comparison groups: healthy volunteers (HV) and patients who met criteria for another non-schizophrenia spectrum personality disorder (NSS). METHODS: We tested 48 DSM-III-R SPD patients, 22 NSS and 32 HV on a neuropsychologic battery that included the California Verbal Learning Test (CVLT), Trail Making A and B, the DOT test of working memory, the Stroop Color-Word Interference, the Paced Auditory Serial Addition Test (PASAT), the Wechsler Memory Scale Visual Reproduction Test (WMSV-R), and the Wechsler Adult Intelligence Scale vocabulary and block design. RESULTS: Normative standards for performance were created using the HV group. SPD patients performed significantly worse compared with HVs; specifically, SPD patients demonstrated impaired performance on the PASAT and the WMSV-R immediate and delayed recall compared to HV. Moreover, SPD patients were impaired in the PASAT and the WMSV-R immediate condition compared with the NSS group. The NSS patients did not differ from HV on any of the cognitive tasks. The interpersonal factor of the schizotypal symptoms inversely correlated with the PASAT score (r = -.32, p <.006). CONCLUSIONS: Compared with HVs, SPD patients demonstrate modest cognitive impairment. These differences reached statistical significance for the PASAT (an auditory working memory task), and the WMSV-R immediate and delayed recall (a learning-recall test). In contrast, performance of NSS patients did not differ from that of HVs. The types of deficits observed in SPD patients are qualitatively similar to but milder than those seen in patients with schizophrenia.

Adult↗
PubMed2002

The borderline diagnosis I: psychopathology, comorbidity, and personality structure.

Borderline personality disorder (BPD) is a complex and serious mental disorder associated with severe functional impairment, substantial treatment utilization, and a high rate of mortality by suicide. Recently, BPD has become a focus of intensifying study. In Part I of this three-part article meant to provide a foundation to researchers on the current status of the borderline diagnosis and prospects for its future development, we examine the psychopathology, comorbidity, and personality structure of BPD. Although the descriptive characteristics of BPD are well-represented by DSM-IV diagnostic criteria, other important aspects of BPD psychopathology are not included. The descriptive criteria in conjunction with semistructured interviews have, however, increased the ability of investigators to diagnose BPD as reliably as many Axis I disorders. Frequent comorbidity of BPD with Axis I disorders necessitates a broad assessment of psychopathology to help account for clinical heterogeneity. Because of the absence of evidence of the validity of the diagnostic threshold for a categorical diagnosis of BPD, and because of the heterogeneity within the diagnosis, investigators should also supplement their DSM-IV diagnoses with assessments of underlying personality trait structures. Although there are a number of competing models of personality structure, they have remarkable convergence on a set of three to five basic personality dimensions.

Borderline Personality Disorder↗