The Biology of Borderline (and a Diagnostic Tip)

Derick E. Vergne, MD Disclosures
March 23, 2015  Medscape Psychiatry

The molecular biology of BPD must consider factors that modulate susceptibility. Although this is in theory true with all neuropsychiatric disorders, it is especially informative in the understanding of the pathophysiology of BPD. Psychodynamic theory implicates faulty attachment of the infant to the mother at critical periods of development. "Emotional neglect" is a term coined by neuroscientists to describe the same process. Nevertheless, some children exposed to emotional neglect may develop BPD, whereas others may not.

Some insights on the molecular biology of BPD have come from research on a polymorphism of the promoter site for serotonin transporter (SERT), in which possession of at least one copy of an allele for the gene encoding SERT confers vulnerability to depression.[17] Yet not everyone possessing the SERT gene suffers from neuropsychiatric consequences. The consequences of early adverse events, such as maltreatment or perceived abandonment (ie, faulty attachment), appears to somehow "turn on" these genes and turn potential for illness into active illness.[17] The answer as to why some people are affected and others are not may lie in the way that a susceptible brain interacts with the environment.[18]

As a result of such a predisposition, the brain can be more susceptible to symptoms, such as impulsive aggression, repeated self-injury, and chronic suicidal tendencies, which make those who suffer from it frequent users of mental healthcare resources. Several genes have been identified in the past decade as candidates for vulnerability to BPD; these include COMTDAT1GABRA1GNB3GRIN2BHTR1BHTR2A5-HTTMAO-AMAO-BNOS1NR3C1TPH1, and TH, and they have gathered interest owing to the different aspects of monoamine density and metabolism they regulate.[19,20]

All of these genes coincide with the regulation of some key neurotransmitter systems, including serotonin, GABA, glutamate, dopamine, norepinephrine, and some of the neuropeptide systems, including oxytocin, neuropeptide Y, and corticotropin-releasing factor. However, these genes have not fully explained why some people develop BPD and others do not.

The field of epigenetics describes the way in which environmental factors have the capacity to alter genetic transcription and the synthesis of protein, leading to health or illness. Epigenetics has a place in neuropsychiatry and may account for the moderation of adverse events in the relationship between susceptibility genes and illness. Epigenetics refers to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are DNA methylation and histone modification, both of which serve to regulate gene expression without altering the underlying DNA sequence.

Further studies have replicated findings on the role of significantly increased methylation of MAO-A in patients with BPD, as well as COMT and the glucocorticoid receptor NR3C1.[20,21] The environment of early life adversity tends to promote the methylation of the promoter region of the glucocorticoid receptor gene NR3C1, leading to a receptor that is ineffective in binding flowing glucocorticoids, thereby failing to provide feedback inhibition (ie, turning the system off).[21] This phenomenon has been observed in the hippocampus of suicide victims with a history of childhood abuse, for example.[21]Ultimately, this leads to chronic activity of corticosteroids and the resultant neuropsychiatric sequelae, including BPD.


BPD entails the convergence of different factors that are interdependent but that under certain conditions, such as trauma, may modulate each other (eg, genetic susceptibility) in the context of faulty attachment or emotional neglect, to produce the characteristics of the syndrome. To avoid misdiagnoses and unnecessary and potentially harmful treatment, the clinician should always pay attention to the presence of trauma in patients who show severe emotional dysregulation that may masquerade as other disorders in the DSM.