Medscape Psychiatry

The Biology of Borderline (and a

Diagnostic Tip)
Derick E. Vergne, MD
March 23, 2015

Background
Diagnosis in psychiatry continues to be based on observation. However,
economic forces are driving the norm of inaccurate diagnoses after an initial
interview lasting less than an hour. To that extent clinicians are taught to rely
heavily on the history documented in a patient's medical chart, the diagnostic
information found in all records is the result of the same short interview,
followed by even shorter follow-up visits. When external influences curtail
information-gathering rather than allowing sufficient time for diagnosis, the
information will often be incomplete and potentially inaccurate.
Psychiatrists are best served by a keen understanding of the natural history of
disease and its many facets, coupled with thorough observation of behavior
(ie, mental status), to arrive at an accurate diagnosis. More than 100 years ago,
Kraepelin and colleagues[1] taught us to use proper observation as a guiding
light in diagnosis:
...after the first thorough examination of a new patient, each of us had to throw
in a note [in a "diagnosis box"] with his diagnosis written on it. After a while,
the notes were taken out of the box, the diagnoses were listed, and the case
was closed, the final interpretation of the disease was added to the original
diagnosis. In this way, we were able to see what kind of mistakes had been
made and were able to follow-up the reasons for the wrong original diagnosis.
The importance of gathering sufficient information for diagnosis is
particularly important for borderline personality disorder (BPD), which
encompasses multiple symptoms that overlap across many diagnoses in the
Diagnostic and Statistical Manual of Mental Disorders (DSM), making its
identification challenging.[2]

Defining Borderline Personality Disorder

The DSM-5 defines BPD as "a pervasive pattern of instability of interpersonal
relationships, self-image, and affects, and marked impulsivity, beginning in
early adulthood and present in a variety of contexts, as indicated by five (or
more) of the following"[2]:
1. Frantic efforts to avoid real or imagined abandonment.
2. A pattern of unstable and intense interpersonal relationships characterized
by alternating between extremes of idealization and devaluation.
3. Identity disturbance: markedly and persistently unstable self-image or sense
of self.
4. Impulsivity in at least two areas that are potentially self-damaging (eg,
substance abuse, binge eating, and reckless driving).
5. Recurrent suicidal behavior, gestures, or threats, or self-mutilating behavior.
6. Affective instability due to a marked reactivity of mood (eg, intense
episodic dysphoria, irritability, or anxiety usually lasting a few hours and only
rarely more than a few days).
7. Chronic feelings of emptiness.
8. Inappropriate, intense anger or difficulty controlling anger (eg, frequent
displays of temper, constant anger, recurrent physical fights).
9. Transient, stress-related paranoid ideation or severe dissociative symptoms.
Perhaps a more global description of BPD would be that the inner lives of
people who suffer from it are chaotic and characterized by anger or rage
directed both outside (ie, to others via unstable interpersonal relationships)
and inside (ie, to self via impulsivity, poor decision-making, or drug use, for
example).

Trauma, BPD, and Oxytocin

One observation that appears to be consistent across the illness continuum of
BPD is the presence of childhood trauma. [3] Trauma or neglect is observed in
up to 87% of patients with BPD, and of these patients, 40%-71% have been
sexually abused.[4] Moreover, 30.2% of patients with BPD may also be
diagnosed with post-traumatic stress disorder (PTSD).[5] In other words,
patients with a history of trauma are more likely to develop BPD and PTSD,

but in 24.2% of patients where both disorders coexist, [5] diagnostic accuracy
can be a challenge if DSM criteria are solely used. Focusing on trauma and its
history, quality, and phenomenology can provide an idea of where to begin in
terms of diagnosis.
We are beginning to understand to what extent early life stress relates to
"chronic emptiness" and the "inability to form stable interpersonal
relationships"; an inverse relationship between early stress and oxytocin
levels, which is a neuropeptide related to attachment and bonding in
mammals, has been observed.[6] In particular, BPD has been associated with
excessive socioaffective vigilance and enhanced reactivity to emotional and
social stimuli.
Hypervigilance to emotionally charged social situations has been associated
with enhanced amygdala reactivity to minimally unpleasant and even neutral
stimuli.[7,8] Although causation cannot be inferred, examination of
hypothalamic and extrahypothalamic stress response reveals at least partial
mediation of the association between oxytocin levels and BPD
psychopathology. In other words, the stress response affects how oxytocin
levels and BPD symptoms relate.
This is further supported by a recent trial in which adult participants, both with
and without BPD, were randomly assigned to received either 40 IU of
intranasal oxytocin or placebo, both followed by the Trier Social Stress Test,
which is designed to induce anxious states.[9] This trial found a decrease in
stress-induced dysphoria in participants with BPD after oxytocin
administration. In rodent knockout studies, activation of oxytocin receptors in
the medial amygdala is necessary for social recognition in the mouse.[10] In
human functional MRI connectivity studies, aside from the effect of oxytocin
on reducing amygdala response to fear-related stimuli, there was also reduced
coupling of the amygdala to midbrain structures, pointing to the effect of
oxytocin on reducing the amygdala's activation of more limbic (ie, primitive)
areas.[11]
Oxytocin has also been studied in the context of attachment, [12] as defined and
conceptualized by the subjective experience of anxiety to loss and
abandonment.[13] Research is beginning to demonstrate a consistent relationship
among secure and insecure attachment; oxytocin levels; and differences in
activation of the medial prefrontal cortex (mPFC), where thinking and
emotion interact, and the ventral striatum (ie, nucleus accumbens or pleasure
center of the brain).[14] A clearer pattern is emerging in which patients with a

diagnosis of BPD exhibit faulty attachment behavior, which is correlated with

a decrease in oxytocin levels and decreased nucleus accumbens and mPFC
activity, with an increase in the activity of the insula. [14] Current theoretical
models point to mPFC deficits in integration between cognition and emotional
processing stimuli, with a resultant incapacity or reduced ability for
attachment and empathy,[15] which is seen in patients with BPD.[16]

Borderline Biology
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 COMT, DAT1,
GABRA1, GNB3, GRIN2B, HTR1B, HTR2A, 5-HTT, MAO-A, MAO-B, NOS1,
NR3C1, TPH1, 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.

Summary
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.

References
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