Borderline personality disorder Item Type Article Authors Gunderson, John G.; Herpertz, Sabine C.; Skodol, Andrew E.; Torgersen, Svenn; Zanarini, Mary C. Citation Gunderson, John & Herpertz, Sabine & E. Skodol, Andrew & Torgersen, Svenn & C. Zanarini, Mary. (2018). Borderline personality disorder. Nature Reviews Disease Primers. 4. 18029. 10.1038/nrdp.2018.29. DOI 10.1038/nrdp.2018.29 Publisher NATURE PUBLISHING GROUP Journal NATURE REVIEWS DISEASE PRIMERS Rights Copyright © 2018, Springer Nature. Download date 22/05/2024 11:09:20 Item License http://rightsstatements.org/vocab/InC/1.0/ Version Final accepted manuscript Link to Item http://hdl.handle.net/10150/631040 1 BORDERLINE PERSONALITY DISORDER 2 3 John G. Gunderson1, Sabine C. Herpertz2, Andrew E. Skodol3, Svenn Torgersen4, and Mary C. Zanarini5 4 5 6 7 8 9 10 1. Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA 2. Department of General Psychiatry, Center of Psychosocial Medicine, University of Heidelberg Medical School, Heidelberg, Germany 3. Department of Psychiatry, University of Arizona College of Medicine, Tucson, AZ, USA 11 4. Department of Psychology, University of Oslo, Oslo, Norway 12 5. Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, 13 14 15 16 17 MA, USA Correspondence to J.G.G. jgunderson@mclean.harvard.edu 18 19 ABSTRACT| Caretakers are often intimidated or alienated by patients with borderline 20 personality disorder (BPD), compounding the clinical challenges posed by the disorder’s 21 severe morbidity, high social costs, and substantial prevalence in many health care 22 settings. BPD is found in ~1.7% of the general population, but in 15-28% of patients in 23 psychiatric clinics or hospitals, and in a large proportion of individuals seeking help for 24 psychological problems in general health facilities. BPD is characterized by extreme 1 25 sensitivity to perceived interpersonal slights, an unstable sense of self, intense and 26 volatile emotionality, and impulsive behaviors that are often self-destructive. Most 27 patients gradually enter symptomatic remission and their rate of remission can be 28 accelerated by evidence-based psychosocial treatments. Although self-harming 29 behaviors and proneness to crisis can decrease over time, the natural course and 30 otherwise effective treatments of BPD usually leave many patients with persistent and 31 severe social disabilities, relating to depression or self-harming behaviors. Thus, 32 clinicians need to actively inquire about the more central issues of interpersonal 33 relations and unstable identity. Failure to correctly diagnose patients with BPD begets 34 misleading pharmacological interventions that rarely succeed. Whether the definition of 35 BPD should change is under debate, linked to not fully knowing the nature of this 36 disorder. 37 38 39 [H1] INTRODUCTION Borderline personality disorder (BPD) has a suspect origin within psychoanalysis, 40 an uncertain fit within classification systems and a reputation for being untreatable, 41 which collectively, have all made the ownership of this disorder by psychiatry and by 42 medicine insecure. Aggravating this insecurity are the insistent complaints by the many 43 patients with this disorder of being ignored or mistreated. Indeed, patients with BPD 44 face severe stigma not only from the public but also from clinicians, owing to their 45 reputation for being hostile and intractable.1 46 BPD was initially defined in 1978, following which, this disorder was indexed in 47 the Diagnosis and Statistical Manual of Mental Disorders (DSM), Third Edition (DSM-III) 48 in 1980 and in the International Classification of Diseases 10 years later (as emotionally 2 49 unstable personality disorder; Figure 1). The clinical and research literature 50 subsequently has logarithmically risen. 51 BPD is characterized by extreme sensitivity to perceived interpersonal slights, an 52 unstable sense of self, intense and volatile emotions, and impulsive behaviors (Figure 53 2). As efforts to treat patients with BPD are often thwarted by patient anger, recurrent 54 suicidality, and non-compliance, the diagnosis has a reputation for intractability and 55 untreatability. However, three independent scientific developments have challenged this 56 reputation. Studies have demonstrated that BPD is treatable2–4, that most patients 57 recover symptomatically5,6 and that the disorder has a biological and genetic basis7. 58 Given these developments, the BPD diagnosis has met most of the standards for 59 diagnostic validity. However, persistent questions about the definition, core pathology, 60 and treatments of BPD remain, and patients are often avoided, misunderstood, and 61 mistreated. 62 63 This Primer identifies the significant advances that have been made in understanding, 64 treating, and validating BPD. In addition, this Primer describes the epidemiology of 65 BPD, pathophysiology, diagnostic methods and challenges, and quality of life issues 66 faced by patients. 67 68 [H1] EPIDEMIOLOGY 69 An overview of 13 epidemiological studies from different countries composed of 70 face-to-face interviews of the general population reporting about all types of personality 71 disorders demonstrated a two-year to five-year prevalence of between 0% and 4.5%, 3 72 with a median of 1.7% and a mean of 1.6 % for BPD, the fourth most prevalent of the 73 ten DSM III and DSM IV personality disorders.8–10 However, a two-year to five-year 74 prevalence has limited value for understanding the importance of the disorder 75 throughout life and from an individual’s point of view, the lifetime prevalence is more 76 relevant. The NESARC study in the United States showed a lifetime prevalence for BPD 77 of 5.9%11 close to four times as high as the average two-year to five-year prevalence 78 found in epidemiological studies of the general population.. A four times as high lifetime 79 prevalence as short time prevalence was also similar to what the NESARC study found 80 for the seven personality disorders they investigated both for short-time and life-time 81 prevalence (BPD was not studied short-time). More-accurate estimates are obtained by 82 repeated assessment and not relying on retrospective memory. In one other study in the 83 United States that evaluated individuals four times from 14 to 32 years of age 9, the 84 average short-term prevalence of BPD was 1.5% and the cumulative prevalence was 85 5.5 %. Importantly, the short-term prevalence did not increase from year to year; some 86 individuals lost the diagnosis, other individuals without the diagnosis previously received 87 it later for the first time in the study. Relatively few patients had a stable diagnosis from 88 one wave to the next. Generally, patients undergo remission, and few relapse (see 89 Quality of life)5,6. BPD can also be diagnosed in childhood with reliability, validity, and 90 stability similar to the diagnosis of BPD in adulthood12 (Box 1). A notable finding from 91 community based samples is that the prevalence of BPD is relatively similar in males 92 and females, in contrast to the 3:1 female to male gender ratio of the diagnosis in 93 clinical settings cited in the DSM-511,13. 4 94 Although the prevalence of BPD in the general population is not much higher 95 than the average prevalence of personality disorders, the prevalence of BPD is 96 dramatically higher among patients in psychiatric clinical populations. Indeed, BPD has 97 a high prevalence in all treatment settings 14,15; patients with BPD constitute ~15-28% of 98 all patients in psychiatric outpatient clinics or hospitals16–18 , 6% of primary care visits19 99 and 10-15% of all emergency room visits13,20. In one study from Oslo, Norway, 100 individuals receiving psychiatric treatment (by all institutions, even general practitioner) 101 had a 14 times higher rate of BPD than individuals not receiving treatment21. No other 102 personality disorder displayed by far the same tendency with regards to treatment, even 103 if other personality disorders showed similar or higher reductions in quality of life8,22,23. 104 105 [H2] Socio-demographics 106 As the number of short-time BPD cases even in large studies of the general 107 population is rather low, not many statistically significant results are obtained, even if 108 some non-significant differences between those with BPD and those without are 109 observed. In one study, individuals with BPD were more often single , and had lower 110 education and income than those without BPD24. To increase statistical power of 111 epidemiological studies, the number of BPD diagnostic criteria met by individuals can be 112 studied as a dimensional measure of BPD psychopathology and multivariate statistical 113 analysis carried out to avoid results that are due to correlations between the predictors. 114 This was carried out in a study in Oslo, Norway, that demonstrated an association 115 between the number of BPD criteria present, and younger age, less education, and 5 116 being single in the center of the city; when controlled for covariance between the 117 variables8. 118 119 120 [H1] MECHANISMS/PATHOPHYSIOLOGY A neurobiological model of BPD proposes phenotypes that are the product of 121 interactions of genetic and environmental influences affecting brain development via 122 hormones and neuropeptides. In addition, early childhood maltreatment and the quality 123 of early life parenting care can affect gene expression and brain structure and functions, 124 resulting in behavioral traits that are stable throughout life25. However, prefronto-limbic 125 dysfunction (the brain mechanism most frequently associated with BPD) seems to be a 126 transdiagnostic phenomenon that is related to negative affectivity in the context of social 127 stress and is found in patients with other psychiatric disorders26 and even in healthy 128 individuals who have faced early life maltreatment27. Prefronto-limbic dysfunction seems 129 sensitive to change over time, and research is needed to understand this process, as 130 well as other processes that might be (or act) in the pathogenesis and progression of 131 BPD. In general, a dysfunction of single brain circuits is not specific for BPD but rather 132 is the co-occurrence of all or at least several of the dysfunctions described in this 133 section. 134 135 136 [H2] Environmental risk factors The risk of BPD results from the interaction of genetic factors and life 137 experiences. Inherited temperamental factors sensitize and might predispose 138 individuals to adverse life experiences28 (see Genetic factors and Gene–Environment 139 interactions, below). 6 140 Adverse childhood experiences are strongly associated with BPD in clinical and 141 community samples29,30. Indeed, childhood trauma is the most significant environmental 142 risk factor of a BPD diagnosis although it is not a necessary precondition for developing 143 BPD.31 Although not specific for BPD, childhood maltreatment including physical abuse, 144 sexual abuse, and neglect significantly increased the risk of BPD in prospective 145 community studies in children32. Inconsistent parenting, maternal over-involvement, 146 aversive parental behaviors, and low parental affection are also associated with the 147 development of BPD, but are also not specific33. In addition, separating children from 148 mothers before 5 years of age predisposes to BPD in adulthood34. The personality 149 profiles of children who have been mistreated are characterized by high neuroticism, 150 low agreeableness, low conscientiousness, and low openness to experience, and tend 151 to persist and are similar to the personality traits of adults with BPD35. 152 Certain critical developmental periods are implicated in the genesis of personality 153 pathology. Abnormal attachment to a primary caregiver, due to either separation or poor 154 parenting, has been observed, and disrupted attachment early in life likely leads to 155 impairments in emotional regulation and self-control36. High stress-reactivity in a child 156 might contribute to problematic attachment. Disorganized attachment between mothers 157 and children predicted borderline symptoms in young adults in a prospective community 158 study37. In adolescence, the development of a stable identity or sense of self is a major 159 task, and might lead to personality pathology if delayed or impeded. 160 Other types of childhood and adolescent psychopathology, such as depressive, 161 anxiety, substance use, and disruptive behavior disorders (e.g., conduct disorder, 162 oppositional defiant disorder, ADHD) predispose to the development of personality 7 163 pathology, including BPD, in adolescents and young adults38,39. Deliberate self-harm, 164 suicide attempts, and other BPD features, such as insecure identity, low goal- 165 directedness, negative affectivity, impulsivity, risk taking behaviors, anger and 166 interpersonal aggression, predict the development and persistence of BPD in children 167 and early adolescents12,40. Adolescents with BPD are more likely to present for clinical 168 care with the more acute manifestations (such as self-harm, suicidal behaviour, 169 impulsivity) of BPD than with the temperamental manifestations (such as identity 170 disturbance, unstable relationships and fears of abandonment)12. 171 [H2] Genetic factors 172 The heritability of BPD is high although studies are rare and different values have been 173 reported; notably, data from twin studies suggest that a common family environment 174 has little contribution to the aggregation of BPD within families41 . When twins are 175 studied using the same person to interview both twins (hence avoiding interviewer 176 variance), the heritability was found to be ~0.707. Similar values have been reported in 177 studies that used both interview and self-report questionnaires42 and in studies that 178 measured BPD twice, namely 10 years apart43. Accordingly, a heritability of ~0.70 is 179 probably the most correct estimate. 180 BPD and the four symptom phenotypes (Figure 2) aggregate in families44,45–47. A 181 meta-analysis did not detect a significant association of BPD with typical candidate 182 genes for vulnerability to psychiatric disorders, e.g. SLC6A4 (encoding the serotonin 183 transporter gene)48. The first genome-wide association study in ~1,000 patients with 184 BPD indicates a genetic overlap with bipolar disorder, schizophrenia and major 185 depression; the implicated genes have effects on very basic properties of neural 8 186 processing such as cell adhesion or myelination and include DPYD (encoding 187 dihydropyrimidine dehydrogenase), PKP4 (encoding plakophilin-4), and SERINC5 188 (encoding serine incorporator 5) 49. Accordingly, gene variants in individuals with BPD 189 are likely not specific for BPD, but raise the question whether genetic overlap is linked 190 to transdiagnostic clinical symptoms or reflects an increased risk for psychiatric 191 disorders in general. Although genetic factors and neurobiological factors have been 192 pursued as risk factors for BPD; they do not have sufficient specificity for early 193 identification or intervention, which is also true for all psychiatric illnesses. 194 195 [H2] Gene–environment interactions 196 Given the significant role of early life maltreatment in the etiology of BPD, 197 detecting epigenetic alterations that could explain BPD symptoms is of high interest. A 198 genome-wide methylation analysis found increased methylation of some genes, for 199 example, MIR124-3, the gene product of which is involved in the regulation of neural 200 plasticity and amygdala functioning; this gene was associated with BPD and childhood 201 maltreatment and might have a role in the pathway from maltreatment in early life to 202 BPD in adulthood50. Alterations in methylation of other genes, e.g. increased 203 methylation of BDNF (encoding brain-derived neurotrophic factor), are associated with 204 early life maltreatment and susceptibility to BPD51. 205 In addition, polymorphisms in genes involved in hypothalamic–pituitary–adrenal 206 (HPA) axis activity, such as FKBP5 and CRHR, may be involved in the etiology of BPD. 207 These variants are more frequent in patients with BPD who had childhood maltreatment 208 than those without childhood maltreatment52. However, associations between childhood 9 209 trauma and polymorphisms in HPA axis genes have also been found in other psychiatric 210 disorders, such as depression, suicide, and post-traumatic stress disorder (PTSD)53. 211 Abnormalities in HPA hormones might mediate the effect of early adversity on brain 212 structure and function in BPD, and impairment of the affect regulation circuitry is a key 213 biopsychological mechanism of this. Variants of FKBP5 and CRHR that are associated 214 with BPD result in enhanced cortisol secretion25, which leads to structural and functional 215 alterations in the brain, for example, the hippocampus 54. In addition, studies in healthy 216 individuals suggest that polygenic variation linked to HPA axis function moderates the 217 effect of early life stress on threat-related amygdala activity55 and that cortisol influences 218 functional connectivity between the amygdala and the dorsal anterior cingulate cortex56. 219 Moreover, parent and child HPA-activity shows higher biological synchrony while 220 contacting with one another, that is they show higher correlations in the context of at- 221 risk conditions such as poor quality of parent-child interaction57. Furthermore, peripheral 222 oxytocin levels seems to be closely linked to parent-child interaction; oxytocin levels rise 223 in parents and offspring as a function of fine-tuned behavioral synchrony 58. Behavioural 224 synchrony is whereby in a synchronous relationship, when a child becomes distressed, 225 the parent will succeed in regulating his/her own feelings of discomfort and adopt a 226 soothing behavior, thereby helping the child to restore balance. 227 228 [H2] Neural circuitry 229 Alterations in several brain circuits have been demonstrated to underlie the 230 phenotypes of BPD (Figure 3). Brain circuits related to the interpersonal instability 231 phenotype include those involved in theory of mind (that is, inferring others’ emotional, 10 232 cognitive and intentional states) and empathy (sharing others’ emotions), and circuits 233 related to the self-disturbance phenotype having a role in abnormalities of self- 234 referential thinking and the sense of the self. Brain circuits related to the 235 affective/emotional dysregulation phenotype consist of interacting bottom-up and top- 236 down processes, whereas circuits involved in the behavioral dysregulation phenotype 237 are involved in the prediction of negative outcomes and inhibitory control. The affective 238 pain processing circuit is thought to mediate hypalgesia in non-suicidal self-injurious 239 behavior in patients with BPD. 240 241 [H3] Interpersonal and the self phenotypes. Midline brain structures have a 242 role in understanding the mental state of others and the understanding of the mental 243 state of oneself, supporting Fonagy’s generative model that the development of the self 244 originates from the contingent resonance of others, particularly early care-givers59 e.g. 245 when the mother based on observing and rightly understanding the affect of her child 246 reciprocates this. Consequently, the National Institute of Mental Health Research 247 Domain Criteria (RDoC; criteria for the study of mental disorders based on dimensional, 248 functional constructs with levels of information ranging from genomics and brain circuits 249 to behavior and self-reports) have included the perception and understanding of the self 250 and the other under the same construct of “Systems for Social Processes”( 251 https://www.nimh.nih.gov/research-priorities/rdoc/definitions-of-the-rdoc-domains-and- 252 constructs.shtml). Midline structures involved both, in understanding the mental state of 253 others and the self, include the medial prefrontal cortex (including the anterior cingulate 254 cortex and dorsomedial PFC), the precuneus and the posterior cingulate cortex, the 11 255 temporoparietal junction, and the temporal poles. These brain regions largely overlap 256 with the default mode network (that is, regions that are active when no focus is on the 257 outside world). 258 Individuals with BPD tend to hypermentalize (that is to overattribute intentions 259 and emotions about the self and others) in a complex and abstract way60. Studies 260 investigating the interference of task-irrelevant social information on performance of a 261 cognitive exercise (whereby participants performed a working memory task while 262 viewing emotional scenes for distraction) demonstrated stronger coupling of the 263 amygdala and the medial prefrontal cortex and (para)-hippocampal areas in patients 264 with BPD compared with healthy individuals61. This finding could be linked to problems 265 in shifting attention away from self-relevant information to the external task in patients61. 266 Another study examined the processing of self-representation or other-representation 267 by instructing participants to evaluate personality traits of oneself (self-representation) 268 and of a close friend (other-representation). Using a two-factorial design, participants 269 had to answer four questions: Are you kind? (1st person on oneself); Is your friend nice? 270 (1st person on the other); According to your friend, are you nice? (3rd person on oneself); 271 According to your friend, is she/he nice? (3rd person on the other). Patients with BPD 272 had higher activation of midline structures in both self-representation and other- 273 representation tasks but no specific abnormalities for a single condition, compared with 274 healthy controls, further supporting an overlap between the neural correlates of self- 275 disturbance and other- disturbance. Interestingly, the hyperactivation of midline 276 structures was associated with less stable social representations62. In addition, 277 individuals with BPD show high levels of alexithymia 63, that is they have major 12 278 problems in identifying and describing their own emotions which may further deteriorate 279 the understanding of others´ emotions64 and has been shown to be related to behavioral 280 dysregulation65. 281 Other studies have assessed theory of mind and empathy in patients with BPD. 282 Theory of mind and empathy are separate abilities and may not co-vary within an 283 individual. Deficits in theory of mind might have a substantial role in interpersonal 284 dysfunction in BPD. For example, in one study, patients with BPD were asked to 285 evaluate the emotional state and – in a more complex task – the intention of another 286 individual, showing decreased activity in the brain social cognition circuit (the 287 temporoparietal junction and the superior temporal sulcus and gyrus, the latter of which 288 is needed for decoding mimics and gestures of others, compared with healthy 289 controls66. The difference between patients and healthy controls increased with task 290 complexity. 66 In addition, reduced activity of the superior temporal sulcus was found in 291 a study in which patients with BPD inferred the emotional state of a person from a 292 situational context67. 293 Interestingly, poorly coordinated social exchange between patients with BPD and 294 healthy individuals was recently demonstrated by reduced cross-brain neural coupling 295 between temporoparietal junction networks compared with social exchange between 296 two healthy individuals when performing a joint-attention task in a hyperscanning 297 context 68. Furthermore, patients with BPD showed reduced functional connectivity 298 between the social cognition network and areas involved in emotional-regulation areas 299 (such as the anterior cingulate cortex) compared with healthy individuals, which might 13 300 facilitate the distorted interpretation of others’ mental states (that is, poor theory of mind, 301 hypermentalizing in particular) in conditions of emotional arousal and stress69. 302 Although individuals with BPD have impairments in theory of mind, they exhibit a 303 comparable or higher degree of empathy than healthy controls63. For example, when 304 individuals were asked how much they feel for a person in distress (that is, were 305 encouraged to share others’ emotions), patients with BPD outperformed controls in 306 terms of empathy and showed insular hyperactivity that was associated with enhanced 307 emotional arousal67. This finding is consistent with an affect-dominated, rather than 308 cognitive-dominated perception of others that makes patients with BPD vulnerable to 309 distressing contagion (although in “mature” empathy one does not confuse the other’s 310 emotion with the self’s emotion, this self-other distinction is missing in emotion 311 contagion) 70. Although the specificity of brain mechanisms underlying abnormal social 312 cognition and empathy functions in BPD still has to be clarified, they differ from those 313 typical of antisocial personality disorder70. 314 A further prominent characteristic of interpersonal dysfunction is rejection 315 hypersensitivity which is also influenced by emotional hypersensitivity (see below). 316 Across different paradigms of social rejection, the dorsal ACC has been found to be 317 activated and to represent a common neural alarm signal of physical and social pain71. 318 In a virtual ball-tossing game where participants were either excluded, included or 319 participated in a control condition, patients with BPD showed higher activation of the 320 dorsal ACC in all conditions suggesting a higher sensitivity of the alarm signal even in 321 situations where exclusion was absent. In addition, higher activation in the dorsomedial 14 322 PFC and precuneus support the notion of hypermentalizing to be typical of BPD in 323 social situations.72 324 [H3] Affect/emotion phenotype. Affective instability is a central feature of BPD 325 psychopathology and describes frequently escalating negative affects which occur to 326 more or less intense stressors and show a delayed regression to baseline. 327 Neuroimaging studies have demonstrated abnormalities in so-called bottom-up and top- 328 down processes in patients with BPD: bottom-up processes originate from perceptual 329 stimulation of the external world and are important for detecting salience, whereas top- 330 down processes involve cognitive control areas that have a role in pursuing goals and 331 strategic decision-making. Bottom-up emotional processing involves the amygdala, 332 hippocampus, insula and rostral anterior cingulate cortex, whereas top-down emotional 333 processing involves prefrontal areas such as the dorsal anterior cingulate cortex and the 334 orbitofrontal, ventrolateral and dorsolateral prefrontal cortices. 335 Emotional hypersensitivity (an attentional bias or hypervigilance towards negative 336 environmental stimuli such as a perceived slight or a critical look by a friend or relative 337 that makes patients vulnerable to rapid changes in affect), and the failure to recruit 338 adaptive affect regulation strategies are apparent in patients with BPD73. In particular, 339 hypervigilance to negative environmental stimuli occurs in response to social threat 340 signals. For example, women with BPD had more frequent and faster fixations of the 341 eyes to images of angry faces than healthy controls in an emotion classification task, 342 and the abnormal eye fixation was associated with increased amygdala activation74. 343 Event-related potentials, based on electroencephalography (EEG), showed increased 344 early occipital P100 amplitudes (in the visual cortex) but decreased later 15 345 temporooccipital N170 and centroparietal P300 amplitudes in response to blends of 346 happy and angry facial emotions, indicating a pre-attentive, rapid and coarse processing 347 of social cues in BPD, instead of a more detailed, elaborate processing75. Interestingly, 348 the P100 amplitudes normalized in individuals in remission from BPD, suggesting an 349 enhanced perceptual bottom-up process reflects an acute feature rather than a trait 76. 350 However, prospective studies are needed. 351 A consistent feature in unmedicated patients with acute BPD is left amygdala 352 hyper-reactivity in response to negative environmental stimuli77. Thus, amygdala 353 hyperactivity is not restricted to stimulus onset, but also results from a deficit in 354 habituation (that is, a form of learning whereby the response to a stimulus is reduced 355 after repeated exposure)78–80. In addition, the central role of amygdala hyperactivity in 356 BPD might also reflect maladaptive cognitive top-down processes that have a role in 357 evaluating and prioritizing negative environmental stimuli81. Smaller volume and 358 metabolic alterations such as reduced N-acetylaspartate concentration found using 359 proton magnetic resonance spectroscopy of the left amygdala have been demonstrated 360 in BPD77,82, particularly in the centromedial amygdala83, which projects to hormonal 361 regulatory centers in the hypothalamus, and to autonomic and behavioral centers in the 362 brainstem. The hypothalamus is enlarged84 and the HPA stress axis is dysregulated in 363 patients with BPD; volume reduction of the amygdala and hippocampus might be more 364 pronounced in patients with early trauma and comorbid PTSD85,86. Notably, gray matter 365 volume reductions in the amygdala are only found in older individuals with BPD, 366 probably indicating a progressive pathology77,87 which, nevertheless, appears to be 367 reversible88. 16 368 Intense and variable emotions are related to amygdala hyperactivity, whereas 369 emotional regulation difficulties in general, and poor capacity of cognitive reappraisal 370 (that is, recognizing the negative pattern of one’s thoughts and changing that 371 pattern to one that is more effective in regulating one’s emotions), in particular, were 372 negatively correlated with prefrontal cortical activity in BPD89. Studies instructing 373 participants to use an adaptive affect regulation strategy (such as cognitive reappraisal), 374 found lower activity in orbitofrontal, ventrolateral or dorsal anterior cingulate cortices in 375 patients with BPD than healthy individuals90,91. However, studies using emotional 376 paradigms (passively looking at emotional facial expressions or scenes) without 377 instruction to regulate emotions demonstrated increased prefrontal cortical activity in 378 patients with BPD, which might reflect patients’ effort to cognitively down-regulate their 379 emotions despite not being successful92,93. In addition, structural alterations of the 380 prefrontal cortex have been demonstrated in patients with BPD, such as smaller grey 381 matter volume77,94, reduced cortical thickness94 and microstructural abnormalities of 382 white matter tracts95. Furthermore, preliminary data suggest low prefronto-limbic 383 connectivity within the affect regulation circuit93, which normalizes after successful 384 psychotherapy96 suggesting that this core mechanism of BPD is reversible. 385 Evaluative-regulatory feedback mechanisms of emotion regulation include 386 interoceptive processes as the physiological dimension of emotional experience, and 387 seem to be disrupted in patients with BPD. In one study, individuals with BPD had lower 388 right dorsomedial prefrontal cortex activation than healthy controls when asked to attend 389 to emotions and bodily feelings (for example, instructed to “feel yourself and be aware 390 of your current emotions and bodily feelings”, compared to cognitive self-reflection 17 391 (instructed to “Think about yourself, reflect who you are, about your goals”)97. As 392 afferent signals from the periphery, such as heartbeat, are relayed via the spinal cord 393 and brainstem to the midbrain and finally to structures of higher order, such as 394 thalamus, insula and prefrontal cortex, decreased mental representation of bodily 395 signals in patients with BPD was suggested by reduced heartbeat-evoked potentials in 396 resting state EEG (a marker for the cortical representation of afferent bodily signals) 397 compared with healthy volunteers98. Indeed, reduced heartbeat-evoked potentials were 398 associated with the severity of emotion dysregulation and smaller volumes of some 399 brain regions, e.g. the left insula which has a major role in the body-brain axis98. 400 Remission from BPD was paralleled by an improvement in cortical representation of 401 bodily signals98. 402 Notably, similar abnormalities of brain function and structure - as described in 403 this section up to now - have been reported in anxiety disorders, avoidant personality 404 disorder and depression. Prefronto-amygdala dysfunction might manifest a 405 transdiagnostic mechanism associated with negative affectivity or the related trait 406 construct of neuroticism. Supporting the latter assumption, neuroticism was recently 407 shown to modulate a wide network of brain regions, including the emotional regulatory 408 network99. 409 410 [H3] Behavioral dysregulation. Impulsivity is a multifaceted construct comprising 411 various components. Impairments in delay discounting (that is, the ability to delay an 412 immediate smaller reward for a larger, not immediate reward), high emotional 413 interference in cognitive functioning, and a reduction in response inhibition (that is, the 18 414 ability to inhibit an already activated behavioral response) in the context of emotional 415 stress have been reported in patients with BPD100,101. Indeed, individuals with BPD 416 consistently choose smaller rewards delivered within a short timeframe over larger 417 rewards delivered at a later timeframe compared with healthy individuals. In a monetary 418 incentive delay task in which three different objects predicted a reward, loss or a neutral 419 outcome, individuals with BPD had reduced activation of the ventral striatum to cues 420 predicting reward and loss, compared with healthy individuals and activation was 421 negatively correlated with impulsivity, suggesting that patients might have a poor ability 422 to predict aversive outcomes102. In an affective go/no-go task, (in which participants 423 were instructed to respond if the presented facial affect was consistent with the target 424 affect for that epoch and to inhibit motor response to those inconsistent with the target 425 affect), BPD was characterized by alterations in ventrolateral prefrontal or orbitofrontal 426 activity, indicating an interference between the motor inhibition task and the processing 427 of emotional stimuli103. Notably, the control of emotional interference at motor inhibition 428 tasks involves brain areas that overlap with the affect regulation circuit, such as the 429 orbitofrontal and subgenual anterior cingulate cortex104. Under high levels of stress (e.g. 430 anger induction), females with BPD had decreased activity of the inferior frontal cortex 431 compared with healthy controls during a go/no-go task, which challenges the capability 432 to inhibit prepotent motor responses105. Accordingly, abnormalities in the inferior frontal 433 cortex may be a neurobiological correlate of motor impulsivity in BPD105. Importantly, in 434 contrast to previous assumptions, a failure of response inhibition beyond situations of 435 intense stress is not characteristic of BPD, but is inherent to ADHD (a highly prevalent 436 comorbid condition of BPD)100. Regarding the specificity of findings within the 19 437 externalizing spectrum of psychopathology, impairments in delay discounting and a 438 close interaction between behavioral dyscontrol and negative emotional states in BPD 439 differs from individuals with antisocial personality disorder, who have less impairment in 440 delay discounting but a generally deficient response inhibition100. 441 442 [H3] Pain processing circuit. The non-suicidal self-injurious behavior in those 443 with BPD serves as a stress relief and is associated with diminished affect-related pain 444 processing. Increased pain thresholds in patients with BPD might be based on two 445 mechanisms106. First, deactivation of the amygdala and enhanced negative coupling 446 between limbic and medial prefrontal areas might reflect an enhanced inhibitory top- 447 down modulation in BPD. Consistent with this theory, amygdala activity decreased more 448 in individuals with BPD than in healthy controls, and functional connectivity with the 449 superior frontal gyrus normalized in BPD after an incision in the forearm107. Second, 450 enhanced coupling between the posterior insula (involved in the processing of affect- 451 related pain), and the dorsolateral prefrontal cortex might reflect an abnormal evaluation 452 of pain that contributes to hypoalgesia in BPD108. Indeed, the experience of pain — not 453 the tissue damage — leads to subjective stress reduction in patients with BPD109. 454 Interestingly, dialectical behavior therapy (DBT) focuses on improving affect regulation 455 strategies (see Management) and decreased inhibitory top-down modulation110. 456 However, low self-worth and a self-critical cognitive style might also constitute a 457 significant mediator between hypoalgesia and non-suicidal self-injurious behavior,111 458 although the significance of this mechanism for BPD is not yet clear. Further studies 459 may improve our understanding of what mechanisms act in each individual in which 20 460 context and how the pain circuit interferes with key regions of the self-processing and 461 self-valuation systems of the brain. 462 463 [H2] Hormones 464 Dysfunction of the HPA axis has a central role in the development of BPD. 465 Indeed, most studies have demonstrated increased levels of stress hormones, such as 466 basal cortisol112, a steeper cortisol awakening response (that is, a sharp increase in 467 cortisol levels after awakening) 113 and reduced feedback sensitivity112 in patients with 468 BPD. Additionally, increased memory retrieval (memory of words, working memory and 469 most pronounced of autobiographical memory) following cortisol administration in 470 patients with BPD suggests alterations in the sensitivity of glucocorticoid receptors to 471 stress hormones; in healthy individuals, cortisol administration was followed by impaired 472 memory retrieval114. In addition, increased HPA activity correlated with early life 473 maltreatment in BPD112. Interestingly, the extent of the cortisol stress response in a 474 parent–young adult conflict discussion was modulated by the quality of parental 475 protection, at least as perceived by individuals with BPD115. 476 Peripheral oxytocin levels are decreased in adults with BPD116, particularly in 477 those with a history of early life maltreatment116, and disorganized attachment 478 representations117. Oxytocin is thought to act as a counterpart to cortisol and buffers 479 chronic stress responses, particularly in the social context118. In BPD, oxytocin seems to 480 dampen subjective and psychophysiological stress responses119 as well as 481 hypersensitivity to social threat74 and other negative emotional stimuli120 by modulating 482 amygdala activity. Variants of OXTR, which encodes the oxytocin receptor (namely the 21 483 rs53576 single nucleotide polymorphism), are modulated by the environment; thus, 484 gene-environmental interactions related to the oxytocin receptor modulate vulnerability 485 to psychopathology in general121 and BPD122. Importantly, these effects might be sex- 486 sensitive123. 487 Few studies have investigated sex hormones in BPD. Testosterone 488 concentrations appear to be increased in female and male patients with BPD, whether 489 assessed as short-term testosterone in saliva113 or long-term testosterone in hair (a 490 cumulative measure representing excretion levels over several months)124. Interestingly, 491 testosterone has been shown to be involved in prefronto-amygdalar inhibition in a social 492 approach-avoidance task whereby participants are instructed to approach and avoid 493 emotional faces by pulling and pushing a joystick, respectively, and therefore, might 494 favor social approach and dominant behavior 124,125. Furthermore, changes in female 495 sex hormones (such as estradiol and progesterone) during the menstrual cycle might 496 affect BPD symptom expression126. 497 498 499 [H1] DIAGNOSIS, SCREENING, AND PREVENTION 500 501 [H2] DSM-5 and ICD-10 diagnostic criteria 502 The DSM-5127 Section II diagnostic criteria for BPD can be divided into four 503 phenotypes, consistent with the general criteria for a personality disorder (Figure 2); 504 diagnosis is made by a polythetic model requiring at least 5 of the 9 criteria (Box 2). Like 22 505 other psychiatric illnesses in the DSM, the BPD diagnostic criteria define an 506 independent category although this category overlaps with other disorders. 507 Meeting increasing numbers of the BPD criteria in the DSM-5 up to a total of five 508 criteria is associated with more-severe illness 128. The presence of even one BPD 509 criterion distinguishes patients with respect to concurrent other mental disorders, 510 current suicidal ideation and past attempts, history of psychiatric hospitalization, and 511 functional impairment129. Although all criteria for BPD are weighted equally for 512 diagnosis, the unstable relationships criterion has the best combined sensitivity and 513 specificity for BPD two years later44 and had the highest familial aggregation in one 514 study41.The criterion of chronic feelings of emptiness was most strongly related to 515 psychosocial morbidity, including history of suicide attempts, hospitalization, social and 516 work dysfunction, and comorbidity with other mental disorders130. 517 In the International Classification of Diseases, 10th Revision (ICD-10) 131, BPD is 518 called emotionally unstable personality disorder and is characterized by unstable sense 519 of self, unstable relationships with other people, and unstable emotions131. 520 521 [H2] Clinical assessment 522 Patients with BPD frequently present for treatment in the midst of an episode of 523 another mental disorder, such as depressive disorders, anxiety disorders, trauma- 524 related disorders, or substance use disorders. Patients might also present after a 525 suicide attempt or other impulsive, self-destructive actions, or might have a current 526 interpersonal crisis (such as a relationship break-up) or other crisis (such as a job loss 527 or school failure) that leads them to seek help. 23 528 In most clinical settings, assessment of patients with suspected BPD will be 529 conducted by interview. As personality is the way people see, relate to, and think about 530 themselves, others, and the environment, the perception of one’s own personality is 531 affected by it and accordingly, the assessment of personality pathology has unique 532 challenges. Indeed, individuals with personality pathology are frequently unreliable 533 observers of their own personality problems and might recognize problems only when 534 they affect their interactions and relationships with others. Rather than directly 535 questioning individuals about their personality, clinicians often look for patterns in the 536 way patients describe themselves, their interpersonal relationships, and their work 537 functioning. Common questions a clinician would pose to an individual with a suspected 538 personality disorder include “how would you describe yourself as a person?”, “how do 539 you think others would describe you?”, “who are the most important people in your life?” 540 and “how do you get along with them?”. In addition, clinicians often also rely on how 541 individuals interact with them during the interview and may interview other individuals 542 close to the patient to gather additional information and perspectives. Several additional 543 factors should be considered during the assessment of a patient for BPD (Box 3). 544 Clinical assessments of borderline personality pathology are challenging. For 545 example, clinicians might overgeneralize their experiences with patients during 546 evaluation to other life situations without sufficient evidence. In addition, clinicians might 547 have a general impression of the patients personality but with inadequate information to 548 evaluate the specific criteria for BPD132. Clinicians will often deviate from their 549 judgments about individual criteria and overdiagnose or underdiagnose BPD without a 550 basis133. These sources of diagnostic unreliability – interpretation, information, and 24 551 criterion variance – have led to the development and use of semi-structured134 and fully- 552 structured diagnostic interviews and self-report questionnaires for the diagnosis of BPD 553 and other personality disorders. Indeed, self-report instruments and semi-structured 554 interviews are more reliable and valid than routine clinical assessments for the 555 diagnosis of personality pathology135 and the combined use of interview and self-report 556 optimally identifies BPD136. 557 558 [H3] Clinical interviews. Most semi-structured interviews include questions to elicit 559 information to determine whether or not a subject or patient meets each of the 560 diagnostic criteria and apply diagnostic algorithms for all DSM-IV and DSM-5 561 personality disorders. These interviews differ primarily in the arrangement of the 562 questions, either by type of disorder or by area of functioning (Table 1). All semi- 563 structured interviews are meant to be administered by trained clinicians who have 564 experience evaluating patients with mental disorders in general and, specifically, 565 patients with personality pathology. Examples of clinical interviews include the 566 Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II), the Structured 567 Interview for DSM-IV Personality Disorders (SIDP-IV), the Revised Diagnostic Interview 568 for Borderlines (DIB-R), and the Childhood Interview for DSM-IV Borderline Personality 569 Disorder (CI-BPD); the latter two assessments are specific to BPD. Some tools were 570 designed for use by non-clinical, lay interviewers in large epidemiological studies (such 571 as Alcohol Use Disorder and Associated Disabilities Interview Schedule-5), which 572 includes questions to assess the criteria for BPD. Other, short interval interviews such 573 as the Borderline Personality Disorder Severity Index-IV and the Zanarini Rating Scale 25 574 for Borderline Personality Disorder are used to track severity and change in BPD 575 pathology over time. 576 577 [H3] Self-report questionnaires. Although patients with personality disorders have 578 difficulty accurately observing themselves, a plethora of self-report instruments have 579 been developed to expedite diagnostic assessments and as first-stage screening 580 assessments (Table 1). Self-report instruments differ in their structure, length, and 581 specificity for BPD. In addition, several self-report instruments are particularly suited for 582 BPD screening in large populations. Of note, the affective instability criterion is the most 583 sensitive and specific manifestation for BPD diagnosis and might be useful for 584 screening137. Other self-report instruments do not assess personality disorders but 585 assess problems in personality functioning. 586 587 [H2] Differential diagnosis and comorbidities 588 As individuals with BPD frequently present for treatment due to an exacerbation of 589 another co-occurring mental disorder, careful assessment of a broad range of 590 psychopathology is indicated in an individual with suspected BPD138,139. Several other 591 disorders might also be present in patients with BPD including mood (e.g., major 592 depressive disorder or bipolar disorder), anxiety, stressor-related (e.g., acute stress 593 disorder, PTSD), substance-related, dissociative, disruptive behavior, somatoform, 594 neurodevelopmental (e.g., attention-deficit/hyperactivity disorder) and other personality 595 disorders10. Indeed, rates of lifetime major depressive disorder range from 61% to 83%, 596 with a median of 71%140–142, and the lifetime rate of anxiety disorders is 88% in patients 26 597 with BPD141 in several large patient samples. A history of trauma, central to the 598 diagnosis of PTSD, is also common in patients with BPD. ADHD has been reported in 599 ~20% of patients with BPD 143. The differential diagnosis between BPD with comorbid 600 major depressive disorder and bipolar disorders is complex (Box 4). 601 602 The type and frequency of co-occurring disorder depends on the population assessed 603 (i.e., patient or general population), clinical setting (e.g., inpatient, outpatient, sub- 604 specialty clinic), the prevalence of the disorders in the population, the duration of the 605 disorders, and the methods of assessment, among other factors. 10 Co-occurring 606 disorders are unlikely to be comorbid in the sense of a disorder that is distinct from the 607 index disease or condition144. Indeed, some patients with BPD do not respond to 608 antidepressants and depressive symptoms can remit with improvement of BPD 145,146, 609 suggesting that depression is linked to patient’s dissatisfaction with life rather than a 610 comorbid depressive disorder. Similarly, remission of BPD usually prompts remission of 611 anxiety disorders147. In addition, the tendency of the DSM to split up psychopathology 612 into different disorders encourages the diagnosis of multiple disorders to describe a 613 patient’s psychopathology and virtually ensures that patients receive more than one 614 diagnosis. This, in turn, has encouraged polypharmacy (see Management). As BPD 615 complicates the treatment of other mental disorders and is associated with a more 616 chronic course for many disorders 148,149 and as effective treatment of BPD can diminish 617 associated psychopathology, 147,150 distinguishing BPD from other mental disorders may 618 be less important than setting priorities among disorders for treatment. 27 619 620 BPD is also associated with non-psychiatric disorders, including arthritis, gastrointestinal conditions, and, in young adults, cardiovascular disease.151 621 622 [H2] Prevention 623 Data is relatively scarce on the prevention of BPD development, including 624 universal prevention, selective prevention (in high-risk populations, such as individuals 625 who have been sexually or physically abused), or indicated prevention (in individuals 626 with signs of BPD or underlying pathological personality traits in childhood or early 627 adolescence). Universal prevention is not practical owing to the relatively low 628 prevalence of BPD in all age groups. Risk factors lack sufficient specificity for BPD to 629 support use in selective prevention. The identification of a BPD prodrome consisting of 630 increased emotionality, hyperactivity or impulsivity, depression and inattention has been 631 supported in one large prospective follow-up study of young girls37. Programs designed 632 for early intervention in young people with precursor signs or a diagnosis of BPD have 633 been developed12,152,153 and sometimes implemented for example, in Australia, 634 Germany and the Netherlands. Certainly, individuals at any age who meet criteria for 635 BPD should receive treatment154. 636 637 638 [H1] MANAGEMENT The treatment of patients with BPD should begin with disclosure of the diagnosis 639 and education about the expectable course, genetics, and treatment of the disorder. 640 This approach can diminish distress and establish an alliance between the patient and 641 the clinician 155. Treatment should also inform patients that effective therapies have 642 been developed, which involve learning to take care of oneself, and that medications 28 643 serve only an adjunctive role. Often patients with BPD will be misdiagnosed132,156, 644 disliked157, and overmedicated 158,159. Such practices persist despite considerable 645 knowledge about how patients can be treated effectively. 646 647 [H2] Evidence-based therapies 648 Five general principles characterizing evidence-based effective treatments for 649 BPD have been developed160,161. First, treatment should be carried out by a primary 650 clinician who develops the treatment plan and goals, oversees the risk of suicide and 651 monitors progress. Second, management should have structure, such that therapies 652 have identifiable goals, the roles of both the patients and treater are specified, 653 boundaries about the availability of the treater have been determined and guidelines for 654 managing safety are established. Third, management should be collaborative and 655 clinicians should solicit their patients’ involvement in setting the treatment goals and, 656 safety plans and within-session participation. Indeed, the patients sense of responsibility 657 for change and self-care is emphasized. Fourth, clinicians should be actively 658 responsive, reassuring patients that they are listening and interested, while also being 659 contained, not being overly emotional or activating. Finally, clinicians should be self- 660 aware, and colleagues should be used to diminish the hazards of personalized 661 reactions of patients. Of particular note is the principle, important for patients with BPD, 662 of reminding clinicians to be aware of how their reactions to patients requires attention 663 because they can be harmful. 664 665 13 forms of psychological therapy have demonstrated efficacy for the treatment of BPD in at least one randomized controlled trial, although DBT has the most research 29 666 support. The availability of these therapies varies worldwide from being not available at 667 all to at best being only inconsistently available. Nowhere is their availability sufficient to 668 meet the public health needs. Four of these therapies have attained widespread 669 recognition along with being grounded in substantive theories about BPD and sustained 670 training opportunities offered by credentialed and committed trainers (Table 2). These 671 therapies — dialectical behavioural therapy (DBT), mentalization-based treatment 672 (MBT), transference focused psychotherapy (TFP) and General (“Good”) psychiatric 673 management (GPM) — all decrease suicidality and self-harm, depression, anxiety, and 674 use of hospitals and emergency rooms in patients with BPD 3,4,162–165. 675 DBT, MBT and TFP are psychotherapies, and intend to change patient’s 676 psychological functions (such as self-awareness, empathy and social skills) through 677 insights, instruction, and corrective interpersonal experiences. DBT is a type of 678 cognitive-behavioral therapy that focuses on diminishing the observable symptoms of 679 BPD. 2 MBT and TFP are psychodynamic therapies that focus on improving patients’ 680 understanding of their motives and feelings that are often unconscious and are thought 681 to prompt symptoms3,166. With all these psychotherapies, the relationship between the 682 patient and the therapist is often a central focus, and these require considerable training 683 and time to learn. 684 685 The three main psychotherapies have been compared with less intensive manualized 686 approaches that are less challenging to learn, more supportive, and more suitable for 687 non-specialist, generalist providers 167,168. GPM is a case management-based therapy 688 that medicalizes BPD and focuses on the patient’s situational stressors. This generalist 30 689 approach is intended to improve patients’ social functioning with the expectation that 690 this improvement will improve self-esteem, self-confidence, and social/interpersonal 691 skills169. The development of a generalist model for the treatment of BPD offers a 692 treatment modality that can be taught to clinicians using standard training programs. 693 GPM is also well suited for integration with stepped care models of health care170. Non- 694 intensive interventions administered by non-specialists are well-suited for early 695 intervention and patients with less-severe BPD171. Such a model has been introduced in 696 Australia with encouraging results171. 697 698 [H2] Effect of co-morbidities 699 The management of patients with BPD is frequently confounded by co-occurring 700 psychiatric disorders. Unlike with other personality disorders, the treatment of BPD 701 should take priority in patients with comorbid major depressive disorder, panic disorder, 702 adult-onset PTSD, intermittent substance abuse or bulimia, as these disorders remit 703 with remission of BPD169. As anxious dysphoria is almost universal in patients with BPD 704 172 705 often are prescribed anti-depressants159,173. 706 and a high proportion of patients have comorbid major depressive disorder, patients The treatment of comorbid bipolar I disorder, early-onset complex PTSD, severe 707 substance abuse and anorexia should be prioritized over the treatment of BPD, as 708 effective treatment of BPD requires the remission of these disorders. The co-occurrence 709 of impulse control disorders (such as severe substance abuse) or severe antisocial 710 personality disorder makes the successful treatment of BPD improbable. Milder forms of 711 these disorders can interfere with the treatability of BPD, but treatment of BPD is 31 712 possible and will secondarily prompt improvement in those disorders174,175. In comorbid 713 bipolar I disorder, a manic episode should always be treated before BPD; BPD and 714 bipolar disorder should be treated as independent disorders as they have little effect the 715 course of the other disorder150. Questioning whether treating comorbid PTSD should 716 take priority is common. The treatment of early onset complex PTSD take priority over 717 treatment of BPD, but otherwise BPD treatment usually improves PTSD and this effect 718 can be augmented by concurrent exposure techniques176,177. 719 720 [H2] Psychoactive medication 721 Patients with BPD who were diagnosed before they received trials with 722 psychoactive medications, often multiple types extending over many years, are 723 uncommon14,15,158. Approximately 40% of patients with BPD were prescribed ≥3 724 psychotropic medications, ~ 20% were prescribed ≥4 medications, and ~10% were 725 prescribed ≥5 medications concurrently after diagnosis of BPD in a 16 year follow up 726 study158. The most common types of medication administered to patient with BPD are 727 selective serotonin reuptake inhibitors, atypical antidepressants, anxiolytics, 728 antipsychotics and mood stabilizers, in that order158. This practice has developed 729 despite that the usefulness of medications has not been established, no class of 730 psychoactive medication is consistently or dramatically effective, and no medications 731 are FDA approved for BPD159,173,178,179,180. Medications are often initiated by clinicians 732 aiming to relieve the patient’s presenting complaints of depression, moodiness, or 733 anxiety; patients do not present asking for personality change. The National Institute for 734 Health and Care Excellence (NICE) guidelines in the United Kingdom state that 32 735 psychotropic medications should not be used to treat the symptoms of BPD but can be 736 prescribed for comorbid disorders for the shortest period possible 179. Once medications 737 are started, patients with BPD typically resist discontinuing them, even when the target 738 symptoms are unchanged or exacerbated. In one study, a high percentage of patients 739 with BPD reported using psychotropic medications at each of eight two-year follow-up 740 periods158. Augmentation of medications is common, but is without empirical support158. 741 A cautious empirical approach to medication management, recognizing their 742 adjunctive role in treating some patients with BPD, can be helpful. This should include 743 informing patients that the benefits of medication are variable and usually modest, 744 encouraging patients to read about prescribed medications, enlisting patients as 745 collaborators to evaluate whether target symptoms alter and tapering or discontinuing 746 ineffective medications before starting another trial. This approach might disappoint 747 patients who had hoped for a more beneficial role of medications, but it is a relief for 748 patients who understand that their illness can be successfully treated by other means 749 after disappointing results from medications. 750 751 [H2] Sociotherapies 752 The support of families, including spouses is often essential for enlisting the 753 collaboration of patients with BPD. Attaining the families’ supportive involvement begins 754 with disclosure of the BPD diagnosis and a discussion about the disorder’s genetics, 755 expectable course, and its treatment. Families are often willing to modify the usual ways 756 of responding to the patient with BPD, and to learn to accommodate the specific 757 sensitivities and problems that characterize individuals with this disorder. Specifically, 33 758 this means learning to validate the distress of the patient with BPD, listening without 759 challenging the patient’s anger, and using professionals to help manage threats of 760 suicide or self-endangering behaviors181,182. Family therapy is usually contraindicated 761 until members are motivated and able to see each other’s perspectives. Family 762 Connections is a consumer-led group therapy that has proven very helpful to many181. 763 The social learning processes within group therapies are often very helpful and 764 cost-beneficial for patients with BPD who typically have problems with listening, sharing, 765 and understanding others. Indeed, the group therapy component accounts for much of 766 the effectiveness of DBT163 and MBT183. However, patients usually resist such 767 treatment, so making individual therapy (which patients desire) contingent on 768 participation in groups might be necessary. 769 770 771 [H2] Overview Great steps forward have occurred in the treatment of BPD. Indeed, combining 772 treatment with informing patients about their likelihood of recovery, patients can have 773 much higher expectations than previously thought. However, challenges remain to 774 develop psychoactive medications that can directly address the emotional reactivity and 775 interpersonal hypersensitivity of BPD, and that can improve persisting social and 776 vocational problems (see Quality of Life). Therapies that target the persisting functional 777 problems of patients are required. 778 779 780 781 782 783 [H1] QUALITY OF LIFE 34 784 785 786 [H2] Course of disease and prognosis 787 (MSAD) and the Collaborative Longitudinal Personality Disorders Study (CLPS)) yielded 788 unexpectedly encouraging perspectives on the symptomatic course of BPD. In the 789 CLPS study, ~85% of patients with BPD had a remission for at least 12 months, of 790 which, relapse rates were 12% (Figure 4)6. In the MSAD study, 99% of patients had a 791 remission period for at least 2 years and 78% of patients had remission for at least 8 792 years, over the 16 year follow-up5. However, symptomatic recurrence occurred at higher 793 rates in the MSAD study (between 10 and 36%, depending on the length of the 794 remission, with lower rates associated with longer periods of symptomatic remission), 795 compared with CLPS.5 Baseline predictors of a poor outcome in the CLPS study at two- 796 year follow-up were more severe borderline psychopathology, functional impairment, 797 and the quality of relationships.184 At 10-year follow-up, the CLPS study found younger 798 age and more education to be associated with good outcomes.6 Predictors of remission 799 by 10-year follow-up in the MSAD study were baseline younger age, absence of 800 childhood sexual abuse, no family history of substance abuse, good vocational record, 801 absence of an anxious cluster personality disorder, lower neuroticism, and higher 802 agreeableness.185 803 Interestingly, some symptoms of BPD were demonstrated to remit more rapidly than 804 others which are more enduring in both the MSAD and CLPS studies186–188. Most 805 impulsive symptoms are acute and have relatively rapid remission, whereas all 806 affective/emotional symptoms are more enduring187. Cognitive/self symptoms are both 807 acute (such as, quasi psychotic thought and serious identity disturbance) and enduring Two major prospective longitudinal studies (The McLean Study of Adult Development 35 808 (such as, odd thinking, unusual perceptual experiences and non-delusional paranoia). 809 Similarly, interpersonal symptoms can be acute or enduring; stormy relationships, 810 devaluation, and demandingness are more acute, whereas fear of aloneness, undue 811 dependency, and masochism are more enduring186. In the MSAD study, the more rapid 812 and stable remission of acute symptoms and the less rapid remission and higher 813 recurrence of temperamental symptoms was demonstrated after 16-years of follow- 814 up187. However, after 10-years of follow-up in the CLPS study, the prevalence of all BPD 815 criteria had declined at similar rates6. 816 817 [H2] Social and Vocational Functioning 818 Individuals with BPD living in the community are often seriously impaired 819 functionally.11,22,189 Prospective studies of the course of BPD have determined the 820 stability of these impairments for some patients. In the CLPS study, individuals with 821 BPD had significantly worse employment functioning than individuals with Cluster C 822 personality disorders (avoidant and obsessive-compulsive personality disorders) and 823 had significantly worse Global Assessment of Functioning (GAF) scores than individuals 824 with Cluster C personality disorders or major depressive disorder, at the two-year 825 follow-up point 190. Similarly, in the MSAD study, 191 patients reported poorer social and 826 vocational functioning than those with other personality disorders at the six-year follow- 827 up period191. However, remitted borderline patients reported better social and vocational 828 functioning than non-remitted borderline patients, and the percentage of patients 829 receiving disability payments was ~35% for those in remission, but increased from 56% 830 to 73% for patients who had not remitted.191 In addition, 43% of patients in remission 36 831 had a GAF score of ≥61 representing good overall functioning at the six-year follow-up 832 period, compared with no patients not in remission.191 833 834 In the MSAD study, survival analyses showed that patient functioning was quite 835 unstable, with some subjects losing their good psychosocial functioning and others 836 attaining it for the first time.192 However, 50% of patients attained recovery (defined as a 837 concurrent remission from BPD and good social and good full-time vocational 838 functioning) after 10 years of prospective follow-up, and 60% of patients attained 839 recovery after 16 years of prospective follow-up. 193Although patients with BPD 840 improved in both the social and vocational realms, they continued to function more 841 poorly than individuals with other personality disorders or major depressive disorders in 842 the CLPS study after 10 years of follow up6. The MSAD findings concerning recovery 843 rates indicate that there are subgroups of borderline patients—a high functioning group 844 and a more poorly functioning group. They also suggest that studies that rely on overall 845 results may inadvertently hide these important differences. 846 847 Patients with BPD who had recovered at some point during the course of disease 848 were significantly more likely to have entered into a marriage or prolonged cohabitation 849 relationship, and become a parent than patients who have never recovered in the 850 MSAD study after 16 years of follow up194. Recovered patients are also significantly 851 older when starting these relationships. Moreover, patients who had recovered were 852 significantly less likely to have divorced or ended a cohabiting relationship, and were 853 less likely to have given up or lost custody of a child (7% vs. 51%). Taken together, 37 854 these results suggest that patients with BPD can have stable intimate relationships and 855 become competent parents. In addition, success in these areas is more likely if patients 856 have recovered symptomatically and have achieved stable psychosocial functioning in 857 other areas. 858 859 [H2] Other health and lifestyle issues 860 After six-year follow-up, patients who had not been in remission were significantly 861 more likely to have a “syndrome-like” condition (e.g., chronic fatigue, fibromyalgia), 862 obesity, diabetes, osteoarthritis, hypertension, back pain, and urinary incontinence than 863 patients who had been in remission.195 They were also significantly more likely to report 864 daily consumption of alcohol, smoking one packet of cigarettes per day, daily use of 865 sleep medications, overuse of pain medications, and lack of regular exercise. In 866 addition, non-remitted patients with BPD were significantly more likely than remitted 867 patients with BPD to have had at least one medically-related emergency room visit, 868 medical hospitalization, or both. At 16-year follow-up, these same variables 869 distinguished ever and never-recovered borderline patients.196 870 A large epidemiological study found elevated rates of a number of conditions 871 among borderline persons living in the community. These conditions were: 872 arteriosclerosis or hypertension, hepatic disease, cardiovascular disease, 873 gastrointestinal disease, arthritis, venereal disease, and any assessed medical 874 condition.197 875 876 [H2] Mortality 38 877 By the time of the 16-year follow-up in the MSAD study, 4.5% of borderline 878 patients had died by suicide and 4.5% had died of other causes187. Although patients 879 with BPD have a known increased risk of suicide, data from the MSAD study suggest 880 that suicide might not be as common as previously estimated. For patients with other 881 personality disorders, 1.4% had died from suicide and 1.4% had died from another 882 cause 187. The average age of non-suicidal deaths was 39 years of age, suggesting that 883 patients with BPD died up to 40 years prematurely, compared with the life expectancy 884 norms of 78 or 79 years of age in the United States.198 885 886 [H1] OUTLOOK 887 One of the major challenges is that we still do not have a satisfactory 888 understanding of what comprises the core psychopathology of BPD. As suggested 889 within this Primer, this core psychopathology could be within the affect/emotion 890 dysregulation phenotype and/or within social processes, reflecting both the 891 interpersonal and self phenotypes. Like for other major mental illnesses, the search for 892 the core psychopathology of BPD identified by specific biomarkers or specific genetic 893 alterations associated with BPD is ongoing, but such markers have not yet been found. 894 The ambiguity inherent in the name “borderline” persists largely as a fall-back option 895 until the core psychopathology has been successfully identified. 896 Growing evidence suggests that BPD is related to a general personality disorder 897 factor (‘g’) that is common to all personality disorders and reflects the severity of 898 personality psychopathology199. General features of personality disorders have less 899 stability than specific trait features, consistent with the notion that personality functioning 39 900 is the more dynamic and changeable aspect of personality pathology, whereas 901 personality traits are stable, but general features are also more closely related to 902 impairment in psychosocial functioning200. The National Institute for Mental Health 903 Research Domain Criteria (RDoC) include ‘perception and understanding of self’ 904 encompassing self-awareness, self-monitoring, and self-knowledge, and ‘perception 905 and understanding of others’ related to social cognitive functions, as two subdomains of 906 ‘Social Processes’ 201, in addition to affiliation and attachment, which are moderated by 907 social information processing including the detection of and attention to social cues. 908 The definition of BPD also faces challenges. The DSM-5 retained the definition 909 for BPD that it has largely sustained since its conception, but an alternative proposal, 910 named the Alternative Model for Personality Disorders (AMPD; Box 5) was developed 911 by the DSM-5 personality disorders working group in 2011. The AMPD model appears 912 in the DSM-5 section III202. In this model, the traditional criteria for BPD are parsed into 913 impairments in personality functioning (self and interpersonal functioning) and into 914 pathological personality traits (negative affectivity, disinhibition and antagonism). These 915 personality trait domains were developed to represent personality disorders based on 916 meta-analyses203 and a field trial survey204. The AMPD criteria for BPD are highly 917 correlated (correlation coefficient of 0.80) with the standard crtieria205, such that 918 application of either criteria to clinical observations made by trained diagnosticians will 919 lead to the reliable identification of BPD . Establishing the reliability, validity, and clinical 920 utility of the AMPD is undergoing active research. The AMPD has several potential 921 advantages over standard DSM-5 criteria. First, it emphasizes the centrality of the self 922 and interpersonal sectors of the psychopathology of BPD, thereby helping identify what 40 923 best distinguishes BPD from other disorders with which it can be confused. Second, the 924 AMPD bridges the definition of BPD to trait structures of normal and abnormal 925 personality and, therefore, links BPD with the known anatomy of personality and will 926 help reflect that most personality disorders do not have discrete boundaries between 927 normal and abnormal functioning. Although these advantages for changing the definition 928 of BPD are substantial, reasons for moving slowly are also apparent206. For example, 929 the heritability of BPD is high compared with other personality disorders, BPD combines 930 externalizing and internalizing symptoms, and has clinical priority over other major 931 psychiatric disorders. Moreover, it doesn’t load on any specific personality factors, 932 rather it is distinguished by loading on a general factor. At this point in the development 933 of the BPD construct it seems important to retain multiple points of view regarding the 934 psychopathology of BPD. 935 A final challenge is that research in BPD is remarkably underfunded. Despite the 936 prevalence of BPD in the general population the high prevalence within treatment 937 facilities, high morbidity and high costs to society (Box 6), BPD comprises <1% of the 938 National Institute for Mental Health funded research. Europe is the foremost leader in 939 BPD-related research and within Europe, Germany stands out for establishing BPD as a 940 major research priority. Reasons for the failure of BPD to gain traction within the 941 research establishment in the United States might be the sustained stigma associated 942 with this disorder. Indeed, patients with BPD are difficult and the temptation is to ignore 943 or avoid these patients, justifying and aggravating their continued protests of being 944 neglected and unheard. 41 945 This Primer has summarized the remarkable body of knowledge that has been 946 acquired since the official recognition of BPD in 1980. Research into the genetic and 947 neurobiological abnormalities of this disorder have earned its place within the 948 biomedical community. However, still, the search for specificity in terms of biological or 949 genetic markers remains as is the case with other mental illnesses. Research into the 950 psychology, development, and response to psychological therapies of BPD have 951 established the place of this disorder within the mental health field’s clinical community. 952 Here, the neurobiological correlates of change in BPD psychopathology and new 953 therapies to better diminish persisting social and vocational impairment require further 954 study. Research into the prevalence and its societal costs of BPD have established this 955 disorder as a still inadequately addressed major public health problem. Increased public 956 awareness, better training of health care professionals, and increased investment in 957 research are needed. 958 959 42 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 References 1. Black, D. W. et al. Attitudes Toward Borderline Personality Disorder: A Survey of 706 Mental Health Clinicians. CNS Spectr. 16, 67–74 (2011). 2. Linehan, M. Cognitive-behavioral treatment of borderline personality disorder. (Guilford Press, 1993). 3. Bateman, A. & Fonagy, P. Effectiveness of Partial Hospitalization in the Treatment of Borderline Personality Disorder: A Randomized Controlled Trial. Am. J. Psychiatry 156, 1563–1569 (1999). 4. Clarkin, J. F., Levy, K. N., Lenzenweger, M. 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Mullins-Sweatt, S. N. et al. Five-Factor Measure of Borderline Personality Traits. J. Pers. Assess. 94, 475–487 (2012). 248. Clark, L. A., Simms, L. J., Wu, K. D. & Casillas, A. Manual for the Schedule for Nonadaptive and Adaptive Personality (SNAP-2). (University of Minnesota Press, 2008). 249. W. John Livesley & Douglas N. Jackson. Dimensional Assessment of Personality Pathology | SIGMA. (2009). Available at: 58 1696 1697 1698 1699 1700 1701 1702 1703 1704 1705 1706 1707 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 1721 1722 1723 250. 251. 252. 253. 254. 255. 256. 257. http://www.sigmaassessmentsystems.com/assessments/dimensionalassessment-of-personality-pathology-basic-questionnaire/. (Accessed: 12th January 2018) Sellbom, M. & Smith, A. Assessment of DSM–5 Section II Personality Disorders With the MMPI–2–RF in a Nonclinical Sample. J. Pers. Assess. 99, 384–397 (2016). Krueger, R. F., Derringer, J., Markon, K. E., Watson, D. & Skodol, A. E. 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Assess. 95, 479–485 (2013). Morey, L. C. Development and initial evaluation of a self-report form of the DSM– 5 Level of Personality Functioning Scale. Psychol. Assess. 29, 1302–1308 (2017). 1724 Author contributions 1725 Introduction (J.G.G.); Epidemiology (S.T.); Mechanisms/pathophysiology (S.C.H.); 1726 Diagnosis, screening and prevention (A.E.S.); Management (J.G.G.); Quality of life 1727 (M.C.Z.); Outlook (J.G.G.); Overview of Primer (J.G.G.). 1728 1729 Competing Interests 1730 S.C.H. was the past president of the International Society for the Study of Personality 1731 Disorders. A.E.S. receives author and editor royalties from American Psychiatric 59 1732 Association Publishing and from UpToDate. All other authors declare no competing 1733 interests. 1734 1735 Publisher’s note 1736 Springer Nature remains neutral with regard to jurisdictional claims in published maps 1737 and institutional affiliations. 1738 1739 1740 60 1741 1742 1743 1744 Box 1. BPD in children and adolescents. Although borderline personality disorder (BPD) is thought to start in childhood or 1745 early adolescence, it typically comes to clinical attention in early adulthood. However, 1746 clinicians have been reluctant to diagnose personality disorders in childhood and 1747 adolescence for several reasons: personality is considered to be in flux during this time; 1748 some immature attitudes and behaviours may be developmentally appropriate; and 1749 diagnosis could be stigmatizing. 1750 A cumulative prevalence of BPD of 1.4% by 16 years of age and 3.2% by 22 1751 years of age has been reported in the United States9. BPD diagnoses in childhood and 1752 adolescence have low to moderate diagnostic stability and moderate to high mean level 1753 (level of manifestations within a population) and rank order (an individual’s position on 1754 manifestations within a group) stability 207. From a systematic review of 10 studies, 14– 1755 40% of children or adolescents <19 years of age retained the BPD diagnosis after 1756 periods of between 2 and 20 years. 207 Thus, individuals with BPD pathology early in life 1757 can improve over time, but those with more-severe symptoms have a risk for BPD in 1758 early adult life and have substantial social, educational, work, and financial impairment 1759 in later life208. 1760 Complex comorbidity of BPD and other mental disorders is found in adolescents 1761 similar to in adults with BPD209. In a large community sample of girls at risk of BPD, the 1762 development of BPD symptoms was associated with impairment in eight domains of 1763 psychosocial functioning (for example, academic achievement, self-perception, social 1764 skills, sexual behavior) in the age range 14-17 years210. Taken together, these data 1765 suggest that BPD should be recognized and treated in children and early adolescence, 61 1766 and early intervention may prevent BPD chronicity and persistent associated 1767 psychosocial morbidity211,212. 1768 62 1769 1770 Box 2. DSM-5 criteria for BPD. 1771 Five or more of the following nine criteria are required for the diagnosis of borderline 1772 personality disorder (BPD) according to the Diagnosis and Statistical Manual of Mental 1773 Disorders, Fifth edition (DSM-5) 127. 1774 • Frantic efforts to avoid real or imagined abandonment 1775 • A pattern of unstable and intense interpersonal relationships that are 1776 characterized by alternating between the extremes of idealization and 1777 devaluation • Markedly and persistently unstable self image or sense of self (identify 1778 disturbance) 1779 • Impulsivity in at least two areas that are potentially self-damaging (for example, 1780 spending, sex, substance abuse, reckless driving or binge eating) a 1781 1782 • Recurrent suicidal behaviour, gestures or threats, or self-mutilating behaviour 1783 • Affective instability due to a marked reactivity of mood (for example, intense 1784 episodic dysphoria, irritability, or anxiety usually lasting a few hours and only 1785 rarely lasting for more than a few days) 1786 • A chronic feeling of emptiness 1787 • Inappropriate, intense anger or difficult controlling anger (for example, frequent displays of temper, constant anger or recurrent physical fights) 1788 • Transient, stress-related paranoid ideation or severe dissociative symptoms 1789 1790 a Does not include suicidal or self-mutilating behaviour . 1791 63 BOX 3. Additional factors to be considered in evaluating patients with BPD. Emotional intensity, anger, neediness, demanding behaviour, and tendencies to either overvalue or devalue the clinician should be anticipated during evaluations of patients with borderline personality pathology 10. Clinicians should elicit information about how the patient views themself and interacts with others, and they must establish that the features of borderline personality pathology are pervasive (manifest in many different life contexts and with many people) and inflexible (persist despite evidence that they are inappropriate, ineffective, or maladaptive). Focusing on maladaptive personality traits such as impulsivity and specific problematic behaviors, such as self-mutilation, is useful for documenting pervasiveness, as by definition personality traits are tendencies or predispositions to think, feel, or behave in patterned ways. Personality pathology is often evident by adolescence or early adulthood, as individuals encounter major life transitions, such as leaving home, becoming financially independent, and forming intimate relationships with people outside their families. Although personality pathology has traditionally been considered as stable and enduring, more recent, rigorous, longitudinal follow-along studies demonstrated that the most patients with BPD can substantially improve over time5,6. As patients with BPD frequently present for care due to an episode of another co-occurring mental disorder the clinician should distinguish signs and symptoms of the more acute disorder (states) from the manifestations of BPD (traits). Valid diagnoses of BPD can be made in individuals with concurrent major depressive disorder213. 64 BOX 4. Bipolar disorders and BPD. A differential diagnostic dilemma that has befuddled clinicians and researchers is between bipolar disorder – especially bipolar II disorder – and borderline personality disorder (BPD) with comorbid major depressive disorder. Bipolar disorders and BPD cooccur in ~10-20% of patients with either disorder, but most patients have only one of these disorders214. Many patients with BPD have been mistakenly diagnosed as having a bipolar disorder at some time215. Episodes of mood disturbances in bipolar disorders last longer and are less connected to external events than the labile affective states of BPD that are commonly triggered by stressful life events. Patients with major depressive disorder and comorbid BPD have significantly higher rates of post-traumatic stress disorder, substance use disorders, somatoform disorders, and other personality disorders than patients with bipolar II disorder without BPD 216. Patients with major depressive disorder and BPD also have more-severe impairment in global and social functioning, and have an increased number of suicide attempts. First-degree relatives of patients with bipolar II disorder have a higher morbid risk for bipolar disorder than patients with major depressive disorder and BPD. 65 Box 5. DSM-5 Alternative Model for Personality Disorders Diagnostic Criteria for BPD. Moderate or greater impairment in personality functioning, manifested by characteristic difficulties in two or more of the following four areas: 1. Identity: markedly impoverished, poorly developed, or unstable self-image that is often associated with excessive self-criticism, chronic feelings of emptiness or dissociative states under stress. 2. Self-direction: instability in goals, aspirations, values, or career plans. 3. Empathy: compromised ability to recognize the feelings and needs of others associated with interpersonal sensitivity (i.e., prone to feel slighted or insulted) or the perceptions of others are selectively biased toward negative attributes or vulnerabilities. 4. Intimacy: intense, unstable, and conflicted close relationships, marked by mistrust, neediness, and anxious preoccupation with real or imagined abandonment; close relationships often viewed in extremes of idealization and devaluation and alternate between overinvolvement and withdrawal. A. Four or more of the following seven pathological personality traits, at least one of which must be impulsivity, risk taking, or hostility: 1. Emotional lability (an aspect of negative affectivity): unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or out of proportion to events and circumstances. 2. Anxiousness (an aspect of negative affectivity): intense feelings of nervousness, tenseness, or panic, often in reaction to interpersonal stresses; 66 worry about the negative effects of past unpleasant experiences and future negative possibilities; feeling fearful, apprehensive, or threatened by uncertainty; fears of falling apart or losing control. 3. Separation insecurity (an aspect of negative affectivity): fears of rejection by and/or separation from significant others, associated with fears of excessive dependency and complete loss of autonomy. 4. Depressivity (an aspect of negative affectivity): frequent feelings of being down, miserable, and/or hopeless; difficulty recovering from such moods; pessimism about the future; pervasive shame; feelings of inferior self-worth; thought of suicide and suicidal behavior. 5. Impulsivity (an aspect of disinhibition): acting on the spur of the moment in response to immediate stimuli; acting on a momentary basis without a plan or consideration of outcomes; difficulty establishing or following plans; a sense of urgency and self-harming behavior under emotional distress. 6. Risk taking (an aspect of disinhibition): engagement in dangerous, risky and potentially self-damaging activities, unnecessarily and without regard for consequences; lack of concern for one’s limitations and denial of the reality of personal danger. 7. Hostility (an aspect of antagonism): persistent or frequent angry feelings; anger or irritability in response to minor slights of insults. Note: Both criterion A and B must be met. Not all facets of a criterion need to be present for a criterion to be met, if one or two manifestations are strikingly descriptive of the 67 patient. For diagnosis, impairments in personality functioning and the individual’s personality trait expression are also relatively inflexible and pervasive across a range of personal and social situations, are relatively stable over time and can be traced back to at least adolescence or early adulthood, are not better explained by another mental disorder, are not solely attributable to the physiological effects of a substance or another medical condition, and are not better understood as normal for an individual’s developmental stage or sociocultural environment. Adapted from DSM-5 127. 68 Box 6. Costs to society. Multiple studies have documented the high direct costs associated with treatment of borderline personality disorder (BPD)217,218. The frequent use of high cost hospital and emergency room services by patients accounts for a higher proportion of these direct costs than outpatient therapies217. Patients who have been in remission195 or who receive evidence-based interventions218 diminish these costs. The estimated reduction in yearly healthcare costs for those who receive evidence-based treatments is $4,139 per patient compared with costs for BPD patients receiving usual care in Australia218. Accompanying the direct costs for BPD are indirect costs associated with patients’ persistent failures in social adaptation, most significantly the lack of vocational productivity. Indirect costs are estimated to be two to four times higher than the costs of direct health care usage217,219. Less easy to document are the costs associated with increased divorce rates, custody battles, automobile accidents, medical disability, and compensatory childcare of patients. The burden of patients with BPD on those who love or care for them is higher than for other major mental illnesses220. This burden is evident in altered lifestyles221, and in feelings of powerlessness, anxiety, hopelessness, and depression of caregivers222,223. 69 Figure 1. Milestones in BPD diagnosis, underlying mechanisms and treatment. Patients who in retrospect had BPD were first described by the problem they caused their physicians in both office practice and hospitals 224,225. Contributions from a psychoanalyst, Otto Kernberg226, a scientist, Seymour Kety227, and a distinguished leader in psychiatry, Roy Grinker228, legitimized the significance of these patients to psychiatry >50 years ago. The diagnostic criteria for BPD arose by the identification of what best distinguished this disorder from schizophrenia and depression124,229,230. In 1980, BPD was classified in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III)202, followed 10 years later by its adoption into the International Classification of Diseases (ICD-10) as emotionally unstable personality disorder)131. CLPS. Collaborative Longitudinal Personality Disorders Study; MSAD, The McLean Study of Adult Development; PSA, psychoanalysis. Figure 2. Symptoms of BPD. In the interpersonal instability phenotype, individuals with borderline personality disorder (BPD) have unstable and conflicted relationships, and patients alternate between over involvement with others and social withdrawal. Patients can become deeply involved and dependent on some individuals, but they become manipulative and demanding when they feel like their needs are not met. Indeed, patients have dramatic shifts in their views toward people with whom they are emotionally involved, leading them to idealize these individuals when they feel that their needs are being met and devaluating them at other times when they feel disappointed, neglected, or uncared for. Patients have difficulty recognizing the feelings and needs of other individuals and are hypersensitive 70 to social threat, particularly real or perceived interpersonal rejection. Patients also fear abandonment by others and go to great lengths to avoid abandonment whether it is real or imagined by, for example, showing provocative behaviours such as clinginess, or threatening or demanding behaviour. In the cognitive/self disturbance phenotype, individuals with BPD have markedly impoverished, poorly developed, or unstable selfimage (such as self-contempt) that is often associated with a chronic feeling of emptiness. Patients also have low self-esteem, are prone to self-criticism and feelings of shame, and can harbor self-contempt or self-hatred. Personal goals, aspirations, values, and career plans are inconsistent, frequently change, and are pursued without conviction. Patients can also experience disturbed cognition, such as transient paranoid ideation or dissociative symptoms when under stress. In terms of the affective/emotional dysregulation phenotype, patients are emotionally labile and react strongly, particularly in interpersonal contexts, with intensely experienced and expressed dysphoric emotions, such as depression, anxiety, or irritability. Patients are prone to intense, inappropriate outbursts of anger, and can engage in physical fights. Behavioral dysregulation in BPD involves problems with excessive behaviors that put the patient at risk for harm and problems with poor impulse control. Individuals with BPD can engage in impulsive spending; indiscriminate sex; substance abuse; reckless driving; binge eating; self-injurious behavior (e.g., cutting, burning); and recurrent suicide gestures, threats, and attempts. Impulsivity in BPD typically occurs in negative, distressing emotional states. Figure 3: Alterations of brain circuits in BPD. 71 Functional alterations in midline structures such as the medial prefrontal cortex, the temporoparietal junction, the posterior cingulate cortex, and the precuneus seem to underlie distorted self thinking and thoughts about others in BPD61,62. Enhanced connectivity between the amygdala and midline structures might be associated with hypermentalizing (that is excessive interpretation of mental states) about the self and others. Low activity in midline structures and reduced activity of the superior temporal sulcus might have a role in deficient reasoning about the mental states of others66,68,70,231 whereas a non-reflective, intense sharing of others’ emotions is associated with overactive insular activity67. Alterations of the affect regulation circuit might be involved in amygdala hyper-reactivity to negative stimuli77, particularly to social threat cues, dysfunctional prefrontal processes90–93 and deficient prefronto-limbic connectivity93. Although affect dysregulation is a central clinical feature of BPD, this mechanism might reflect the trait of negative affectivity that is shared by individuals with the broad spectrum of internalizing disorders and/or be sequelae of early life maltreatment. Impulsivity is based on alterations in the reward and control circuits, delay discounting being mediated in the ventral striatum102 and deficient behavioral inhibition in prefrontal areas103,104. The affective pain processing pathway, which has a major role in non-suicidal self-injurious behavior in BPD, might be based on two mechanisms: a negative functional coupling between the amygdala and the medial prefrontal areas107, and an enhanced coupling between the posterior insula and the dorsolateral prefrontal cortex108. In addition, preliminary data suggest impairments of coordinated activities between social cognition and emotion regulation areas69. 72 INS: insula; DLPFC: dorsolateral prefrontal cortex; VLPFC: ventrolateral prefrontal cortex; OFC: orbitofrontal cortex; DACC: dorsal anterior cingulate cortex; HIP: hippocampus; AMY: amygdala; MPFC: medial prefrontal cortex; PCu/PCC: precuneus/posterior cingulate cortex; STS: superior temporal sulcus; TPJ: temporoparietal junction; VS: ventral striatum. Figure 4. Rates of Symptomatic Remission of BPD. Remission of borderline personality disorder (BPD) in the Collaborative Longitudinal Personality Disorders study. 2 months and 12 months refers to the two definitions of remission; 2 months refers to remission for 2 or more months with 2 or fewer BPD criteria, 12 months refers to remission for 12 or more months with 2 or less BPD criteria. Adapted from 6. 73 Table 1. Illustrative Interview and Self-Report Measures. Name (abbreviation) Scope Comments Refs Semi-structured clinical interviews or clinician rated instruments Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV) International Personality Disorders Examination (IPDE) All personality disorders All personality disorders All personality disorders DSM-IV + ICD-10 Structured Interview for DSM-IV Personality Disorders (SIDP-IV) All personality disorders Structured Clinical Interview for BPD + 5 the DSM-5 Alternative Model for other Personality Disorders Module III personality (SCID-5-AMPD) disorders Revised Diagnostic Interview for BPD only Borderlines (DIB-R) Childhood Interview for DSM-IV Borderline Personality Disorder (CI-BPD) Borderline Personality Disorder Severity Index-IV (BPDSI-IV) BPD only BPD only Items grouped by type of personality disorder . 232 Items grouped by type of personality disorder. 233 Items grouped by topic, such as work, self, interpersonal, affect, reality testing (that is, assessing for psychotic-like symptoms), impulse control. Items grouped by type of personality disorder or by topic. Items grouped by type of personality disorder. Based on DSM-5 AMPD. 234 Items grouped by areas of functioning (impulsive actions, affect, cognition and interpersonal relations). Designed specifically for adolescents. 237,238 Dimensional, short interval change measure that has adolescent and parent versions. Dimensional, short interval change measures. 240 Zanarini Rating Scale for BPD only Borderline Personality Disorder (ZAN-BPD)* Structured Interview for Lay Person Administration Alcohol Use Disorder and BPD, Used in the National Associated Disabilities Interview ASPD, Epidemiologic Survey on Schedule-5 (AUDADIS-5) STPD Alcohol and Related Conditions (NESARC) Self-Report Instruments for Diagnosis 74 235 236 239 241,242 243 Personality Diagnostic Questionnaire-4 (PDQ-4) All Includes clinical significance questions. 244 personality disorders Identity problems, negative relationships, affective instability, self-harm. This measure includes validity scales and has an adolescent version. Borderline Symptom List (BSL) BPD Full and short versions available. Five Factor Borderline Inventory BPD Based on the five-factor (FFBI) model of personality traits. Self-Report Instruments to Assess Pathological Personality Traits 245 Schedule for Nonadaptive and Adaptive Personality-II (SNAPII) Higher order factors and lower order traits. Can be scored for diagnoses. Has youth version. Identity problems, insecure attachment, affective lability, self-harm scales. Dimensional. 248 Based on the DSM-5 AMPD. 251 Personality Assessment Inventory (PAI) BPD and ASPD All personality disorders and traits BPD and OPD traits Dimensional Assessment of Personality Pathology – Basic Questionnaire (DAPP-BQ) Minnesota Multiphasic Personality Personality Inventory-2disorder Restructured Form (MMPI-2traits RF) Personality Inventory for DSM-5 BPD and (PID-5) OPD traits Self-Report Instruments for Screening McLean Screening Instrument BPD for BPD (MSI-BPD) 10 items. Translated into multiple languages and has been used in adults and adolescents. Borderline Personality BPD Has been used for Questionnaire (BPQ) screening in adults and adolescents. Borderline Personality Features BPD Dimensional measure Scale for Children (BPFSC) deigned to assess children and adolescents. Has child and parent versions and has been used for screening. Self-Report Instruments to Assess Impairment in Personality Functioning Severity Indices of Personality Personality Includes 5 domains of 75 246 247 249 250 252 253 254 255 Problems (SIPP-118) General Assessment of Personality Disorder (GAPD) Functioning Personality Functioning personality functioning. 256 Measures self or identity problems and interpersonal dysfunction. 257 Level of Personality Functioning Personality Measures severity of Scale Self-Report (LPFS-SR) Functioning impairment in personality functioning. Based on the DSM-5 AMPD. * Semi-structured, clinical interview and self-report. AMPD, Alternative Model for Personality Disorders; ASPD, antisocial personality disorder; BPD, borderline personality disorder; DSM, Diagnosis and Statistical Manual of Mental Disorders; ICD, International Classification of Diseases; OPD, other personality disorder; STPD, schizotypal personality disorder. 76 Table 2. Major evidence-based treatments. Type of Description therapy Frequency of treatment Training (Hrs/week) Dialectical Individual and group 1hr individual / 2 hr group Two 5-day behaviour components using a / 24/7 availability / 2hr therapy (DBT) cognitive-behavioural therapist consultation (>5 model. Emphasizes hr/wk) workshops patients to build skills for self-harm and emotional regulation. Therapies coach, are active, directive, and validating. Mentalization- Individuals and group 1hr individual / 2hr group based components using a / 1hr therapist treatment developmental model. consultation (4hr/wk) (MBT) Emphasizes patients to consider the effects of the self on others and vice versa. Therapists are active, curious and validating. 77 3-day workshop Transference Individual 2hr individual / when Two 3-day focused psychotherapy using a necessary consultation workshops and psychotherapy psychoanalytic model. (2hr/wk) one year group (TFP) Focuses on the supervision integration of disowned (“split off”) aggression, especially as it occurs within the therapy relationship. Therapists are active, neutral and challenging. General Individual case 1hr individual / when One-day (“Good”) management- necessary consultation workshop, when psychiatric orientated therapy (1hr/wk) necessary management focusing on situational (GPM) stressors and social supervision adaptation. Medication, family and group interventions are added as needed. Therapists are active, directive and challenging. 78