The classification of the personality disorders has posed a challenge to epidemiologists, clinicians, geneticists, and psychologists. Because of the varied academic perspectives on these disorders that range from behaviorist to interpersonal to psychodynamic to trait theory, the schemata that have evolved to categorize the personality disorders have been highly variable and controversial. The result has been a nomenclature for these disorders defined, for example, in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) in polythetic criteria that in some cases reflect an epidemiological and/or behavioral tradition, such as antisocial personality disorder, or in other cases, a psychoanalytically oriented tradition, such as in narcissistic personality disorder. An alternative approach to understanding and classifying psychiatric disorders, which has not been extensively investigated in the personality disorders, is reframing the diagnostic nomenclature in terms of specific and measurable biologically and/or genetically based endophenotypes, which open up the possibility of identifying genetic predisposing factors, as well as providing a possibly more rational classification schema. This approach, while not necessarily incompatible with other diagnostic approaches that are formulated from alternative perspectives such as behavioral or psychodynamic approaches, raises the possibility of generating an underlying “vocabulary” of personality disorders grounded in specific biologic substrates. Combinations of these endophenotypically based dimensions of personality disorders, such as affective instability or impulsivity/aggression, might then become the basis of more complex multifactorial personality disorders recognized by the clinician, such as borderline personality disorder (BPD) or schizotypal personality disorder (SPD). Furthermore, such an endophenotypic approach may help clarify the interaction of underlying genetic predispositions with environmental influences. By identifying measurable characteristics that reflect an underlying genotype or are more closely related to that genotype than to the diagnostic category itself, the opportunity to unravel pathophysiological pathways involving specific candidate genes as well as environmental influences on their expression becomes a more feasible possibility.
There are a variety of endophenotypic strategies, including identifying specific clinical characteristics of a disorder, for example, age of onset, positive family history, or suicide history.1
An endophenotypic strategy for personality disorders might also be based on an underlying dimensional structure of the personality disorders, which has gained increasing acceptance among investigators in the field.2,3
Thus, the strategy of identifying intermediate phenotypes for dimensions of impulsivity, aggression, affective instability, and emotional information processing in the cluster B disorders; dimensions of psychoticlike perceptual distortions, social deficits, and cognitive impairment in the cluster A disorders; and dimensions of anxiety and behavioral inhibition, and compulsivity in the cluster C personality disorders may be a promising one (Table I).
While a dimensional approach is defined at the level of psychopathology, cognitive neuroscience can provide measurable characteristics of performance in domains such as sustained attention or working memory. At a more fundamental psychophysiological or neurophysiological level, characteristics such as P50
evoked potentials, eye movement dysfunction, or startle/blink paradigms can provide promising endophenotypes that have proved useful in the schizophrenia spectrum.3
At a more fundamental biological level, neurochemical parameters, including receptor binding or neuroimaging variables, may be useful as potential endophenotypes.
Dimensions of cluster A, B, and C disorders. DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition.
Ideally, an endophenotype would have high concordance in twins with a high monozygotic-to-dyzygotic twin ratio, high correlation in sibpairs, longitudinal stability in patients and control cohorts, and high discriminability between patients with a specific diagnostic category in comparison to healthy or psychiatric comparison groups. It is desirable for an endophenotype to have a specific mode of inheritance as well, and it is particularly important for it to be relatively convenient and accessible to measure in order to feasibly evaluate the characteristic in large populations.4
Criteria have been developed for the identification of endophenotypes for use in psychiatric genetic studies and include:
- An association with the illness in the general population.
- Heritability and emergence before the onset of illness.
- State independence.
- Close segregation with the illness in families.
- Higher prevalence in nonaffected family members than in the general population, although less than in affected family members.
Because the personality disorders, by definition, represent relatively enduring or persistent traits or coping styles, which may be in some cases related to the susceptibility to major Axis I disorders (eg, SPD to schizophrenia, avoidant personality disorder to social phobia or generalized anxiety disorder), they may lend themselves particularly well to endophenotypic approaches. In this overview, we focus on specific dimensions of personality disorder that may represent behavioral intermediate phenotypes and discuss more biologically based endophenotypes that may underlie these dimensions, with a particular focus on several prototypic personality disorders: BPD, SPD, and avoidant personality disorder. We start with a review of studies suggesting heritability for personality disorders and, for our prototypic disorders in particular, we follow this with a discussion of strategies for genetic studies of personality disorders, and then we discuss specific prototypical disorders and related dimensions.