تکانشگری، جنسیت و پاسخ به چالش فن فلورامین در اختلال شخصیت مرزی

Behavioral impulsivity in borderline personality disorder (BPD) is associated with indices of diminished central serotonergic function, independent of suicidal behavior, depression or alcohol use disorder. Many of these studies have been conducted among males in specialized settings. Studies of BPD females, who constitute the majority of BPD patients, are generally conducted in community settings and report inconsistent findings. We studied gender differences in behavioral impulsivity and the prolactin response to d,l-fenfluramine (FEN) in BPD subjects in a community setting. A FEN challenge study was conducted with 64 BPD subjects (20 male, 44 female), and 57 controls (36 male, 21 female). Axis I and II disorders, including BPD, and suicidal histories were assessed by structured interviews. Controls were free of Axis I and II disorders. Impulsivity and aggression were assessed by the Buss–Durkee Hostility Inventory, Barratt Impulsiveness Scale, Minnesota Multiphasic Personality Inventory-Psychopathic Deviate subscale, and the Brown–Goodwin Lifetime History of Aggression. Male, but not female, BPD subjects had significantly diminished prolactin responses compared to controls. Impulsivity and aggression each predicted prolactin responses. A significant effect of BPD diagnosis on prolactin response was eliminated when impulsivity was co-varied. Impulsivity and aggression were inversely related to delta-prolactin and peak-prolactin responses among male but not female subjects. Gender differences in central serotonergic function may contribute to variations in impulsivity in BPD.

Borderline personality disorder (BPD) is an important clinical model for investigating impulsivity and suicidal behavior, and is defined, in part, by both behaviors (DSM-IV). BPD is one of the most lethal psychiatric disorders, with a suicide completion rate of 9–10% in long-term follow-up. (Stone, 1989 and Paris, 2002). Suicide attempters and completers with BPD exhibit more impulsive behaviors than non-attempters (Soloff et al., 1994) or BPD control subjects (Kjelsberg et al., 1991). Impulsivity in patients with BPD is significantly associated with lifetime number of suicide attempts, even after controlling for co-morbid depression and substance use disorders (Brodsky et al., 1997 and Soloff et al., 2000a). Borderline patients may commit suicide impulsively, in anger, often following a perceived rejection (Kullgren et al., 1986). In a stress–diathesis model of suicidal behavior, impulsivity constitutes a vulnerability involving temperament, increasing the likelihood of suicidal behavior in the presence of acute stressors such as depression, substance abuse, or perceived rejection (Mann et al., 1999). Impulsivity and suicidal behavior are both associated with indices of diminished central serotonergic function, assessed by indirect methods such as CSF 5-HIAA, or neuroendocrine responses to challenge with serotonergic agonists such as d- or d,l-fenfluramine (FEN), meta-chlorophenylpiperazine (m-CPP), or buspirone ( Oquendo and Mann, 2000, Coccaro et al., 1990 and Stanley and Mann, 1988, for reviews). Diminished indices of central serotonergic function have been described in many studies of attempted or completed suicide, and across many, but not all, diagnoses. Åsberg et al. (1986) first reported an association between low CSF 5-HIAA and violent methods of suicide attempt. Other investigators have found relationships between low CSF 5-HIAA or blunted prolactin responses to FEN and high lethality attempts or impulsivity, rather than violence of method ( Mann et al., 1996 and Mann and Malone, 1997). In patients with BPD or other impulsive personality disorders (PD), diminished levels of CSF 5-HIAA are associated with violent attempts ( Träskman-Benz et al., 1986), and non-violent, but ‘genuine’ attempts ( Gardner et al., 1990), lifetime histories of aggression, ( Brown et al., 1982) and impulsive–aggressive behavior independent of suicidal behavior ( Linnoila et al., 1983, Linnoila et al., 1989 and Virkkunen et al., 1987). A blunted prolactin response to serotonergic agonists, and an inverse relationship between prolactin response and behavioral impulsivity, has been described in patients with BPD or other impulsive PDs, independent of histories of suicidal behavior ( Coccaro et al., 1989, O'Keane et al., 1992 and Moss et al., 1990), co-morbid affective disorders, or alcohol use disorders (AUD) ( Coccaro et al., 1989). Subjects with BPD and other impulsive PDs demonstrate a decreased uptake of [F-18] fluorodeoxyglucose on PET neuroimaging in response to FEN challenge in areas of prefrontal cortex associated with regulation of mood and impulse, especially in orbital and medial prefrontal cortex ( Siever et al., 1999, Soloff et al., 2000b, Goyer et al., 1994, De La Fuenta et al., 1997, Raine et al., 1992 and Raine et al., 1997; Oquendo et al., personal communication). Many studies demonstrating serotonergic dysregulation in subjects with BPD or other impulsive PDs have been conducted in highly specialized settings. Brown et al. (1982) first demonstrated an inverse relationship between CSF 5-HIAA and Lifetime History of Aggression (LHA) in male military recruits with BPD, hospitalized for ‘fitness to serve’ assessments. Linnoila et al., 1983, Linnoila et al., 1989 and Virkkunen et al., 1987 used a forensic setting to compare CSF 5-HIAA levels in violent and non-violent, impulsive and non-impulsive, male offenders with BPD. Similarly, Lidberg et al., 1984 and Lidberg et al., 1985 studied impulsive homicidal offenders who killed someone emotionally important to them, and suicide attempters who attempted to kill or actually killed their own children. Coccaro et al. (1989) recruited male patients with PD from a VA hospital setting. A second study advertised for male volunteers ‘who considered themselves to have difficulty managing their aggressive behaviors’ (Coccaro et al., 1996). Studies of BPD subjects conducted in specialized settings or ascertained for impulsivity and aggression, have focused predominately on males, though 76–80% of BPD diagnoses are made in females (Widiger and Weissman, 1991). Studies of female BPD subjects (or mixed gender samples), recruited in community settings, report inconsistent findings in serotonergic challenge studies. Some (Hollander et al., 1994, Stein et al., 1996, Martial et al., 1997 and New et al., 1997), but not all (Rinne et al., 2000 and Herpertz et al., 1997), have failed to demonstrate diminished prolactin responses to serotonergic agonists, or relationships between prolactin response and measures of behavioral impulsivity. Very small sample sizes in these negative studies raise the issue of statistical power and Type II error. Heterogeneity of symptom presentation in BPD, especially in regard to impulsivity and aggression, is an important source of variation in results between studies. Finally, some studies used FEN as their challenge agent while others used m-CPP, which could also contribute to inconsistent findings between studies ( Hollander et al., 1994, Stein et al., 1996 and Rinne et al., 2000). This study examined the prolactin response to d,l-FEN in both male and female subjects with criteria-defined BPD in an effort to address the inconsistencies in prior reports. Our subjects were recruited from inpatient, outpatient and community sources in an urban university hospital setting. Since impulsivity is a diagnostic criterion for BPD regardless of gender, we hypothesized that both genders would demonstrate diminished prolactin responses to FEN compared to matched control subjects, and that the prolactin responses to FEN would vary inversely with severity of impulsivity.