Neuroimaging predictors of response to cognitive remediation and social skills training: A pilot study in veterans with schizophrenia.

Neuroimaging may predict response to cognitive remediation therapy and social skills training (CRT + SST) in schizophrenia. Identifying biological predictors of response is crucial for treatment decision making given not all patients respond to such interventions. Nineteen veterans with schizophrenia enrolled in an 8-week trial of CRT + SST. Ten participants completed diffusion tensor imaging (DTI) at baseline. Baseline fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) and overall average FA predicted improvements in visual-spatial working memory, and social cognition, respectively. Neuroimaging may be useful in identifying therapeutic targets in schizophrenia.

Guanfacine Augmentation of a Combined Intervention of Computerized Cognitive Remediation Therapy and Social Skills Training for Schizotypal Personality Disorder.

OBJECTIVE: Impaired cognition is a hallmark of schizophrenia spectrum disorders, including schizotypal personality disorder, and it is the best predictor of functional outcome. Cognitive remediation therapy has demonstrated efficacy for improving cognition, augmenting other rehabilitation efforts in schizophrenia, and effecting gains in real-world functioning. Pharmacological augmentation of cognitive remediation has been attempted, but the effects of augmentation on combined therapies, such as cognitive remediation and social skills training, have not been studied. METHODS: Twenty-eight participants with schizotypal personality disorder enrolled in an 8-week, randomized, double-blind, placebo-controlled trial of guanfacine plus cognitive remediation and social skills training (15 guanfacine, 13 placebo). Cognition was assessed with the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB), social cognition with the Movie for the Assessment of Social Cognition (MASC), and functional capacity with the University of California San Diego Performance-Based Skills Assessment (UPSA). RESULTS: A statistically significant pre- versus posttreatment effect was observed for MCCB speed of processing, verbal learning, and visual learning and UPSA total score. A significant time-by-medication (guanfacine, placebo) interaction was observed for MCCB reasoning and problem solving and UPSA total score; the time-by-treatment interaction approached significance for MASC hypomentalizing errors. CONCLUSIONS: Both guanfacine and cognitive remediation plus social skills training were well tolerated, with no side effects or dropouts. Participants treated with cognitive remediation, social skills training, and guanfacine demonstrated statistically significant improvements in reasoning and problem solving, as well as in functional capacity and possibly social cognition, compared with those treated with cognitive remediation, social skills training, and placebo. Cognitive remediation plus social skills training may be an appropriate intervention for individuals with schizotypal personality disorder, and guanfacine appears to be a promising pharmaceutical augmentation to this psychosocial intervention.

A Randomized Trial of Dialectical Behavior Therapy in High-Risk Suicidal Veterans.

OBJECTIVE: Despite advances in suicide prevention implemented throughout the US Department of Veterans Affairs (VA) including the hiring of Suicide Prevention Coordinators (SPCs) at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services, suicide by veterans remains a critical problem affecting 20 veterans daily. Few empirically based treatment strategies for suicide prevention for postdeployment military personnel exist. This study aimed to test whether dialectical behavior therapy (DBT), one of the few psychosocial treatments with proven efficacy in diminishing suicidal behavior in individuals with personality disorder, can be applied to veterans irrespective of personality diagnosis. METHODS: From January 2010 to December 2014, 91 nonpsychotic veterans at high risk for suicide (61 men, 30 women) were randomly assigned to a 6-month treatment trial at a veterans' medical center comparing standard DBT to treatment as usual (TAU) and followed for 6 months after trial completion. Primary outcome was suicide attempts, measured with the Columbia-Suicide Severity Rating Scale, and secondary outcomes were suicide ideation, depression, hopelessness, and anxiety. There were no exclusions pertaining to substance abuse, homelessness, or medical comorbidity. RESULTS: Both DBT and TAU resulted in improvements in suicidal ideation, depression, and anxiety during the course of the 6-month treatment trial that did not differ between treatment arms. Survival analyses for suicide attempts and hospitalizations did not differ between treatment arms. However, DBT subjects utilized significantly more individual mental health services than TAU subjects (28.5 ± 19.6 vs 14.7 ± 10.9, F1,77 = 11.60, P = .001). CONCLUSIONS: This study is the first to examine 6-month DBT in a mostly male, veteran population. Increased mental health treatment service delivery, which included enhanced monitoring, outreach, and availability of a designated SPC, did not yield statistically significant differences in outcome for veterans at risk for suicide in TAU as compared to the DBT treatment arm. However, both treatments had difficulty with initial engagement post-hospitalization. Future studies examining possible sex differences and strategies to boost retention in difficult-to-engage, homeless, and substance-abusing populations are indicated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02462694.

Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder.

OBJECTIVE: Siever and Davis' (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT. METHODS: Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale. RESULTS: fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale). CONCLUSION: These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity-part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation.

The Neurobiological Basis of Adolescent-onset Borderline Personality Disorder.

OBJECTIVE: Over the past two decades, neurobiological studies in adult onset borderline personality disorder have made important strides, but inquiry into adolescent-onset BPD is still in its infancy and our understanding of the neurobiology of adolescent BPD remains highly tentative. METHODS: This paper highlights recent findings in genetics, neuroendocrinology and neuroimaging for adult and adolescent-onset BPD. RESULTS: Neurobiological studies of adolescent-onset BPD to date have focused mainly on volumetric studies of various brain regions and measurements of HPA axis components, with comparatively few publications on brain functioning. CONCLUSION: Such information is essential to developing more effective screening, treatment and preventive strategies.

OBJECTIF: Au cours des vingt dernières années, les études neurobiologiques du trouble de la personnalité limite (TPL) apparu à l'âge adulte ont fait de grands progrès, mais l'étude de l'apparition de la TPL à l'adolescence en est encore à ses premiers pas, et notre compréhension de la neurobiologie du TPL adolescent demeure très provisoire. MÉTHODES: Cet article présente les résultats récents de la génétique, de la neuroendocrinologie et de la neuroimagerie pour le TPL apparu à l'âge adulte et à l'adolescence. RÉSULTATS: Les études neurobiologiques du TPL apparu à l'adolescence ont porté jusqu'ici surtout sur les études volumétriques des diverses régions cérébrales et sur des mesures des composantes de l'axe hypothalamo-hypophyso-surrénalien, et n'ont donné lieu comparativement qu'à peu de publications sur le fonctionnement du cerveau. Conclusion: Cette information est essentielle au développement de stratégies efficaces de dépistage, de traitement et de prévention.

Developmental trajectories to male borderline personality disorder.

Due to the higher diagnostic prevalence of borderline personality disorder (BPD) in females, there exists a dearth of literature on the manifestations of BPD in men and minimal information on male developmental trajectories to the disorder. To identify precursors of BPD in males, surveys were administered to parents about their BPD male offspring and non-BPD male siblings. Questions covered aspects of probands' lives from infancy to late adolescence. BPD offspring were identified through self-reported clinical diagnoses and standardized diagnostic criteria embedded within the survey. A total of 263 male offspring (97 meeting strict criteria for BPD and 166 non-BPD siblings) were studied. The authors found that parents describe the early emergence of a constellation of symptoms in their BPD sons that include separation anxiety starting in infancy, body image concerns in childhood, and impulsivity, emptiness, and odd thinking in adolescence. This trajectory differs from the developmental course found in females diagnosed with BPD.

Paranoid personality disorder.

Paranoid personality disorder (PPD) is currently included in DSM-IV's "odd cluster" or "cluster A." In the present article, the authors review available information pertaining to the psychometric properties of PPD, as derived from the relevant literature and from databases of personality disorder study groups. There is comparatively little published evidence for the reliability and validity of PPD, and researchers by and large have tended not to study the disorder, either because of investigators' difficulty recruiting individuals with PPD into research studies, or (as seems more likely) because the trait-paranoia from which many psychiatric patients suffer has seemed better explained by other DSM-IV disorders on Axis I and/or Axis II than by PPD. Given the scant empirical evidence on PPD, it seems reasonable to remove it as an independent diagnosis from the next edition of DSM, and instead to encourage clinicians to code trait-paranoia using a dimensional approach.

Schizotypal personality disorder.

Early phenomenological descriptions of schizophrenia have acknowledged the existence of milder schizophrenia spectrum disorders characterized by the presence of attenuated symptoms typically present in chronic schizophrenia. The investigation of the schizophrenia spectrum disorders offers an opportunity to elucidate the pathophysiological mechanisms giving rise to schizophrenia. Differences and similarities between subjects with schizotypal personality disorder (SPD), the prototypical schizophrenia personality disorder, and chronic schizophrenia have been investigated with genetic, neurochemical, imaging, and pharmacological techniques. Patients with SPD and the more severely ill patients with chronic schizophrenia share cognitive, social, and attentional deficits hypothesized to result from common neurodevelopmentally based cortical temporal and prefrontal pathology. However, these deficits are milder in SPD patients due to their capacity to recruit other related brain regions to compensate for dysfunctional areas. Individuals with SPD are also less vulnerable to psychosis due to the presence of protective factors mitigating subcortical DA hyperactivity. Given the documented close relationship to other schizophrenic disorders, SPD will be included in the psychosis section of DSM-5 as a schizophrenia spectrum disorder as well as in the personality disorder section.

Schizoid personality disorder.

Schizoid personality disorder (ScPD) is one of the "odd cluster" or "cluster A" personality disorders in DSM-IV. In the present article, the authors review information pertaining to the psychometric characteristics of ScPD as gleaned from a search of relevant publications as well as from databases of personality disorder study groups. Comparatively little evidence exists for the validity and reliability of ScPD as a separate, multifaceted personality disorder. Some authors, moreover, have contended that the group of patients termed "schizoid" actually fall into two distinct groups--an "affect constricted" group, who might better be subsumed within schizotypal personality disorder, and a "seclusive" group, who might better be subsumed within avoidant personality disorder. The research-based justification for retaining ScPD as an independent diagnosis is sufficiently sparse for it to seem reasonable to remove ScPD from the list of personality disorders in DSM-V, and instead to invite clinicians to code for schizoid traits using a dimensional model.

Evidence-based pharmacotherapy for personality disorders.

Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost any other diagnostic group. Prescribing practices in these populations are often based on anecdotal evidence rather than rigorous data. Although evidence-based psychotherapy remains an integral part of treatment, Axis II psychopathology is increasingly conceptualized according to neurobiological substrates that correspond to specific psychopharmacological strategies. We summarize the best available evidence regarding medication treatment of personality disordered patients and provide optimal strategies for evidence-based practice. Most available evidence is concentrated around borderline and schizotypal personality disorders, with some additional evidence concerning the treatment of avoidant and antisocial personality disorders. Although maladaptive personality symptoms respond to antidepressants, antipsychotics, mood stabilizers, and other medications, evidence-based pharmacotherapy is most useful in treating circumscribed symptom domains and induces only partial improvement. Most available evidence supports use of medication in reducing impulsivity and aggression, characteristic of borderline and antisocial psychopathology. Efforts have also begun to reduce psychotic-like symptoms and improve cognitive deficits characteristic of schizotypy. Indirect evidence is also provided for psychopharmacological reduction of social anxiety central to avoidant personality disorder. Evidence-based practice requires attention to domains of expected clinical improvement associated with a medication, relative to the potential risks. The development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings of personality disorders and their component dimensions. Increasing efforts to translate personality theory and social cognitive neuroscience into increasingly specific neurobiological substrates may provide more effective targets for pharmacotherapy.

Parental burden associated with borderline personality disorder in female offspring.

To identify aspects of parental burden associated with borderline personality disorder (BPD), an anonymous internet survey linked to BPD support websites was developed for parents to complete on their BPD offspring and unaffected siblings. The questions cover aspects of the child's life from pregnancy through young adulthood, and query about the impact of the child's BPD on six domains of the parent's life, including physical and emotional health, marriage, job, standard of living, social life, and career trajectory. Additionally, financial burden was assessed with questions pertaining to insurance and out-of pocket costs associated with the BPD disorder. BPD offspring were identified by meeting diagnostic criteria embedded within the survey and having been given a diagnosis of BPD by a professional at some point in their life. We report on 233 female offspring meeting strict criteria for BPD. Parents of daughters with BPD endorsed varying levels of impact on the six domains comprising burden with the largest impact on emotional health which was impacted in over 88% of the respondents. Over 50% of parents endorsed four or greater of the six burden items. Particular aspects of the offspring's BPD symptom profile correlated with intensity of parental burden included including problems in adolescence with acting out behavior (p < .000), property destruction (.003), delusional symptoms (.007), and hallucinatory symptoms (.008). A subgroup of respondents provided data on specific financial expenses. The average and median out-of-pocket expense was $60,087, and $10,000. Insurance costs totaled an average of $108,251 with a mean of $20,000. The average cost per year after diagnosis was $14,606 out-of-pocket and $45,573 billed to insurance. The median cost per year after diagnosis was $3,667 out-of-pocket, and $12,500 billed to insurance. After adjusting for household income, a female proband who had been raped incurred roughly $40,000 more in BPD-related costs, while a diagnosis of conduct disorder led to about $50,000 in additional costs. Parents of female offspring with BPD experience burden in multiple domains of their life and many have incurred substantial financial expense. Increasing awareness of co-morbid conditions in the BPD proband that significantly increase parental burden may be indicators for the provision of increased family support.

Treatment utilization by gender in patients with borderline personality disorder.

Minimal data exist on treatment utilization by gender in borderline personality disorder (BPD). This study used an online questionnaire to investigate initial and lifetime patterns of utilization of multiple treatment modalities by patients with BPD, and parental satisfaction with treatment. Respondents were parents of probands diagnosed with BPD who completed a 100-question anonymous Internet survey. Of the 495 surveys that were analyzed, 409 pertained to female subjects with BPD and 86 to male subjects with BPD. Results for probands with BPD across gender were notable for similar high lifetime levels of use of care, including hospitalization, day programs, and halfway houses, but not similar levels of use of drug/alcohol rehabilitation services, which was greater among the male subjects with BPD. The male subjects with BPD received significantly less lifetime psychotherapy and pharmacotherapy than the female subjects with BPD, although the duration of medication and psychotherapy treatment did not differ by gender. These results highlight the need for more research to better understand what might account for these gender differences in treatment and improve strategies to provide appropriate care for male patients with BPD.

Parental viewpoints of trajectories to borderline personality disorder in female offspring.

To characterize precursors and trajectories in the development of borderline personality disorder (BPD), anonymous internet surveys were administered to parents about their BPD offspring and non-BPD siblings. Questions covered aspects of probands' lives from pregnancy through young adulthood. BPD offspring were identified through both lifetime clinical diagnoses and diagnostic criteria embedded within the survey. We report on 234 female offspring meeting strict criteria for BPD, and 87 non-BPD female siblings. Parents of daughters with BPD describe the presence of affective symptomatology starting in infancy, including significant differences from non-BPD probands in moodiness. These affective symptoms persist after infancy, and are joined by interpersonal difficulties that manifest themselves in toddlerhood and childhood. By adolescence, difficulties with impulsivity, aggression, acting out, and self-destructive behaviors dominate the profile.

Phenotype, endophenotype, and genotype comparisons between borderline personality disorder and major depressive disorder.

Borderline personality disorders (BPD) and major depressive disorder (MDD) are distinct disorders with overlapping biological processes pertaining to emotional regulatory functions. However, while both disorders share affective symptomatology, the disturbance central to BPD is affective lability and its character is entirely different from the affective disturbance of MDD. This review highlights data from the last ten years and compares the two disorders' phenotypes, putative endophenotypes and genotypes, focusing heavily on neuroimaging findings. The familiality and phenotypic differences suggest that BPD differs in important ways with respect to symptomatology, prognosis, and heritability. The neurobiological findings in both MDD and BPD are still preliminary at present, and no coherent model for either disorder can be said to have emerged. Overlapping biological processes including amygdala hyperreactivity, volume changes in subgenual anterior cingulate cortex, and deficient serotonergic function appear to underlie emotional dysregulation in both disorders. However, the disorders seem to differ in their patterns of brain region involvement, neurohormonal indices, and sleep architecture. At present, the minimal data available for putative genotypes of BPD is still emerging, nonspecific to the disorder and demonstrates significant overlap with MDD. The ability to discern commonalities and differences in the neurobiology of these two disorders is limited by the differing methodologies applied in different studies. Definitive clarification of what MDD and BPD have in common and in what ways they are distinct will only be derived from studies that examine both illnesses using the same study design and methodology.

Pergolide treatment of cognitive deficits associated with schizotypal personality disorder: continued evidence of the importance of the dopamine system in the schizophrenia spectrum.

Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D(1) and D(2) receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.

Laboratory induced aggression: a positron emission tomography study of aggressive individuals with borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is often associated with symptoms of impulsive aggression, which poses a threat to patients themselves and to others. Preclinical studies show that orbital frontal cortex (OFC) plays a role in regulating impulsive aggression. Prior work has found OFC dysfunction in BPD. METHODS: We employed a task to provoke aggressive behavior, the Point Subtraction Aggression Paradigm (PSAP), which has never previously been used during functional brain imaging. Thirty-eight BPD patients with intermittent explosive disorder (BPD-IED) and 36 age-matched healthy control subjects (HCs) received (18)fluoro-deoxyglucose positron emission tomography ((18)FDG-PET) on two occasions with a provocation and nonprovocation version of the PSAP. Mean relative glucose metabolism was measured throughout the cortex, and difference scores (provoked - nonprovoked) were calculated. A whole brain exploratory analysis for the double difference of BPD-IED - HC for provoked - nonprovoked was also conducted. RESULTS: BPD-IED patients were significantly more aggressive than HCs on the PSAP. BPD-IED patients also increased relative glucose metabolic rate (rGMR) in OFC and amygdala when provoked, while HCs decreased rGMR in these areas. However, HCs increased rGMR in anterior, medial, and dorsolateral prefrontal regions during provocation more than BPD-IED patients. CONCLUSIONS: Patients responded aggressively and showed heightened rGMR in emotional brain areas, including amygdala and OFC, in response to provocation but not in more dorsal brain regions associated with cognitive control of aggression. In contrast, HCs increased rGMR in dorsal regions of PFC during aggression provocation, brain regions involved in top-down cognitive control of aggression, and, more broadly, of emotion.

Recent advances in the biological study of personality disorders.

While it is premature to provide a simple model for the vulnerability to the development of either borderline (BPD) or schizotypal (SPD) personality disorder, it is clear that these heritable disorders lend themselves to fruitful neurobiological exploration. The most promising findings in BPD suggest that a diminished top-down control of affective responses, which is likely to relate to deceased responsiveness of specific midline regions of prefrontal cortex, may underlie the affective hyperresponsiveness in this disorder. In addition, genetic and neuroendocrine and molecular neuroimaging findings point to a role for serotonin in this affective disinhibition. Clearly SPD falls within the schizophrenia spectrum, but precisely the nature of what predicts full-blown schizophrenia as opposed to the milder symptoms of SPD is not yet clear.

The case for shifting borderline personality disorder to Axis I.

Through reviewing what is known about the nature, course, and heritability of borderline personality disorder (BPD), we argue for a reconceptualization of this disorder that would lead to its placement on Axis I. Borderline personality disorder is a prevalent and disabling condition, and yet the empirical research into its nature and treatment has not been commensurate with the seriousness of the illness. We not only review empirical evidence about the etiology, phenomenology, and course of the disorder in BPD but we also address fundamental misconceptions about BPD that we believe have contributed to misunderstanding and stigmatization of the disease. Finally, we suggest future directions for research that might permit the identification of core features of this disorder, with a focus on the importance of naturalistic assessments and of assessments through the course of development.

The effects of guanfacine on context processing abnormalities in schizotypal personality disorder.

BACKGROUND: The signature of impaired cognition in people with schizotypal personality disorder (SPD) may be centrally related to working memory impairments. Guanfacine, an alpha2A agonist that acts post-synaptically in the prefrontal cortex (PFC), has shown potential for reducing working memory limitations in other populations. This study examined the potential of guanfacine for improving context processing, a feature of working memory, in SPD. METHODS: 29 individuals with SPD entered into a 4-week, randomized parallel-design, double-blind, placebo-controlled trial of guanfacine treatment, followed by a 4-week open-label extension. A modified version of the AX-Continuous Performance Test (AX-CPT) was administered. On this task, evidence of intact context processing includes few BX errors (false cue, correct probe) and higher levels of AY errors (correct cue, false probe). RESULTS: At the end of double-blind treatment, participants treated with guanfacine demonstrated a significant reduction in BX errors and a small but significant increase in AY errors, a pattern that was not seen in the participants treated with placebo. CONCLUSIONS: SPD participants improved in their context processing toward a normal response bias, making fewer BX and more AY errors, after being treated with guanfacine.