Neurobiology of Borderline Personality Disorder (BPD)

1. Neurobiology of Borderline Personality Disorder (BPD) Duyen Luong Nov 27, 2003

2. Overview • DSM-IV criteria • Epidemiology • Heritability • Impulsivity • Affective instability • Treatment • Conclusions

3. DSM – IV Criteria • A pervasive pattern of instability of interpersonal relationships, self-image and affects, and marked impulsivity • Present by early adulthood • Present in a variety of contexts • Indicated by at least five of the following: • Frantic efforts to avoid real or imagined abandonment (excluding suicidal or self-injurious behaviors) • Pattern of unstable and intense interpersonal relationships, characterized by alternating between extremes of idealization and devaluation • Identity disturbance (self-image or sense of self)

4. DSM – IV Criteria – cont’d 4. Impulsivity in at least 2 areas that are potentially self-injurious 5. Recurrent suicidal behavior, gestures or threats, or self-mutilating behavior 6. Affective instability as a result of marked reactivity of mood 7. Chronic feelings of emptiness 8. Inappropriate, intense anger or difficulty controlling anger 9. Transient, stress-related paranoid ideation or severe dissociative symptoms

5. Epidemiology • Prevalence: • 10% in outpatient settings • 15-20% in inpatient settings • 1-2% in the general population • Frequently comorbid with axis I disorders, especially mood, substance use, and anxiety disorders • Up to 80% experience a major depressive episode in lifetime • Over 2/3 of BPD patients will have problems with drug or alcohol abuse or dependence • Reflect underlying traits of impulsivity and affective instability • Approx 60% of patients with BPD make a suicide attempt; 10% actually succeed • More often in women than men

6. Heritability? • Norwegian twin study: MZ (35%) > DZ (7%) • The prominent features of impulsivity appear to run in families • First-degree relatives of patients with BPD have 11.6% morbid risk of BPD • Some have argued that perhaps it is not BPD that is inherited per se, but the underlying personality traits • i.e., impulsivity and affective instability (temperament) • The co-occurrence of these two traits may particularly predispose an individual to BPD • Recent research efforts have focused on the neurobiology of these two traits

7. Impulsivity • Involve at least 4 main NT systems: 5-HT*, DA, NE, and GABA • DA: mesolimbic pathway modulate affective responses to the environment • Increases in DA activity in this pathway enhance irritative aggression • Most studies find that increases in DA is associated with increased aggression (mice) • NE: in both AM and humans, increase in NE activity associated with increased aggressive behavior • Patients with personality disorders that have characteristically high levels of risk-taking, irritability, and verbal aggression seem to have hyper-responsive NE system • GABA: inhibitory effect on aggressive behavior

8. Impulsivity – 5-HT • Decreased serotonergic activity is associated with measures of impulsive aggression in patients with personality disorders • Low CSF 5-hydroxyindoleacetic acid (5-HIAA; main 5-HT metabolite) seen in: • BPD patients without depression but with high scores on lifetime aggression • BPD patients with violent suicidal behavior • Impulsive violent and nonviolent offenders with BPD • Overall, among BPD patients, lower CSF 5-HIAA levels associated with higher levels of aggression and suicidal behavior

9. Impulsivity – cont’d Drug Challenge in human studies • Fenfluramine (FEN) releases 5-HT and blocks its reuptake (i.e., 5-HT agonist); causes a dose-dependent increase in prolactin • Prolactin response to FEN depends on pre- and postsynaptic 5-HT functioning • Measure prolactin response to FEN challenge to indirectly assess serontonerigic activity • Patients with BPD show a blunted prolactin response to FEN challenge compared to healthy controls (i.e., hypofunctioning of 5-HT system) • BPD: response to FEN was negatively related to measures of assaultativeness and impulsivity • Suicide attempts have also been associated with blunted prolactin responses to FEN among personality disordered (incl. BPD) patients

10. Impulsivity – cont’d • PET neuroimaging to assess fluorodeoxyglucose (FDG) uptake as a measure of cortical metabolism after FEN challenge • patients with BPD showed diminished glucose uptake in the frontal cortex, particularly in the orbital and medial regions of the PFC following challenge • Lesions to these regions associated with profound dysregulation of affect and impulse (major traits of BPD) • Authors suggest that the decreased responsiveness of the serotonergic system in the PFC may be the biological predisposition to disinhibition, impulsivity, and impulsive aggression seen in BPD

11. Affective Instability Acetylcholine (ACh)*, NE, and GABA Rich cholinergic enervation of limbic structures (e.g., amygdala, hippocampus, and cingulate cortex) Recall limbic system and emotion regulation NE: increased NE activity associated with heightened responsivity to the environment GABA: serves to dampen rapid cycling of emotion Decreased GABA activity could potentially lead to affective instability

12. Affective Instability – ACh Procaine (ACh agonist) induces a high degree of dysphoria in BPD compared to patients with affective disorders and normal individuals Administer physostigmine (ACh agonist) to patients with BPD and controls BPD group respond with affective shift towards depression that is greater than that observed in controls This shift is also faster in BPD than in controls Therefore, since ACh agonist can rapidly disrupt affect in patients with affective instability  support for the involvement of ACh dysregulation in affective instability

13. Pharmacological Treatment As of 2002, no FDA approved drug to specifically treat BPD or any of its core traits SSRIs first choice for both the impulsive and affective symptom clusters Efficacious for decreasing impulsive aggression, verbal aggression, and aggression against objects Nonspecific to BPD; global improvements Not much evidence of efficacy of other drugs (e.g., TCAs, antipsychotics, MAOIs) Most treatment interventions combine drugs with psychotherapy (e.g., dialectical therapy)

14. Conclusions • Core symptom clusters appear to be heritable • Hypofunctioning of serotonergic system related to the impulsivity in patients of BPD • Hyperfunction of cholinergic system associated with affective instability • Many other NT systems are involved in BPD • Currently, no drug approved specifically to treat BPD