Borderline personality disorder (BPD) is a disabling condition with high morbidity and mortality, yet the empirical research into its nature and treatment has not been commensurate with the seriousness of the illness. Despite recent advances in the treatment of BPD, it remains notoriously difficult to treat effectively, with many patients responding poorly even to the most widely accepted treatment strategies (1). In addition, because the disorder has as cardinal symptoms anger and interpersonal disruptiveness, it is often difficult to form a therapeutic alliance with afflicted patients. These features draw attention away from evidence that BPD is a serious mental disorder that deserves much more investigative scrutiny than it has received. A logical consequence of taking this disorder seriously is to consider reclassifying the disorder into Axis I. This reclassification would, we believe, provide a stimulus to new research into the nature and treatment of this severe illness.

Evidence for the Validity of BPD

The validity of the BPD diagnosis remains a question in the minds of many clinicians, and some doubt its existence altogether (2). A widely accepted approach to validating the boundaries of psychiatric disorders is the set of guidelines established by Robins and Guze (1970) (3), which considers accrual of information from five lines of evidence important for establishing the validity of a mental disorder. These criteria include: 1) a careful delineation of symptoms; 2) information about the course of illness; 3) evidence of familial clustering; 4) predictable treatment response, especially to somatic treatments; and 5) biological markers (3,4). We review each of these criteria as it relates to BPD.

Core Symptoms of BPD

A Single Diagnostic Construct?

The current DSM criteria were developed from observations by experienced clinicians, and it remains a question as to whether these criteria cluster into one syndrome or into independent symptom dimensions. A factor analysis of symptoms in a large sample of BPD patients (n 141) revealed three factors: disturbed relatedness (unstable relationships, identity disturbance, and chronic emptiness), behavioral dysregulation (impulsivity and suicidality/self-mutilatory behavior), and affective dysregulation (affective instability, inappropriate anger, and efforts to avoid abandonment) (5). These factors were replicated in the CLPS (Collaborative Longitudinal Personality Disorders Study)—a prospective descriptive study of a large sample (n 668) of patients with personality disorders, including schizotypal, borderline, avoidant, and obsessive-compulsive personality disorders and major depressive disorder (MDD) with no personality disorder (6).

Recent data, however, raise questions about the 3-factor model and instead suggest a single underlying core that leads to the diverse symptoms of BPD. Although Sanislow found that the 3-factor model yielded a better fit with their data than a single-factor model, the factors identified (disturbed relatedness, behavioral dysregulation, and affective dysregulation) were highly intercorrelated (r .90, .94, and .99, respectively), lending support to a single overarching BPD construct. A subsequent factor analysis identified three similar factors but also concluded that the factors were too highly intercorrelated to be considered separate factors (7). Providing even further evidence for BPD as a unified syndrome, a recent large study explored several 1-, 3-, and 4-factor models of DSM-IV BPD criteria and concluded that the BPD criteria describe a single construct rather than multiple co-occurring syndromes (8). Finally, a confirmatory factor analysis of DSM-III-R BPD criteria in a large clinical and non-clinical sample showed that a single factor fit the data best (9). This study also showed that “frantic efforts to avoid abandonment” was the criterion with the highest specificity and positive predictive power. Affective instability was also highly informative as to BPD diagnosis, whereas identity disturbance and feelings of emptiness were less informative. Even though factor analyses lend support to the presence of a unitary latent diagnostic construct, heterogeneity is observed in the clinical presentation of BPD. This might arise out of the fact that different aspects of the disorder might be present at different times, making the disorder appear quite heterogeneous when observed cross-sectionally. This highlights the importance of a developmental approach to characterizing the core features of BPD.

Specificity of BPD.

The high rate of comorbidity with other disorders has also led to skepticism about the validity of the BPD diagnosis. Data from CLPS showed that the Axis I comorbidities most commonly seen with BPD were posttraumatic stress disorder (PTSD) and substance abuse. Although BPD subjects showed a high rate of MDD (79% lifetime), this was not higher than the prevalence of MDD across personality disorders (66%– 82%). The most common Axis II comorbidities of BPD were antisocial and dependent personality disorders (10). Two-year follow-up found a significant association between BPD and MDD as well as PTSD (11).

The high rate of comorbid mood disorders in BPD has led some to argue that BPD is a bipolar spectrum illness. Empirical support for this view comes from a study following BPD patients, which showed a 15% rate of onset of bipolar I or II disorder over 3 years, compared with no new cases in an other personality disorder (OPD) group (2). Other studies, however, have failed to show elevated rates of bipolar diagnoses in BPD (10,12–14). Longitudinal follow-up of the CLPS sample showed modestly increased rates of bipolar I and II disorders in the BPD compared with the OPD group over 4 years (15). Although evidence suggests a moderately increased risk for bipolar disorder in BPD patients, the risk is not nearly as high as for MDD or substance abuse. Furthermore, if BPD were a bipolar spectrum disorder, one would expect BPD to run in families with bipolar disorder, and evidence suggests that this is not the case (16,17). In addition, if BPD were a bipolar spectrum disorder, then treatment with antidepressant drugs should worsen mood instability, as in bipolar disorder, whereas antidepressant drugs stabilize mood in BPD (18). Taken together, these data support some increased risk for bipolar disorder in BPD but also a heightened risk for other disorders. From a clinical vantage point, BPD is not most fruitfully viewed as a bipolar variant, because the prognosis and treatment recommendations differ substantially. However, the substantial phenotypic resemblance as well as the common comorbidity raise the possibility that BPD might be viewed as an affective spectrum illness as has been previously suggested (4); however, it seems to fit squarely in neither the unipolar nor bipolar group (Supplement 1).

Course/Prognosis

Borderline personality disorder is present in approximately 2% of the general population, making it as prevalent as schizophrenia and bipolar I disorder (19,20). Borderline personality disorder is heavily represented in clinical populations (21), and patients with BPD require extensive mental health services (22–25). The completed suicide rate in BPD approaches 10%, and at least 75% of afflicted individuals attempt suicide at least once (26). Borderline personality disorder is strongly associated with elevated risk of medical emergency room visits (24) and generalized occupational and psychosocial dysfunction (27).

Although BPD is associated with severe symptoms and functional impairment, the prognosis is not as unfavorable as had been previously assumed. Large longitudinal studies have shown that many BPD patients experience improvement and even resolution of borderline features over time, although a subset of patients experience long-term disability (28,29). Specifically, 88% of a sample of patients with BPD achieved remission over 10 years, with approximately one-third of those achieving remission in the first 2 years. Of note, remission in this sample was defined as not meeting the threshold for a full BPD diagnosis (30), but subjects might have continued to be symptomatic. Symptoms of affective instability seem to be the most consistent over time, enduring in many cases over 27 years (28,31).

Heritability and Familiality

Although limited in number, family studies of BPD show that the first-degree relatives of BPD probands are 10 times more likely to have been treated for BPD and significantly more likely to have been treated for MDD than the first-degree relatives of schizophrenia probands (32). Subsequent family studies of BPD showed that affective instability and impulsivity as well as BPD diagnosis itself were significantly more common in first-degree relatives of BPD patients than of OPD or schizophrenia patients (17,33). In addition, MDD appeared more often in the relatives of BPD than of OPD patients, regardless of whether the BPD proband had a history of MDD (17). To tease apart the transmission of BPD from that of MDD, a study examined BPD outpatients with no history of MDD and demonstrated an increased risk for depression in the first-degree relatives, suggesting a common etiologic factor linking the two disorders (34). 

Family studies indirectly reflect genetic heritability; however, only twin studies provide definitive evidence for it. Limited twin study data are available for BPD. One such study examining 92 monozygotic twins and 129 dizygotic twins showed that BPD was substantially heritable, with 69% of the variance in BPD accounted for by genetic factors (35). A recent study of Chinese twins showed similar heritability rates for cluster B personality disorders of 65%; however, BPD was not independently assessed (36). In a study of twin pairs in childhood, parents assessed personality disorder features in their monozygotic and dizygotic twins and demonstrated that 76% of the variance in BPD features seems to be genetic (37). Although the number of studies showing heritability for BPD are few, all such studies undertaken show substantial heritability.

Predictability of Treatment Response

We have reviewed evidence for the validity of BPD that meets the first three criteria for diagnostic validity: a delineation of symptoms; information about the course of BPD; and evidence of familial clustering. A feature that does set BPD apart from other mental illnesses is the absence of a predictable, robust response to somatic treatments. This is problematic not only because it leaves patients without the benefit of highly effective pharmacotherapy but also because psychiatrists often use information from pharmacologic treatment response as an avenue of investigation into the neurobiology of mental illnesses. The fact that depression, for example, responds to antidepressant drugs gave rise to the monoamine hypothesis of depression. The fact that conventional antipsychotic drugs block D2 receptors gave rise to the dopamine hypothesis of schizophrenia. Evidence for the importance of cellular signaling pathways in bipolar disease came out of exploration of the mechanism of action of lithium and other mood stabilizers. The contrasting reality that BPD patients seem to respond to medications in a circumscribed and often transient manner, combined with the fact that the agents that have proven somewhat helpful come from almost all known psychotropic drug classes, has meant that a unifying theory of the biological underpinnings of BPD has not yet emerged. Much more needs to be learned about the neurobiology of BPD to permit the development of treatments specific to this disorder.

Although the modest efficacy and wide diversity of medication classes used in BPD present clinical and theoretical challenges, we believe that a feature of the disorder itself, the fluctuating symptoms of BPD, also contributes to the difficulty in defining highly effective pharmacotherapy for BPD. It might be that the widely used techniques in medication trials to assess treatment response— brief cross-sectional assessments of an individual in a clinical research office—might not be optimal to detect response in BPD. Because the symptoms of BPD fluctuate dramatically and flare up especially in the context of close relationships, cross-sectional assessments might be inadequate to detect a response to treatment with any sensitivity or specificity. 2 BIOL PSYCHIATRY 2008;xx:xxx A.S. New et al. www.sobp.org/journal ARTICLE IN PRESS To a greater degree than other psychiatric populations, BPD patients might seem asymptomatic or highly symptomatic at the particular moment, depending on an immediate antecedent interpersonal interaction or on the relationship developed with the specific staff member assessing them. A better approach would be to assess patients across multiple situations, such that both average levels of symptoms and variability in symptoms over time can be measured. Methods for ecological momentary assessment of symptoms are becoming more readily available, including event-contingent recording methods (38), in which patients report on their behavior and mood in relation to specific social interactions over time. This method allows for the documentation of the naturalistic contexts in which symptoms arise and might provide a more clinically relevant assessment of treatment response. A recent study using event-contingent recording in BPD patients proved its feasibility in this population (39).

Biological Markers

Although there are no clear neurobiological markers for BPD, the absence of such markers is a ubiquitous concern across all psychiatric diagnoses. In BPD, as in other psychiatric disorders, findings from brain imaging studies, neurochemical markers, and genetic studies do not point to a simple pathophysiology. The body of research on neurobiological abnormalities in BPD has been thoroughly reviewed elsewhere (40,41). Briefly, studies employing a variety of methods have found widely replicated decreases in serotonergic responsiveness in BPD (42– 45). These findings have informed neuroimaging research in BPD, in which a predominance of studies have employed pharmacologic probes of serotonin (46 –50) or positron emission tomography ligands targeting serotonin receptors (51,52). A limitation of these findings is that abnormalities have tended to relate less to the overarching diagnosis than to symptoms dimensions (53). Another limitation is that the scope of neurochemical systems studied is narrow, focusing almost exclusively on serotonin. An extremely limited number of studies have explored other neurotransmitter systems in BPD, including dopamine (54) and acetylcholine (55).

Brain imaging studies have provided evidence for disruption of the neural circuitry in BPD (reviewed elsewhere [56]). However, two relatively consistent findings from brain imaging studies emerge: 1) BPD patients seem to have decreased volume in anterior cingulate gyrus (ACG), especially of gray matter, compared with healthy control subjects (57–59); 2) positron emission tomography studies have shown that orbital frontal cortex (OFC) and ACG are less active in BPD than control subjects (46 – 49,60). Functional magnetic resonance imaging (fMRI) studies have shown this less consistently (61– 63), although the orbital floor is evaluated less effectively with fMRI, because of susceptibility artifact. Thus, brain regions, such as OFC and ACG, that normally put the brakes on expressions of emotions, might fail to come “on line” in BPD when needed. Although brain imaging findings in BPD are suggestive, it is important to note that many of the circuits implicated in BPD are the same as those implicated in MDD and bipolar disorder (64,65). For example, decreased subgenual ACG has been shown in depression (66 – 68) and in some studies of bipolar disorder (69,70). In addition, functional imaging studies have shown decreased activation in areas of prefrontal cortex in MDD (71), bipolar disorder (72), and PTSD (73). Clearly, new approaches in brain imaging will be needed to develop specific neural circuitry models for each of these disorders.

To move forward in understanding BPD specifically, it will be necessary to target those symptoms that are specific to BPD. Although affective dysregulation is a core feature of BPD (27,53,74) and might be the most prevalent and enduring symptom (75), it is also seen in bipolar disorder and to some degree in MDD. Too little attention has been paid to the interpersonal disruptions that are central to BPD. A recent review has argued that the relational style characteristic of BPD is “intense and unstable, marked . . . by abandonment fears and by vacillating between idealization and devaluation (and that this style offers) the best discriminators for the diagnosis” of BPD (76). Evidence for this view stems from consistent observation of profound interpersonal impairment in BPD (9,27,77), with more impairment in interpersonal functioning in BPD than in MDD, obsessive-compulsive disorder or OPDs (78). Furthermore, suicide attempts in BPD are more often associated with interpersonal stressors than suicide attempts in MDD (79).

Notwithstanding the centrality of interpersonal disruptions in BPD, very little empirical work has been done on what underlies these symptoms. One domain that has received some empirical scrutiny is the recognition of facial emotional expression. Borderline personality disorder patients correctly identify emotional expressions even more sensitively than healthy control subjects; however, they tend to over-read anger in neutral faces (80 – 83). More research into emotional information processing in BPD would be very helpful, because these skills are essential for navigating interpersonal relationships. If BPD patients over-read and misread emotional cues, this might help to explain the puzzling symptom of exaggerated emotional responses in interpersonal interactions. If indeed BPD patients over-read emotional responses and this deficit is present from early childhood, this might play a role not only in the disrupted interpersonal relationships but also, possibly, in the development of emotion dysregulation. Infants and children learn how to modulate emotions through relationships with caregivers (84), and individuals who continuously misread emotional cues are robbed of this basic mechanism of learning how to modulate emotion. New research into this aspect of BPD will be enhanced by rapid developments in the neuroscience of social interaction.

Implications of Shifting BPD to Axis I

The distinction between Axis I and Axis II disorders in the DSM system has received little empirical investigation, and the lack of empirical grounding for many assumptions that underlie the distinction has been well-argued by Siever and Davis (85). Some of the most compelling of these arguments include the fact that the current DSM-IV–TR definition of a personality disorder as “an enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture, is pervasive and inflexible, has an onset in adolescence or early adulthood, is stable over time and leads to distress or impairment” could well apply to many Axis I disorders also. For example, schizophrenia confers pervasive and enduring patterns of behavior that are inflexible, typically with onset in adolescence that become chronic in nature. However, we do not view schizophrenia as a disorder of “character.” Clearly, if schizophrenia fits the DSM definition of a personality disorder, the definition is overly inclusive. Simply stating that a character disorder is not better accounted for by an Axis I disorder begs the question of how to set personality disorders apart from Axis I disorders. Major depressive disorder is perhaps the prototype of an episodic disorder, yet even MDD can be associated with chronic mood symptoms that interfere with functioning.

Another feature used to distinguish personality disorders from other psychiatric illnesses is that personality disorders have traditionally been conceptualized as resulting from environmental factors, whereas Axis I disorders have been viewed as having a “biological” or “organic” basis (85). As reviewed in the preceding text, however, twin studies suggest that BPD is quite heritable. Although environmental stresses might play a role in the development of BPD, this is the case with many Axis I disorders as well, including MDD, in which environmental stresses in conjunction with vulnerability genes can give rise to the disorder (86). Thus neither the presentation nor the etiology of BPD differentiates it clearly from disorders classified on Axis I.

Not only is the distinction between Axis I and Axis II disorders problematic but BPD in particular does not fit in with traditional conceptualizations of personality disorders. For example, personality disorders have been viewed as egosyntonic, whereas the symptoms of BPD are often quite egodystonic, leading patients to seek treatment for their symptoms (87).

The current revision of DSM recognizes the difficulty in distinguishing Axis I from Axis II and is considering the possibility of abolishing Axis II or the reclassification of some Axis II disorders to Axis I (L.J. Siever, personal communication, September 2007). The present review does not take on that debate but instead argues that in light of what is known about BPD, this disorder specifically reaches the threshold for reclassification.

Misconceptions about BPD

So where do doubts about the validity of BPD as a major mental disorder come from? Although some of the difficulty in taking BPD seriously might relate to the complexity and heterogeneity of the symptoms, the high level of comorbidity, and poor medication response, these features are not unique to BPD. We believe that the evidence for the Robins and Guze criteria strongly argue for the consideration of BPD as a serious mental illness, and as such, BPD ought to be classified on Axis I.

We believe two fundamental misconceptions have contributed to misunderstanding and have been impediments to serious investigative scrutiny of this illness. The first relates to the name “borderline personality disorder” itself, which implies that this disease lies on the “border” between two states, a view that has its origins in early psychoanalytic conceptualizations of the disorder that are no longer widely accepted. A second misconception is that BPD is the direct consequence of early life trauma rather than a phenotypic expression of a vulnerability to symptoms and behaviors that then emerge in the context of past and present-day stressful life events.

The misconception that BPD is the result exclusively of environmental influences and not also influenced by heredity is not well-grounded empirically. The view that the cause of BPD is childhood trauma has held so fast that some therapists have used “recovered memory therapies” in the treatment of BPD, encouraging patients to file lawsuits even with little evidence of childhood trauma and no spontaneous memory of trauma (88). The field has moved strongly to condemn this approach.

The finding of heritability brings into serious question the view that trauma is the sole etiology of BPD. It suggests, alternatively, the possibility of an innate hypersensitivity to stress. A traumatic etiology for BPD is also brought into question by the consideration that, because most childhood trauma is perpetrated by family members (89) and this disorder is heritable, the family members perpetrating abuse are more likely than the average population to have BPD themselves. If the caregivers of BPD patients have BPD, they are more likely to have poor frustration tolerance, excessive anger and aggression, and therefore to be at risk for engaging in abuse towards their children. A further source of doubt about the traumatic etiology of BPD is that much of the research done to assess childhood trauma is based on data obtained retrospectively from adults with BPD, which is subject to the “negative halo” recall bias inevitable with already-ill probands (90). This bias might be especially pronounced in BPD patients who, as a group, are highly prone to cast a negative emotional tone over memories of prior experiences (91).

Although skepticism about the traumatic etiology of BPD is warranted, studies have shown that adults with BPD are more likely than those without BPD to give histories of early physical and sexual abuse and of witnessing domestic violence (92). Data from CLPS suggest that BPD is more strongly correlated with childhood abuse and neglect than are MDD or OPDs (93). In a community sample, childhood physical and sexual abuse were not predictors for BPD (94). However, a recent study suggests that childhood physical and sexual abuse are among a number of independent predictors of BPD (95), and a meta-analysis of 21 studies, with over 2000 subjects, looking at BPD and child abuse yielded a pooled effect size of only r .28 (96).

Although childhood sexual abuse specifically has been implicated in BPD, it is not an inevitable prerequisite for the illness’s development (97). An estimated 20%– 45% of BPD patients have no history of sexual abuse (97), whereas 80% of individuals with sexual abuse histories have no personality pathology (98).

Table 1. BPD and Trauma: Studies Supporting and Undercutting a Traumatic Etiology for BPD 

Table 2. BPD and Genetic Factors: Studies Supporting a Familial/Heritable Role for BPD

Longitudinal studies of children followed after a report of child abuse show that a substantial proportion with quite severe abuse remains functionally resilient, with little impairment across social, occupational, and interpersonal domains (99). Unfortunately, longitudinal studies of children with childhood trauma to date have not assessed for BPD (89,99).

Taken together, these results support a model of the etiology of BPD as multifactorial, with childhood abuse as a contributing factor (95) but in which other factors such as family psychiatric history also play an important role (Tables 1 and 2). To clarify more fully the role of childhood trauma in the development of BPD, it will be necessary to follow prospectively children at risk for BPD.

Summary

We have suggested BPD’s inclusion among the mood disorders because of the centrality of affective dysregulation symptoms in BPD as well as the comorbidity and co-familiality with MDD. Viewing BPD in this context opens up new avenues for research. One fruitful path in BPD research might be to build upon new findings in depression research (64). This logically would include continued exploration of the circuits implicated in both mood disorder and BPD and to search for diagnostic specificity in these circuits. We have suggested that a fruitful area to pursue will be exploring deficits in social cognition, with particular emphasis on the developmental trajectories of affective symptoms and interpersonal dysfunction in BPD. It is clear, however, that a deeper understanding of the neurobiology of BPD has the potential to open avenues for novel treatments as well as to diminish the stigma that serves to worsen the clinical course and outcome of this already disabling and hard-to-treat illness. 

References

Paris J (2005): Recent advances in the treatment of borderline personality disorder. Can J Psychiatry 50:435– 441.

Akiskal HS, Chen SE, Davis GC, Puzantian VR, Kahgarian M, Bolinger JM (1985): Borderline: An adjective in search of a noun. J Clin Psychiatry 46:41– 48.

Robins E, Guze SB (1970): Establishment of diagnostic validity in psychiatric illness: Its application to schizophrenia. Am J Psychiatry 126: 983–987.

Schulz SC, Goldberg SC (1984): Is borderline personality disorder an illness? Psychopharmacol Bull 20:554 –560.

Sanislow CA, Grilo CM, McGlashan TH (2000): Factor analysis of the DSM-III-R borderline personality disorder criteria in psychiatric inpatients. Am J Psychiatry 157:1629 –1633.

Sanislow CA, Grilo CM, Morey LC, Bender DS, Skodol AE, Gunderson JG, et al. (2002): Confirmatory factor analysis of DSM-IV criteria for borderline personality disorder: Findings from the collaborative longitudinal personality disorders study. Am J Psychiatry 159:284 –290.

Johansen M, Karterud S, Pedersen G, Gude T, Falkum E (2004): An investigation of the prototype validity of the borderline DSM-IV con- struct. Acta Psychiatr Scand 109:289 –298.

Fossati A, Maffei C, Bagnato M, Donati D, Namia C, Novella L (1999): Latent structure analysis of DSM-IV borderline personality disorder criteria. Compr Psychiatry 40:72–79.

Clifton A, Pilkonis PA (2007): Evidence for a single latent class of Diagnostic and Statistical Manual of Mental Disorders borderline personality pathology. Compr Psychiatry 48:70 –78.

McGlashan TH, Grilo CM, Skodol AE, Gunderson JG, Shea MT, Morey LC, et al. (2000): The Collaborative Longitudinal Personality Disorders Study: Baseline Axis I/II and II/II diagnostic co-occurrence. Acta Psychiatr Scand 102:256 –264.

Shea MT, Stout RL,Yen S, Pagano ME, Skodol AE, Morey LC, etal.(2004): Associations in the course of personality disorders and Axis I disorders over time. J Abnorm Psychol 113:499 –508.

Fyer MR, Frances AJ, Sullivan T, Hurt SW, Clarkin J (1988):Comorbidity of borderline personality disorder. Arch Gen Psychiatry 45:348 –352.

Zanarini MC, Frankenburg FR, Hennen J, Reich DB, Silk KR (2004): Axis I comorbidity in patients with borderline personality disorder: 6-year follow-up and prediction of time to remission. Am J Psychiatry 161: 2108 –114.

Links PS, Heslegrave RJ, Mitton JE, Van Reekum R, Patrick J (1995): Borderline psychopathology and recurrences of clinical disorders. J Nerv Ment Dis 183:582–586.

Gunderson JG, Weinberg I, Daversa MT, Kueppenbender KD, Zanarini MC, Shea MT, et al. (2006): Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder. Am J Psychiatry 163:1173–1178.

Kelsoe JR (2003): Arguments for the genetic basis of the bipolar spectrum. J Affect Disord 73:183–197.

Silverman JM, Pinkham L, Horvath TB, Coccaro EF, Klar H, Schear S, et al. (1991): Affective and impulsive personality disorder traits in the relatives of patients with borderline personality disorder. Am J Psychiatry 148:1378 –1385.

Coccaro EF, Kavoussi RJ (1997): Fluoxetine and impulsive aggressive behavior in personality disordered subjects. Arch Gen Psychiatry 54: 1081–1088.

Coid J, Yang M, Tyrer P, Roberts A, Ullrich S (2006): Prevalence and correlates of personality disorder in Great Britain. Br J Psychiatry 188: 423– 431.

Lenzenweger MF, Lane MC, Loranger AW, Kessler RC (2007): DSM-IV personality disorders in the National Comorbidity Survey Replication. Biol Psychiatry 62:553–564.

Zimmerman M, Rothschild L, Chelminski I (2005): The prevalence of DSM-IV personality disorders in psychiatric outpatients. Am J Psychiatry 162:1911–1918.

Comtois KA, Russo J, Snowden M, Srebnik D, Ries R, Roy-Byrne P (2003): Factors associated with high use of public mental health services by persons with borderline personality disorder. Psychiatr Serv 54: 1149 –1154.

Bender D, Dolan R, Skodol A, Sanislow CA, Dyck IR, McGlashan TH, et al. (2001): Treatment utilization by patients with personality disorders. Am J Psychiatry 158:295–302.

Frankenburg FR, Zanarini MC (2004): The association between borderline personality disorder and chronic medical illnesses, poor health-related lifestyle choices, and costly forms of health care utilization. J Clin Psychiatry 65:1660 –1665.

Lieb K, Zanarini MC, Schmahl C, Linehan MM, Bohus M (2004): Borderline personality disorder. Lancet 364:453– 461.

Black DW, Blum N, Pfohl B, Hale N (2004): Suicidal behavior in borderline personality disorder: Prevalence, risk factors, prediction, and prevention. J Personal Disord 18:226 –239.

SkodolAE,GundersonJ,McGlashanT,DyckIR,StoutRL,BenderDS,et al. (2002): Functional impairment in patients with schizotypal, border- line, avoidant, and obsessive compulsive personality disorders. Am J Psychiatry 159:276 –283.

Zanarini MC, Frankenburg FR, Hennen J, Reich DB, Silk KR (2005): The McLean Study of Adult Development (MSAD): Overview and implica- tions of the first six years of prospective follow-up. J Personal Disord 19:505–523.

Paris J, Zweig-Frank H (2001): A 27-year follow-up of patients with borderline personality disorder. Compr Psychiatry 42:482– 487.

Zanarini MC, Frankenburg FR, Hennen J, Reich DB, Silk KR (2006): Prediction of the 10-year course of borderline personality disorder. Am J Psychiatry 163:827– 832.

Paris J (2003): Personality Disorder Over Time: Precursors, Course and Outcome. Washington DC: American Psychiatric Press.

Loranger AW, Oldham JM, Tulis EH (1982): Familial transmission of DSM-III borderline personality disorder. Arch Gen Psychiatry 39:795– 799.

Zanarini MC, Frankenburg FR, Yong L, Raviola G, Bradford Reich D, Hennen J, et al. (2004): Borderline psychopathology in the first-degree relatives of borderline and axis II comparison probands. J Personal Disord 18:439 – 447.

Riso LP, Klein DN, Anderson RL, Ouimette PC (2000): A family study of outpatients with borderline personality disorder and no history of mood disorder. J Personal Disord 14:208 –217.

Torgersen S (2000): Genetics of patients with borderline personality disorder. Psychiatr Clin North Am 23:1–9.

Ji WY, HuYH, Huang YQ, Cao WH, Lv J, Qin Y, et al.(2006): (A twin study of personality disorder heritability.) [Article in Chinese] Zhonghua Liu Xing Bing Xue Za Zhi 27:137–141.

Coolidge FL, Thede LL, Jang KL (2001): Heritability of personality disorders in childhood: A preliminary investigation. J Personal Disord 15:33– 40.

Moskowitz DS, Pinard G, Zuroff DC, Annable L, Young SN (2001): The effect of tryptophan on social interaction in everyday life: A placebo-controlled study. Neuropsychopharmacology 25:277–289.

Russell JJ,Moskowitz DS, Zuroff DC, Sookman D, Paris J (2007): Stability and variability of affective experience and interpersonal behavior in borderline personality disorder. J Abnorm Psychol 116:578 –588.

Bohus M, Schmahl C, Lieb K (2004): New developments in the neurobiology of borderline personality disorder. Curr Psychiatry Rep 6:43–50.

New AS, Goodman M, Treibwasser J, Siever LJ (2008): Recent advances in the biological study of personality disorders. Psych Clin North Am 31.

CoccaroEF,SieverLJ,KlarHM,MaurerG,CochraneK,CooperTB,etal. (1989): Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry 46:587–599.

O’Keane V, Maloney E, O’Neil H, O’Connor A, Smith C, Dinan TG (1992): Blunted prolactin response to d-fenfluramine in sociopathy: Evidence for subsensitivity of central serotonergic function. Br J Psychiatry 160: 643– 646.

Siever L, Trestman RL (1993): The serotonin system and aggressive personality disorder. Int Clin Psychopharmacology 8:33–39.

Dougherty DM, Bjork JM, Huckabee H, Moeller F, Swann A (1999): Laboratory measures of aggression and impulsivity in women with borderline personality disorder. Psychiatry Res 85:315–326.

Siever LJ, Buchsbaum MS, New AS, Spiegel-Cohen J, Wei T, Hazlett EA, et al. (1999): d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography. Neuropsychopharmacology 20:413– 423.

New A, Hazlett E, Buchsbaum MS, Goodman M, Reynolds D, Mitropoulou V, et al. (2002): Blunted prefrontal cortical 18fluorodeoxyglucose positron emission tomography response to meta-chloropiperazine in impulsive aggression. Arch Gen Psychiatry 59:621– 629.

Soloff PH, Meltzer CC, Greer PJ, Constantine D, Kelly TM (2000): A fenfluramine-activated FDG-PET study of borderline personality disorder. Biol Psychiatry 47:540 –547.

Leyton M,Okazawa H,Diksic M, Paris J, Rosa P, Mzengeza S, et al.(2001): Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder. Am J Psychiatry 158:775– 782.

New AS, Buchsbaum MS, Hazlett EA, Goodman M, Koenigsberg HW, Lo J, et al. (2004): Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression. Psychopharmacology (Berl) 176:451– 458.

Frankle WG, Lombardo I, New AS, Goodman M, Talbot PS, Huang Y,et al. (2005): Brain serotonin transporter distribution in subjects with impulsive aggressivity: A positron emission study with [11C]McN 5652. Am J Psychiatry 162:915–923.

Soloff PH, Price JC, Meltzer CC, Fabio A, Frank GK, Kaye WH (2007): 5HT2A receptor binding is increased in borderline personality disorder. Biol Psychiatry 62:580 –587.

Siever L, Torgersen S, Gunderson J, Livesley W, Kendler K (2002): The borderline diagnosis III: Identifying endophenotypes for genetic studies. Biol Psychiatry 51:964 –968.

Friedel RO (2004): Dopamine dysfunction in borderline personality disorder: A hypothesis. Neuropsychopharmacology 29:1029 –1039.

Gurvitz IG, Koenigsberg HW, Siever LJ (2000): Neurotransmitter dysfunction in patients with borderline personality disorder. Psychiatr Clin North Am 23:27– 40.

Schmahl C, Bremner JD(2006): Neuroimaging in borderline personality disorder. J Psychiatr Res 40:419 – 427.

Tebartzvan E, Hesslinger B, Thiel T, et al.(2003):Frontolimbic brain abnormalities in patients with borderline personality disorder: A volumetric magnetic resonance imaging study. Biol Psychiatry 54:163–171.

Hazlett EA, New AS, Newmark R, Haznedar MM, Lo JN, Speiser LJ, et al. (2005): Reduced anterior and posterior cingulate gray matter in borderline personality disorder. Biol Psychiatry 58:614 – 623.

Minzenberg MJ,Fan J, New AS, Tang CY, Siever LJ.(2008): Frontolimbic structural changes in borderline personality disorder. J Psychiatr Res 42:727–733.

Goyer PF, Andreason PJ, Semple WE, Clayton AH, King AC, Compton-Toth BA, et al. (1994): Positron-emission tomography and personality disorders. Neuropsychopharmacology 10:21–28.

Schmahl C, Bohus M, Esposito F, Treede RD, DiSalle F, Greffrath W, et al. (2006): Neural correlates of antinociception in borderline personality disorder. Arch Gen Psychiatry 63:659 – 667.

Minzenberg MJ, Fan J, New AS, Tang CY, Siever LJ (2007): Fronto-limbic dysfunction in response to facial emotion in borderline personality disorder: An event-related fMRI study. Psychiatry Res 155:231–243.

Schnell K, Dietrich T, Schnitker R, Daumann J, Herpertz SC (2007): Processing of autobiographical memory retrieval cues in borderline personality disorder. J Affect Disord 97:253–259.

Ressler KJ, Mayberg HS (2007): Targeting abnormal neural circuits in mood and anxiety disorders: From the laboratory to the clinic. Nat Neurosci 10:1116 –1124.

Blumberg HP, Charney DS, Krystal JH (2002): Frontotemporal neural systems in bipolar disorder. Semin Clin Neuropsychiatry 7:243–254.

Caetano SC, Kaur S, Brambilla P, Nicoletti M, Hatch JP, Sassi RB, et al. (2006): Smaller cingulate volumes in unipolar depressed patients. Biol Psychiatry 59:702–706.

Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC (2005): Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: Diagnostic specificity and prognostic implications. Am J Psychiatry 162:1706 –1712.

Ballmaier M, Toga AW, Blanton RE, Sowell ER, Lavretsky H, Peterson J, et al. (2004): Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: An MRI-based parcellation of the prefrontal cortex. Am J Psychiatry 161:99 –108.

Hajek T, Carrey N, Alda M (2005): Neuroanatomical abnormalities as risk factors for bipolar disorder. Bipolar Disord 7:393– 403.

Sassi RB, Brambilla P, Hatch JP, Nicoletti MA, Mallinger AG, Frank E, et al. (2004): Reduced left anterior cingulate volumes in untreated bipolar patients. Biol Psychiatry 56:467– 475.

Davidson RJ, Irwin W, Anderle MJ, Kalin NH (2003): The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry 160:64 –75.

Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Har- ris BC, et al. (2003): A functional magnetic resonance imaging study of bipolar disorder: State- and trait-related dysfunction in ventral pre-frontal cortices. Arch Gen Psychiatry 60:601– 609.

Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. (1999): Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: A PET investigation. Am J Psychiatry 156:575–584.

Gunderson JG, Phillips KA (1991): A current view of the interface between borderline personality disorder and depression. Am J Psychiatry 148:967–975.

McGlashan TH, Grilo CM, Sanislow CA, Ralevski E, Morey LC, Gunderson JG, et al. (2005): Two-year prevalence and stability of individual DSM-IV criteria for schizotypal, borderline, avoidant, and obsessive-compulsive personality disorders: Toward a hybrid model of axis II disorders. Am J Psychiatry 162:883839.

Gunderson JG (2007): Disturbed relationships as a phenotype for borderline personality disorder. Am J Psychiatry 164:1637–1640.

Hill J, Pilkonis P, Morse J, Feske U, Reynolds S, Hope H, et al. (2008): Social domain dysfunction and disorganization in borderline personality disorder. Psychol Med 38:135–146.

Jovev M, Jackson HJ (2006): The relationship of borderline personality disorder, life events and functioning in an Australian psychiatric sample. J Personal Disord 20:205–217.

Brodsky BS, Groves SA, Oquendo MA, Mann JJ, Stanley B (2006): Interpersonal precipitants and suicide attempts in borderline personality disorder. Suicide Life Threat Behav 36:313–322.

Wagner AW, Linehan MM (1999): Facial expression recognition ability among women with borderline personality disorder: Implications for emotion regulation? J Personal Disord 13:329 –344.

Blair RJ, Colledge E, Murray L, Mitchell DG (2001): A selective impairment in the processing of sad and fearful expressions in children with psychopathic tendencies. J Abnorm Child Psychol 29:491– 498.

Lynch TR, Rosenthal MZ, Kosson DS, Cheavens JS, Lejuez CW, Blair RJ (2006): Heightened sensitivity to facial expressions of emotion in borderline personality disorder. Emotion 6:647– 655.

Donegan NH, Sanislow CA, Blumberg HP, Fulbright RK, Lacadie C, Skudlarski P, et al. (2003): Amygdala hyperreactivity in borderline personality disorder: Implications for emotional dysregulation. Biol Psychiatry 54:1284 –1293.

Moriceau S, Sullivan RM (2005): Neurobiology of infant attachment. Dev Psychobiol 47:230 –242.

Siever LJ, Davis K (1991): A psychobiological perspective on the personality disorders. Am J Psychiatry 148:1647–1658.

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. (2003): Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386 –389.

Paris J (2007): The nature of borderline personality disorder: Multiple dimensions, multiple symptoms, but one category. J Personal Disord 21:457– 473.

Paris J (1995): Memories of abuse in borderline patients: True or false? Harv Rev Psychiatry 3:10 –17.

Silverman AB, Reinherz HZ, Giaconia RM (1996): The long-term sequelae of child and adolescent abuse: A longitudinal community study. Child Abuse Negl 20:709 –723.

Paris J (2000): Childhood precursors of borderline personality disorder. Psychiatr Clin North Am 23:77– 88, vii.

Bailey JM, Shriver A (1999): Does childhood sexual abuse cause borderline personality disorder? J Sex Marital Ther 25:45–57.

Herman JL, Perry JC, van der Kolk BA (1989): Childhood trauma in borderline personality disorder. Am J Psychiatry 146:490 – 495.

Battle CL, Shea MT, Johnson DM, Yen S, Zlotnick C, Zanarini MC, et al. (2004): Childhood maltreatment associated with adult personality disorders: Findings from the Collaborative Longitudinal Personality Disorders Study. J Personal Disord 18:193–211.

Bierer LM, Yehuda R, Schmeidler J, Mitropoulou V, New AS, Silverman JM, Siever LJ (2003): Abuse and neglect in childhood: Relationship to personality disorder diagnoses. CNS Spectr 8:737–754.

Bandelow B, Krause J, Wedekind D, Broocks A, Hajak G, Ruther E (2005): Early traumatic life events, parental attitudes, family history, and birth risk factors in patients with borderline personality disorder and healthy controls. Psychiatry Res 134:169 –179.

Fossati A, Madeddu F, Maffei C (1999): Borderline personality disorder and childhood sexual abuse: A meta-analytic study. J Personal Disord 13:268 –280.

Goodman M, Yehuda R (2002): The relationship between psychological trauma and borderline personality disorder. Psychiatric Annals 32: 337–346.

Paris J (1998): Does childhood trauma cause personality disorders in adults? Can J Psychiatry 43:148 –153.

McGloin JM, Widom CS (2001): Resilience among abused and neglected children grown up. Dev Psychopathol 13:1021–1038.