REVIEW

Family Studies of Borderline Personality Disorder: A Review

Candace N. White, EdM, John G. Gunderson, MD, Mary C. Zanarini, EdD, and James I. Hudson, MD, ScD

This paper reviews the literature examining the psychopathology found in relatives of individuals with borderline personality disorder (BPD). Reecting changes in how BPD has been conceptualized, researchers have investigated the prevalence of schizophrenia, then mood disorders, and more recently, impulse spectrum disorders in these relatives. This literature does not support a link between BPD and schizophrenia, is ambiguous about a link between BPD and major depressive disorder, and suggests a familial aggregation of impulse spectrum disorders and BPD, as well as of BPD itself. Because of signicant methodological problems, most notably indirect assessments and inadequate sample size, major questions persist about the familial aggregation of this disorder that require more denitive methods. (HARV REV PSYCHIATRY 2003;11:819.)

Since the introduction of borderline personality disorder (BPD) into the DSM in 1980, our understanding of its etiology has gradually shifted. Attributions initially emphasized environmental causes but now lean toward interaction of environmental triggers with an underlying genetic predisposition. The list of disorders thought to be related to BPD has also changed over time. Clinicians of the 1970s and earlier, who had a broad concept of schizophrenia, concluded that BPD was probably part of a schizophrenia spectrum.1 Thus early family history studies often used probands with schizophrenia as comparison groups. Subsequently, research and clinical observation led to the conceptualization of BPD as an affective spectrum disorder.2 Later interpretation of BPD as an impulse spectrum disorder3 gave rise to examination of antisocial personality disorder

From McLean Hospital, Belmont, Mass., and the Department of Psychiatry, Harvard Medical School, Boston, Mass. Original manuscript received 7 May 2002, accepted for publication 17 June 2002; revised manuscript received 30 July 2002. Reprint requests: John Gunderson, MD, Psychosocial and Personality Research Program, McLean Hospital, 115 Mill St., Belmont, MA 02478.
c 2003 President and Fellows of Harvard College

(ASPD) and substance abuse in the relatives of probands with BPD. During the several decades of reconceptualization, multiple family history studies have been completed. Although such research cannot separate genetic from environmental causes, the ndings inform both perspectives. In this review we examine these investigations: their methodology, their results, and their implications for understanding the etiology of BPD. We searched Medline for articles published in English up to 1 January 2001 containing the terms borderline and BPD, occurring together with family, history, or review. We then examined the reference sections of the resulting papers for additional sources. We found a total of 15 studies assessing the prevalence of psychiatric disorders in relatives of probands with BPD (see Table 1). We focus on familial aggregation of disorders that are thought to be related to BPD. For inclusion, a disorder must have been included in at least two family history studies, to allow comparison of the results. The disorders included are schizophrenia and schizotypal personality disorder (STPD) in the schizophrenia spectrum; major depressive disorder (MDD) and bipolar disorder in the affective spectrum; and substance use disorders and ASPD in the impulsive spectrum. For each of these disorders, we will note the prevalence or lifetime morbidity risk in relatives of BPD probands and will comment on any signicant differences in such rates between relatives of BPD probands and comparison groups.

TABLE 1. Risk of Psychiatric Disorders in Relatives of BPD Probands Risk (%) ASPD
20.7 0 6.2 0.7

Study

BPD

STPD

Any cluster B disorder MDD Schizophrenia

7.4 (mild and severe alcoholism)

Bipolar disorder

Any mood disorder

Substance use/ dependence

Stone et al.12

6.7a

Loranger et al.8 Pope et al.22 6.2 7.7 0.5 (MR) 1.5

11.7 (MR) 0.8b

6.4 (MR) 4.6

Soloff & Millward14 13.3 13.3 0

7.0

8.7 2.6

11.5 (alcohol abuse/ dependence), 0.8 (opioid dependence) 11.8 (alcoholism)

Baron et al.9

17.9 (MR)

4.8 (eccentric/ peculiar behavior) 3.1

Loranger & Tulis35 50 26.6 (MR) 31.2 (MR) 0.7 (MR) 23.3 4.5 (MR) 0 0

Schulz et al.23 Links et al.10 0 9.6 13.6 (MR)

15.3 (MR)

Zanarini et al.11

24.9 (MR)

13.6 (alcohol or drug abuse) 18.5 (MR alcoholism) 16.7 (alcoholism) 21 (MRalcoholism), 9.4 (drug use) 24.3 (MRalcohol), 10.7 (MRdrug abuse/dependence) 4.6 15.3 (alcoholism), 1.5 (drug abuse) 1 (MR) 17.9 (MRalcohol use disorder), 6 (MRdrug use disorder)

6.5 7.5 15.3 1.5 (bipolar II)

Reich36 Schulz et al.13

Gasperini et al.24 Silverman et al.15 3.1 10.2 (MR) 21.5 (MR)

2.5 (MR) (manic disorder)

10 21 22.2 25.9

Johnson et al.37 Riso et al.24

1.9

29.6

25.9 (alcohol abuse/ dependence), 20.4 (drug abuse/ dependence)

ASPD, antisocial personality disorder; BPD, borderline personality disorder; MDD, major depressive disorder; MR, morbidity risk; STPD, schizotypal personality disorder. a Stone and colleagues did not use a classication system with standardized diagnostic criteria for BPD, instead employing the concept of borderline personality organization. b Pope and colleagues reported the prevalence of disorders in relatives of BPD probands. Comparisons between groups were examined only for any cluster B and any mood disorder. Signicantly different from comparison groups ( p < 0.05). Signicantly different from comparison groups ( p < 0.01).

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Within this literature, some authors have calculated morbidity risk (thereby approximating lifetime prevalence by correcting for the fact that not all relatives will have passed through the period of risk for development of a disorder), while others have simply reported prevalence at the time of the study. Because researchers have used widely differing methods to estimate the morbidity risk of psychiatric disorders among relatives of probands with BPD, we concluded that we could not calculate a meaningful combined estimate using meta-analytic techniques. Rather, we simply report the estimates, note that they span a certain range, and compare them to those from population-based studies.47 Such estimates can offer a rst approximation of the true values and help in planning future studies in this area. After we review the results of the 15 investigations involving relatives of BPD probands, we examine methodological issues. To do this, we compare the methods used to those that are proposed as standards for conducting such research. Because the question of whether BPD is itself familial is so important, we focus on the nine studies that have considered this issue. We conclude by highlighting the persistent questions raised by this literature and identifying topics for further research.

Schizotypal Personality Disorder

Soloff and Millward14 found a signicantly higher prevalence of eccentric/peculiar behavior in relatives of probands with BPD than in relatives of those with depression or schizophrenia ( p = 0.03). This, however, might also be attributable to their denition of BPD, which included STPD traits. Only Baron and colleagues9 examined the prevalence of STPD in relatives of BPD probands and used STPD probands as a comparison group. In this study relatives of pure STPD probands were signicantly more likely ( p < 0.05) to receive a denite or probable STPD diagnosis (20%) than were relatives of normal controls (9.1%) or relatives of BPD probands (3.1%). Of note, these researchers found a larger morbidity risk for BPD in relatives of normal controls than in relatives of STPD probands, and a greater prevalence of STPD in relatives of normal probands than in relatives of BPD probands. In summary, these results do not uphold the hypothesis that BPD is genetically linked to schizophrenia or STPD. Thus, there is little support for the concept of BPD as a schizophrenia spectrum disorder.

AFFECTIVE SPECTRUM DISORDERS SCHIZOPHRENIA SPECTRUM DISORDERS

The conceptualization of BPD in the 1970s as a schizophrenia spectrum disorder was prompted in part by the broad concept of schizophrenia in use at that time, by the significance assigned to patients psychosis-like experiences, and by an adoption study in which persons labeled as having borderline schizophrenia were found to have a disorder that was genetically linked to schizophrenia.1 The nature of the relationship between BPD and depression has been the subject of much literature and controversy.2,16,17 The concept of BPD as an affective spectrum disorder arose because of the high frequency of depressive symptoms in patients with BPD and has been buttressed by evidence of neurobiological overlap.18 Because the overlap in phenomenology (i.e., both lability and impulsivity) with bipolar disorder is so evident, the relationship between these two disorders has attracted increasing interest.1921

Schizophrenia
Four811 of the eight studies that assessed schizophrenia in relatives of BPD probands found no cases among these individuals. In the remaining four,1215 the prevalence of schizophrenia in relatives ranged from 0.7%12 to 4.58%.13 In the reports citing a prevalence of 4.58%13 and 2.6%,14 approximately half of the BPD probands were comorbid for STPD. This might explain the high risk for schizophrenia among relatives in the two studies. Using an earlier denition of BPD, Soloff and Millward14 subdivided their BPD sample into unstable, schizotypal, and mixed subgroups. The mixed subgroup had a signicantly higher prevalence of schizophrenia in relatives than did either of the other two subgroups. This clarication suggests that it may be the STPD/BPD comorbidity, not STPD alone, that correlates with a high prevalence of schizophrenia in relatives.

Mood Disorders
In the six studies assessing mood disorders in relatives of BPD probands,9,11,12,2224 prevalence ranged from 6.2%22 to 50%.23 Two of the studies12,23 calculated risk for mood disorders in general, without differentiating between bipolar and unipolar conditions. They found a lifetime prevalence of 20.7%12 and 50%.23 In studies that differentiated between unipolar and bipolar disorders, MDD, rather than bipolar disorder, accounted for most of the mood disorder prevalence11,15,22 (see Table 1).

Major Depressive Disorder

Ten studies assessed the prevalence or morbidity risk for MDD in relatives of BPD probands.811,1315,22,24,25 These yielded estimates between 4.6%22 and 31.2%,11 with

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particularly low estimates from investigations using chart reviews.8,22 By comparison, a recent estimate of the lifetime prevalence of MDD in the general population of the United States was 17%.26 Two studies14,24 compared the prevalence of MDD in relatives of BPD probands and relatives of MDD probands. One14 found risk for MDD to be signicantly less in relatives of BPD probands than in relatives of primary depressive disorder probands. The other24 found no signicant differences in relatives risk for MDD between the MDD and BPD proband groups. Three studies8,13,24 showed that relatives of BPD probands had a signicantly higher prevalence of MDD than did relatives of persons who had neither disorder. Two of the studies8,13 found this to be true in comparison to relatives of schizophrenia probands, and one24 found it to be true in comparison to never-psychiatrically-ill controls but not to mood disorder probands. To determine whether an elevated prevalence of MDD in relatives of BPD probands was due to the co-occurrence of MDD in the BPD probands (since MDD is known to be familial), three studies11,22,27 compared the prevalence of MDD in relatives of pure BPD probands (i.e., individuals without comorbid affective disorder) and relatives of BPD probands with comorbid MDD. In all three investigations, relatives of the pure BPD group had a signicantly lower risk for affective disorder than did relatives of the proband group with co-occurring BPD and MDD. These results have led previous reviewers15,16 to conclude that BPD and MDD are independent disorders that frequently co-occur. This type of comparison can provide evidence that MDD in a proband with BPD is associated with a greater probability that a relative will have MDD. However, it does not directly address the question of whether BPD and MDD coaggregate within families (that is, whether the risk of MDD is elevated in relatives of BPD probands and, conversely, whether the risk of BPD is elevated in relatives of MDD probandsindependent of the familial aggregation of MDD). The most informative determination in this regard from studies of BPD probands is whether the prevalence of MDD without BPD is elevated in relatives of BPD probands who do not have MDD. (See Hudson et al.28,29 for further discussion of methods to assess familial coaggregation with

studies using case-control sampling.) Riso and colleagues,25 for example, found a higher prevalence of MDD in the relatives of BPD probands without mood disorder than in relatives of probands with neither BPD nor MDD. They found no differences in the prevalence of mood disorders between relatives of BPD probands without MDD and relatives of 119 probands with mood disorder (including 45 with MDD). Thus, this investigation provides tentative evidence for coaggregation of MDD and BPD in families.

Bipolar Disorder
Seven studies8,10,11,13,15,22,24 calculated a prevalence or morbidity risk for bipolar disorder in relatives of BPD probands. Results ranged from 0.54%8 to 4.5%10 gures roughly equivalent to the 1.6% lifetime prevalence of bipolar disorder in the general population.26 These rates were no higher than those found in relatives of comparison group probands. In the two studies using comparison groups of bipolar disorder probands,8,22 the rates for bipolar disorder in relatives of the BPD probands (with or without concurrent mood disorder) were nonsignicantly lower. In neither study was the rate of BPD increased in relatives of bipolar disorder probands. Thus there is no evidence suggesting a familial relationship between the two disorders. In summary, these results provide provocative but unconvincing evidence for a familial relationship of BPD with MDD, but none for a familial relationship of BPD with bipolar disorder. This disparity, in itself, is confusing. Larger, better designed studies are needed.

IMPULSE SPECTRUM DISORDERS

The suggestion that BPD represents an impulse spectrum disorder derives from the many seemingly impulsive behaviors that characterize BPD patients, including substance abuse, violence, self-injurious acts, and disordered eating.3,30 The linkage of ASPD and substance abuse/dependence as impulse spectrum disorders has been shown both epidemiologically31 and genetically.3234

Substance Use Disorders

Eleven studies915,2224,35 calculated the lifetime prevalence or morbidity risk for alcohol abuse or dependence in relatives of BPD probands. Estimates for risk in relatives ranged from 7.4%12 to 25.9%.24 The studies differed in their comparisons, however: some required alcohol dependence, whereas others included persons with a diagnosis of alcohol abuse. Notably, the inclusion of only severe alcoholics may account for the low prevalence found by Stone and colleagues.12 Nevertheless, this range appears to be somewhat higher than

Although here and elsewhere we provide estimates of the prevalence of disorders in the general population, these should be used only to make very rough comparisons with the prevalences found in individual studies. Such rates depend on many factors (e.g., demographics, ascertainment, assessment methods) that may vary from one investigation to the next. For this reason, within-study comparisons between groups would be far more informative.

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the 14.1% lifetime prevalence of alcohol dependence26 but nearly twice the 9.4% lifetime prevalence of alcohol abuse26 seen in the general population. The difference is greater when the estimate is contrasted with the lifetime prevalence rates for females, who comprise the majority of most BPD samplesi.e., abuse, 6.4%; and dependence, 8.2%.26 The prevalence of alcohol abuse was nonsignicantly higher in relatives of BPD probands than in those of normal controls.9,12,24 Two studies13,23 found prevalence of alcohol abuse or dependence to be signicantly higher in relatives of BPD probands than in relatives of schizophrenia probands. However, no researchers separated BPD probands with and without alcohol use disorders for such examination. Thus, it is unclear to what extent the elevated prevalence of alcohol abuse or dependence in relatives of BPD probands may be due to the well-documented familial aggregation of alcohol abuse or dependence. Furthermore, no studies have looked at the prevalence of BPD in probands with alcohol abuse/dependence. Six studies calculated a prevalence of drug abuse or dependence in relatives of BPD probands; their estimates ranged from 0.8%22 to 20.4%.24 Lifetime prevalence in the general population is 4.4% for abuse and 7.5% for dependence (3.5% and 5.9%, respectively, for females).26 Although trends were detected toward more abuse in relatives of BPD probands than in relatives of comparison probands,13,15,24 the differences were not signicant.

prevalences of ASPD and substance use disorders in relatives of persons with BPD seem to be markedly increased. Thus, the existing evidence offers clear evidence in support of a relationship between BPD and impulse spectrum disorders.

BORDERLINE PERSONALITY DISORDER

Nine studies812,22,24,36,37 examined the occurrence of borderline psychopathology (by various denitions) in relatives of BPD probands. Four of them811 reported lifetime morbidity risk for BPD in relatives; ve12,22,24,36,37 calculated only the unadjusted lifetime prevalence. The prevalence or morbidity risk for BPD in relatives ranged from 0.8%22 to 24.9%.11 Epidemiological studies47 indicate a 0.63% prevalence of BPD in the general population. Hence, the range reported here demonstrates a 4- to 20-fold increase of BPD in relatives of BPD probands compared to the general population. As noted in the methodological review of these nine studies (see below), the studies reporting the highest risk in relatives9,11 assessed the relatives indirectly. Six of the nine studies examined the prevalence or morbidity risk for BPD in relatives of BPD probands and in those of comparison groups. Four8,9,11,37 of the six found a signicantly higher prevalence or morbidity risk for BPD in the relatives of the BPD probands. The fth36 found a trend ( p = 0.07), but this result was derived from only 12 BPD probands. The only investigation that did not nd a higher prevalence of BPD among relatives of BPD probands12 was conducted prior to the establishment of DSM criteria for BPD. Three studies22,24,37 examined the prevalence of Cluster B disorders (which includes histrionic, antisocial, and narcissistic personality disorders, as well as BPD) in relatives of BPD probands. All three had small numbers of probands and expanded to include other Cluster B disorders to enhance the power to detect coaggregation, at the cost of losing specicity for BPD. Johnson and colleagues37 and Riso and coworkers,24 using structured interviews for assessment of relatives, calculated a prevalence in relatives of 21% and 22.2%, respectively. The latter authors found a signicantly higher risk for Cluster B disorders in relatives of BPD probands than in relatives of never-psychiatrically-ill controls; they found a similarly high prevalence of Cluster B disorders in the relatives of probands with mood disorders. Pope and colleagues22 (using less rigorous methods than those employed in the other two studies) found a low prevalence (7.7%) of Cluster B disorders among relatives of probands with BPD. Nonetheless, the gure was still signicantly higher than those estimated for the relatives of schizophrenia and bipolar disorder probands. The high prevalence of Cluster B personality

Antisocial Personality Disorder

Seven studies10,11,1315,22,23 assessed the familial aggregation of ASPD in the relatives of BPD and comparison probands. The prevalence/morbidity risk in relatives ranged from 0%13 to 13.6%.11 The highest prevalences were found in studies that relied on semistructured interviews of probands or relatives.10,11,13 The median prevalence of 7% is twice that seen in the general population (3.5%26 ). Of the ve studies that compared the prevalence of ASPD in relatives of BPD probands to the prevalence in relatives of other probands,11,1315,23 only Schulz and colleagues13 found a signicant difference. ASPD was signicantly more common among the relatives of borderline probands without ASPD than comparison probandsin this case, schizophrenia probands without ASPD. Taken together, these results suggest familial aggregation of BPD and ASPD. It is notable that the case for BPD as an impulse spectrum disorder (i.e., related to substance use disorders and to ASPD) rests largely on studies in which BPD probands were compared to schizophrenia probands. It is possible that relatives of individuals with schizophrenia have an unusually low risk for impulsive spectrum disorders. Nonetheless, the

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disorders observed in this review in relatives of BPD probands suggests that certain traits within this cluster, such as affective instability or impulsivity, may aggregate with BPD in families (see Discussion, below). To examine the evidence for the familial aggregation of BPD, we calculated ratio of the risk of BPD in relatives of probands with BPD versus the risk in relatives of probands without BPD. For this analysis, we included all studies that made BPD diagnoses of probands using DSM criteria by either chart review or structured interview, assessed BPD (or Cluster B disorders) in relatives, and employed a comparison group. For the estimate of risk, we used either the crude lifetime prevalence or the estimated morbidity risk. If both measures could be calculated, we chose the morbidity risk because it represents a more accurate assessment of true risk. The six studies shown in Table 28,9,11,22,24,37 met these inclusion criteria for risk-ratio analysis. To judge from these studies, BPD is consistently more common among the relatives of BPD probands than among the relatives of non-BPD probands. However, the differences in diagnostic criteria for BPD, in the diagnoses of comparison groups, in recruitment procedures, and in interview methods of these studies may have substantially altered the true estimate of risk. Certainly this heterogeneity precludes a solid estimation of risk ratio using meta-analytic techniques.

This limits the conclusions that can be drawn, in two important ways. First, a wide range of prevalences for a given disorder among relatives of probands with BPD is consistent with the data; that is, the data cannot distinguish whether the true level of familiality is very large or very small. Second, it is difcult to compare the risks of disorders in the relatives of BPD probands with the risks in relatives of nonBPD probands. For example, suppose that the lifetime risk for BPD among relatives of probands with BPD is 10%. To have 90% power to show that this risk is signicantly greater than a 4% risk of BPD among relatives of another proband group would require a sample of over 400 relatives per group. None of the studies approach this sample size. Thus, all studies are seriously underpowered, creating a high likelihood of a type-II error (i.e., not detecting true differences between groups).

Representativeness
Five of the nine studies shown in Table 3 included both males and females, over a wide age range, in their proband samples. Loranger and colleagues8 had only females in their BPD proband sample, and Johnson and coworkers37 included only adolescents. Because the relatives included both males and females over a wide age range, it is possible in principle to examine effects of age and gender. Although most studies adjusted for age in their estimates of prevalence in relatives, none examined the effects of gender.

METHODOLOGICAL ISSUES
In reviewing the methodological issues of the nine studies of BPDs familial aggregation,812,22,24,36,37 we follow the standards for family risk studies established by Knowles and colleagues38 and used by Dahl27 in 1994 on a portion of this literature. The methodological quality of the family studies is assessed on the following variables: sample size, proband demographic representativeness, and subject selection; diagnostic criteria and assessment means (e.g., structured interview, questionnaire), and percentage of relatives directly interviewed (see Table 3).

Subject Selection
For all studies, case-control sampling was used; that is, subjects were selected for the presence or absence of certain conditions. The ascertainment for all studies except one9 involved selecting patients with BPD from either inpatient or outpatient settings. None attempted to locate individuals with BPD who were not seeking treatment or a random sample of persons with BPD from the general population. The remaining study9 recruited college students and hospital staff, producing a small group of BPD probands (n = 17) and a much larger group of normal controls (n = 90).

Sample Size
In the nine studies reviewed here, the number of BPD probands ranged from 11 to 83, and the number of relatives assessed ranged from 31 to 249. Generally, the number of relatives assessed was proportional to the number of probands; a mean of 3.35 relatives was assessed for each proband. All but one of these studies employed indirect methods to assess at least some of the relatives. The exception was Reich and colleagues investigation,36 which assessed all available relatives (60%) by asking them to complete a questionnaire. Because the sample sizes used in these studies were small, the condence intervals for the estimates of effects are wide.

Diagnostic Assessments
The ideal family study would employ standardized diagnostic criteria and would conrm the diagnosis using a second method. Not surprisingly, the earliest family studies generally had the weakest diagnostic methodology. Stone and colleagues,12 for example, did not employ standardized diagnostic criteria for BPD. The subsequent family studies have all used DSM-based diagnostic criteria but have varied as to which DSM system and which assessment instrument they utilized. Loranger and colleagues8 selected probands using

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TABLE 2. Family Studies of BPD Meeting Criteria for Assessment of Risk Ratios Relatives Probands Study Diagnostic method Group type n n At riska BPD Morbidity Risk ratio (n) casesb risk (%)c (95% CI)

Loranger et al.8 DSM-III criteria Inpatients retrospectively applied BPD 83 338 249 to charts Schizophrenia 100 482 353.5 Bipolar disorder 100 537 413.5 Pope et al.22,d DSM-III criteria Inpatients retrospectively applied BPD 33 130 to charts Schizophrenia 39 181 Bipolar disorder 34 173 Baron et al.9,e SIB College students, hospital staff BPD 17 60 39 Pure STPD 36 56 36 Normal 90 376 344 Zanarini et al.11 DIB, DIPD Outpatients BPD 48 240 177 ASPD 29 139 97.5 DTPD, dysthymic other PD 26 109 83.3 Johnson et al.37 SCID-II Inpatients BPD ? 39 AVPD ? 62 No PD 17 46 Riso et al.24,f PDE Outpatients BPD 11 54 Mood disorder 119 563 Normal 45 229

29 5 3 10 4 1 7 2 14 44 4 8 4 2 0 12 121 16

11.65 1.41 0.73 7.7 2.2 0.6 17.9 5.6 4.1 24.9 4.1 9.6 10.3 3.2 0 22.2 21.2 7.0

8.2 (3.2, 21) 16 (4.9, 52)

3.5 (1.1, 11) 13 (1.7, 103)

3.2 (.72, 15) 4.4 (1.9, 10)

6.1 (2.2, 16) 2.6 (1.2, 5.3)

3.2 (.61, 17)

0.96 (0.5, 1.9)h 3.6 (1.6, 8.2)i

AVPD, avoidant personality disorder; ASPD, antisocial personality disorder; BPD, borderline personality disorder; CI, condence interval; DIB, Diagnostic Interview for Borderlines; DIPD, Diagnostic Interview for Personality Disorders; DTPD, dysthymic personality disorder; PD, personality disorder; PDE, Personality Disorder Examination; SCID-II, Structured Clinical Interview for DSM-III-R; SIB, Schedule for Interviewing Borderlines; STPD, schizotypal personality disorder. a Determined by the method used to calculate morbidity risk. Pope et al. and Johnson et al. did not calculate morbidity risk and therefore did not report the number of relatives at risk for BPD. b Loranger et al. included as cases only those relatives who had been treated for a mental disorder. c Values were age-corrected by the Str mgren method in the studies by Loranger et al. and Baron et al. and by the Weinberg short method o in the study by Zanarini et al.; they were not corrected in the remaining investigations. d Pope et al. assessed the dramatic cluster of personality disorder (i.e., histrionic personality disorder, BPD, and ASPD) rather than BPD alone. e Baron et al. corrected for use of the family history method. f Riso et al. included only probands with BPD and no mood disorder; they assessed Cluster B rather than BPD alone in relatives. g Risk ratio adjusted for gender, birth cohort, interview status, and proband comorbidity; unadjusted risk ratio is 1.0 (0.61, 1.8). h Risk ratio adjusted for gender, birth cohort, interview status, and proband comorbidity; unadjusted risk ratio is 3.2 (1.6, 6.3).

DSM-II (i.e., criteria for personality disorder not otherwise specied, rather than specically for BPD). As noted earlier, Loranger and colleagues8 and Pope and coworkers22 used chart review to assess both probands and relatives. In Baron and colleagues sample,9 15 of the 17 BPD probands had probable BPD. Reich36 measured Axis II in probands and relatives with the Personality Diagnostic Questionnaire, an instrument likely to produce false positives. (Of note, de-

spite the high sensitivity of this questionnaire, it identied no relatives with BPD from the normal control group.) Although ve studies911,24,37 used DSM-based structured interviews to establish the proband diagnoses, DSM criteria have changed over the years, and only Zanarini and colleagues11 conrmed the diagnosis using a second method. Axis I assessment has also progressed over time, from unstructured methods,8,12,22 to the Schedule for Affective

TABLE 3. Methodological Issues in Studies of BPD Coaggregation Sample

Study
3.5 ++ (psychosis, normal) Unclear Not recorded 10%

Demographic Relative comparability raters (and diagnosis) of Relatives Relatives directly blind to comparison BPD included (n/% Relatives/ interviewed Interrater probands Method of probands (n) of total)a reliability diagnosis? assessing relativesc (% of total) proband (n) probandsb

Stone et al.12

39 inpatients

135/100%

Loranger et al.8 83 female inpatients 3 0 98% 3.9 2.3 0e 0

338 (249 at risk)/29%

++ (schizophrenia, bipolar disorder)

Yes

Pope et al.22

33 inpatients

130/100%

Not recorded 7592%

Yes No

Baron et al.9

Links et al.10 3.3 [No comparison groups] ++ (ASPD, dysthymia) 0 + (normal) 0 36

17 college students, hospital staff 69 inpatients

+ (schizophrenia, bipolar disorder) +++ (STPD, normal)

60 (39 at risk)/ 100% of those 15 years old 229/100% of those 18 years old 3.7

Not recorded

Not recorded

Zanarini et al.11 48 outpatients

Not recorded

Yes

Reich36 2.6

240 (177 at risk)/ 100% of those 18 years old 31/60% (all available) 3.9 ++ (AVPD, no PD) 85

Not recorded

Yes

Johnson et al.37

12 recruited for a treatment study Adolescent inpatientsf 4.9 +++ (mood disorder, normal)

39/100% of those 18 years old

91%

Yes

Riso et al.24

11 outpatients

54/100% of those 15 years old

Interview, BPO criteria;d probands and some relatives Chart review, DSM-II criteria; probands and relatives Chart review, DSM-III criteria; relatives Structured interview (SIB), DSM-III criteria; probands Structured interview (DIB), DSM-III criteria; relatives Structured interview (DIPD), DSM-III criteria; probands Questionnaire (PDQ), DSM-III criteria; relatives Structured interview (SCID-II), DSM-III-R criteria; relatives Structured interview (PDE, FH / PD), DSM-III-R criteria; relatives 46.3 Moderate to high Yes

ASPD, antisocial personality disorder; AVPD, avoidant personality disorder; BPD, borderline personality disorder; BPO, borderline personality organization; DIB, Diagnostic Interview for Borderlines; DIPD, Diagnostic Interview for Personality Disorders; FH/PD, Family History Interview for Personality Disorder; PD, personality disorder; PDE, Personality Disorder Examination; PDQ, Personality Diagnostic Questionnaire; SCID-II, Structured Clinical Interview for DSM-III-R; SIB, Schedule for Interviewing Borderlines; STPD, schizotypal personality disorder. a For the studies that calculated morbidity risk, we have recorded both the total number of relatives and, when reported, the number of relatives at risk. b Demographic comparability of comparison groups rated as: + = comparison groups used but demographic information not recorded; ++ = demographic differences (age, sex, race) recorded; +++ = matched by age, sex, and race. c The method of assessment of probands and relatives (instrument), criteria used; who supplied the diagnosis of the relative. d BPO is a much broader construct than BPD. It is identied by three criteria: lapses in reality testing, unstable identity, and primitive defenses. e 70% of the relatives of normal subjects received direct blind interviews. f There were 49 probands with an Axis II disorder, but the n for each disorder was not recorded.

15

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Disorders and Schizophrenia,9,10 to the Structured Clinical Interview for the DSM,11,24,36,37 an instrument that assesses all Axis I diagnoses.

Rater Reliability and Blindness

As shown in Table 3, there is an obvious progression in the assessment of relatives. Stones pioneering study12 employed multiple methods to assess relatives; these methods (some blind, some not) were without established reliability. (It is also worth noting that the family members included in Stones study, unlike those in the other studies reviewed here, were not limited to rst-degree relatives.) In six8,11,22,24,36,37 of the eight subsequent studies reviewed, assessments of relatives were blind to the probands diagnosis. Interrater reliability was recorded in only four studies.8,9,25,37

Direct versus Indirect Assessment

Although family history (relying primarily on the probands report) and family study (relying primarily on direct interviews of relatives) usually produce similar results, direct interviews remain the standard for establishing valid diagnostic assessments. The ideal study would blindly assess all relatives directly; direct interviews usually detect less severe cases of the disorder in question4042 and avoid unidentiable reporting biases,43 resulting in a higher prevalence.25,4446 In four10,12,24,37 of the nine studies included here, the researchers directly interviewed a fraction of the relatives (more than 50% in two cases12,37 ). In Baron and colleagues investigation,9 70% of the relatives of normal control probands but none of the relatives of BPD and STPD probands received direct interviews. Johnson and coworkers37 and Riso and colleagues24 reported no difference between BPD and comparison groups in the proportion of relatives who were directly interviewed. Stone and coworkers12 did not mention whether there was a signicant difference among their groups in number of relatives directly interviewed. No studies indicated whether relatives refused participation or how many declined to have direct interviews. The two studies that found the highest risk for BPD in relatives (24.9%11 and 17.9%9 ) relied solely on indirect interviews when obtaining information on relatives of BPD probands. Moreover, Links and colleagues10 reported a BPD prevalence of 3.4% when relatives were interviewed directly but 15.1% when indirect methods were employed. To compensate for the expectation of false negatives from indirect assessments, the authors lowered the threshold for achieving a BPD diagnosis when indirect methods were used: relatives who were indirectly assessed were required to demon-

strate only three of the seven criteria for BPD, while those directly interviewed had to meet all seven. Of note, Baron and coworkers9 adopted a similar compensatory strategy and found signicant differences in prevalence of BPD in relatives only after making this correction. These results suggest that the reported risk for BPD in relatives may increase with the use of indirect methods. Although this discrepancy is unusual, Andreasen and colleagues40 have previously reported a similar situation with other psychiatric conditions (ASPD and psychotic disorders), presumably due to the relatives underreporting. This explanation might also hold true for BPDi.e., relatives with BPD might underreport their symptoms when directly interviewed, possibly because of denial or fear of stigma, thereby causing false negatives. Conversely, when indirect methods are used, BPD probands might exaggerate BPD features among their relatives, thereby causing false positives. The latter explanation is consistent with the tendency of persons with BPD to devalue or vilify members of their family.47 An implication of this review is that future family studies should incorporate both direct and indirect methods, as Links and colleagues10 did, comparing the frequencies of BPD determined with each method and exploring reasons for the differences.44

Comparison Groups
Proper selection of comparison groups is an essential feature of family studies using case-control sampling. The ideal family study would have at least one comparison group of individuals who are representative of those at risk for the BPD and are derived from the same population source (e.g., hospital, community) that gave rise to BPD cases, but do not have BPD. The comparison group(s) and the BPD probands should have the same distribution of any variables that could inuence risk of BPD, including all forms of psychopathology (see Wacholder et al.48 ). Only three studies,9,24,36 all of which used normals as a comparison group, came close to fullling such requirements. Comparison groups of probands with psychiatric disorders other than BPD, the strategy used in most of the studies reviewed here, are also useful, primarily to examine patterns of coaggregation of BPD with other disorders in families. They are less useful in assessing the family aggregation of BPD itself, because it is possible that relatives of probands with a condition other than BPD, such as a mood disorder, may have an elevated prevalence of BPD compared to relatives of probands with neither BPD nor mood disorder. The ideal family study would include comparison groups that could reect a suspected relationship due to comorbidity (or other overlap in psychopathology). In this regard, the comparison groups selected for BPD family risk studies have changed over the years. As noted, most of the earlier

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studies compared BPD probands to probands with Axis I disordersi.e. schizophrenia or mood disorders. No studies, however, have included comparison groups consisting of probands with substance abuse or eating disorders, which are suspected to be familial. Two studies have used personality disorder comparison groupsi.e., avoidant personality disorder37 and ASPD.11 Of these, only the latter can be said to be a truly near-neighbor comparison group. Comparability of basic demographic features that might inuence prevalence of disorders can be achieved either by matching or by statistical control. In only two9,24 of the ten studies reviewed were comparison group probands matched by age, sex, and race; in another four,8,11,12,37 demographic similarities and differences were identied, but whether groups matched was not reported.

DISCUSSION
A signicant amount of research has been published on the familiality of BPD and its coaggregation with other disorders. As noted above, these studies have generally supported the idea that BPD breeds true. However, major problems exist in the quality of the methodology employed in these investigations. The fact that no adequately sized study using direct assessments of relatives has been conducted for BPD contrasts dramatically with the fact that by 1995, this method had been utilized in ten studies of mood disorders, eight of anxiety disorders, nine of schizophrenia, and ve of alcohol abuse/dependence.49 In the absence of such an investigation for BPD, Dahls conclusion27 in 1994 that BPDs familiality had not been convincingly established unfortunately still holds true. The need for such research is underscored by Torgersen and colleagues recent twin study,50 which suggested a surprisingly strong heritability (0.52 0.69) for BPD. That report draws attention to the need for research examining both genetic and environmental underpinnings of the disorder. Family studies, done well, could help to clarify which traits are transmitted. The existing studies investigating BPDs coaggregation with schizophrenia and bipolar disorder have been negative. Those that looked at depressive or impulse spectrum disorders yielded results that are promising but still ambiguous. Studies with more rigorous methodology are needed to conrm such linkages. Results obtained so far point toward the use of an alternative strategyi.e., following Silverman and colleagues approach15 and examining the familial aggregation of BPD component traits, such as affective instability and impulsivity, from a dimensional perspective. In this investigation, the familial aggregation was stronger for impulsivity and affective instability than for BPD. Moreover, these traits appeared to aggregate separately, with both be-

ing necessary for a diagnosis of BPD. Similarly, Livesley and colleagues51 have proposed that emotional dysregulation is the core aspect of the BPD construct; in their genetic factor analysis, this dimension seemed to account for much of the genetic variance. Such investigations suggest that the component traits of BPD may be inherited independently. A clear implication of this review is that a future family study should examine whether affective and impulsive traits, as well as other BPD characteristics such as aggressivity and unstable interpersonal relationships, aggregate individually or coaggregate with other traits in families. As noted, the evidence for increased Cluster B disorders in families of BPD probands also supports the value of such a study. We would hypothesize that individuals with BPD share the histrionic personality disorder trait of affective instability; those with ASPD share BPD traits of impulsivity and aggressivity; and those with narcissistic personality disorder share the BPD trait of interpersonal instability. Such a model predicts that persons with any of these personality disorders are likely to have relatives with similar traits, but that to develop BPD requires a combination of several such traits.

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