BIOL PSYCHIATRY 1990;28:247-254
2,~7
CSF Metabolites in Borderline Personality Disorder Compared with Normal Controls David L. Gardner, Peter B. Lucas, and Rex W. Cowdry
Cerebrospinal metabolites were measured in 17 patients with borderline personality disorder and 17 normaI consols. There were no significant differences between the two groups in levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylglycol (MHPG). Within the borderline group, lower levels of CSF 5-HIAA were significantly associated with a history of genuine suicide attempts, but were not associated with violence, self-mutilation, or with the presence of major depression. Thus, CSF 5-HIAA levels are not distinctively low in a diagnostic group characterized by impulsivity and suicidal behavior, but within that group may be associated with genuine suicide attempts.
Introduction Violence and suicide in human beings are complex and mu!tidetermined behaviors, which may be linked to a variety of situational stresses, psychodynamic mechanisms, and sociological factors. It has become increasingly clear that there are also biological factors that may predispose to violent or suicidal behavior. Animal research has identified relationships between aggressive behavior and central Jiervous system neurotransrnitters, including the catecholamines, serotonin, and gamma-amino butyric acid (Eichelman 1979; Garattini et al. 1969; Welch and Welch 1969). Human studies have found a strong association of both aggressive behavior and suicide with the serotonergic system. Violent or suicidal behavior has been linked to low concentrations of the serotonin metabolite 5hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) across a variety of diagnostic groups (Asbe~ et al. 1987). Preliminary. studies also suggest an association of suicidal behavior with abnormal serotonin-mediated platelet aggregation (McBride et al. 1987) and with reduced (Coccaro et al. 1989) or exaggerated (Fishbein et al. 1989) neuroendocrine responses to the serotonergic challenge agent fenfluramine. Borderline personality disorder (BPD) involves both affective dysreguiation and behavioral dyscontrol. The affective dysregulation is characterized by mood lability with episodes of rage and/or dysphoria superimposed on a chronic depression. Additionally, episodes of major depression occur in 40%-60% of patients with BPD (Carroll and Greden 1981; Sdoff et al. 1982; Baxter et a_i. 1984; Pope et al. 1983; Beeber et al. 1984;
From the Cl~aical and Research Services Branch, National Institute of Mental Health, Washington, DC (D.L.G., R.W.C.), and the Clinical Neuroscieact, s Branch, Nationa~ Institute of Mental Health, Bethesda, ~ (P.B.L.). Dr. Lucas is now with the Department of Psychiatry, Veterans .~.dministration Hospital, Sepulveda, CA. Address reprint requests to David L. Gardner, M.~., NqMH Neurosciences Center at ~t~ Elizabeths, WashingWn, DC 20032. Received November 7, 1989; revised January 11, 1990. Published 1990 by Elsevier Science Publishing Co., Inc.
0006-3223/~/$00:q0
248
BIOL PSYCHIATRY 1990;28:247-254
D.L. Gardner et al.
Steiner et al. 1984; Torgerson 1984; Grunhaus et al. 1985). The behavioral dyscontrol is characterized by impulsivity, violence, self-destructive behavior (including drugs and alcohol abuse, self-injury, and overdoses), ar. ,,;enuine suicide attempts. BPD thus presents an oppowanity to examine whether ~ diagnostic group characterized by impulsivity and behavioral dyscontrol demonstrates abnormalities in CSF monoamine metabolites compared with normal controls, and whether, within the group, CSF monoamine metabolites are correlated with depression, the frequency of self-injury, or the occurrence of genuine suicide attempts. Subjects a n d M e t h o d s Fem,~le patients with BPD were referred to the National Institute of Mental Health for evalua~'ion and possible participation in biological and pharmacological studies of BPD. They were interviewed by two members of the research team and were offered the opportunity to participate in the research program if they met the following criteria: (1) had met at least five of eight DSM-IH criteria (American Psychiatric Association 1980) for BPD; (2) had a duration of illness of at least 2 years since age 18 years; (3) had no history of schizophrenia; (4) had no alcohol or substance dependence or prolonged abuse within the past 2 years; (5) had no serious cardiovascular, renal, hepatic, or neurological disorder; (6) were able to be medication free for at least 2 weeks before entry into the study. I n f o ~'~dconsent for participation was obtained through extensive discussions and through detailed consent documents. Seventeen female patients participated in this study. Nine of the patients were participants in a 3-week inpatient evaluation, and 8 participated in an outpatient evaluation with a brief hospitalization for the lumbar puncture (LP). Extensive clinical histories were taken to identify current or past episodes of DSM-III major mood disorder, suicidal or parasuicidal behavior, and violent acts. Using a previously described approach to classification (Gardner and Cowdry 1985), suicidal and parasuicidal behavior were identified either as genuine suicide attempts (high risk/low rescue act with an expressed intent to die) or as parasuicidal behavior (overdose or intentional physical self-injury such as wristcutting, clinically determined to be primarily an attention-seeking, ragcful, or dysphoriarelieving act). Individuals were then classified according to whether they had had a current episode of major depression, had ever made a genuine suicide attempt, had ever intentionally injured themselves physically, or had ever intentionally harmed another person physically. Metabolite values for normal controls were obtained from the pool of normal control values from the Intramural Research Program, National Institute of Mental Health by selecting the female normal control closest in age to each patient. The normal controls had been recruited through the normal volunteer office at the National Ir -titute of Mental Health, Bethesda, MD. All had no personal history of a psychiatric disorder and no history of a psychiatric disorder in any first-degree relative. All subjects had normal physical examinations, were free of medication for at least 2 weeks prior to the LP, and followed a low-monoamine, alcohol-free, and caffeine-restricted diet for at least 5 days prior to the LP. Lumbar punctures were performed on an inpatient unit. All subjects fasted and remained at bedrest after midnight prior to the LP. The lumber punctures were performed between 8:30 AM and 9:00 AM with the subject in the lateral decubitus position. The first 12 ml
CSF Metabolites in BPD
toOL PSYCHIATRY 1990;28:247-254
249
Table 1. CSF Metabolite Levels in Borderline Patients and Normal Controls CSF metabolites MHPG (pmol/ml) 5-HIAA (pmol/ml) HVA (pmolhrd) HVA/5-HIAA HVA/MHPG 5-HIAA/MHPG
Normal controls n = 17 47.53 88.14 180.57 2.17 3.92 !.85
(11.99) (33.79) (60.79) (0.71) (1.48) (0.52)
Borderline pts n = 17 43.42 103.62 185.55 1.81 4.38 2.50
(9.65) (31.94) (66.39) (0.46) (1.51) (0.97)"
Values are mean (SD). °p < 0.02, Wileoxon, 2-tailed test.
of CSF was collected as a pool and placed on ice at the bedside. It was then aliquoted and frozen at - 8O°C for subsequent analysis. Levels of CSF 5-HIAA, homovanillic acid (HV.a0, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured using high-pressure liquid chromatography ~,~, ~,~ptuDt e-,~ with ,,,,,,.,,.,,,,,,,,,,~,,,,,"l°,'-"-"s'°"'~"ol ~,,,,,,,.u,,,,a°*°"a'"(Scheiaia et al. 1983; Seppala et al. 1984).
Results The mean ages of the normal controls and borderline patients were 28.71 years and 31.12 years, respectively [analysis of variance (ANQVA), F = 1.02, p = ns]. The mean values of CSF metabolites are shown in Table 1. There were no significant differences between the normal controls and the borderline patients on measures of CSF MHPG (47.53 versus 43.42) (pmol/ml), 5-HIAA (88.14 versus 103.62) (pmol/ml), or HVA (180.57 versus 185.55) (pmol/ml). The ratio of 5-HIAAJMHPG is significantly lower in the normal controls than in the borderline patients. Within the group of patients with BPD, we examined the association of CSF metabolites with current major depression, past history of genuine suicide attempts, past history of physical self-injury (e.g., self-mutilation), and past history of physical violence toward other people (see Table .9). Borderline patients with a past history of genuine suicide attempts in addition to parasuicidal behavior (n = 12) have significantly lower levels of CSF 5-HIAA tha~, those bordedine patients who have only shown parasuicidal behavior (n = 5) [95.32 versus 123.54 (pmol/ml), Wilcoxon p < 0.05, one-tailed test]. There are no significant differences for levels of MHPG or HVA between the two suicide groups. Three of the 17 patients, denoted by solid circles in Figure 1, had attempted suicide by violent means (two attempts by hanging and one completed suicide with a self-inflicted gunshot). The use of violent m e ~ s in these patients does not appear to be associated with particularly low concentrations of CSF 5-HIAA. There are no significant differences in levels of CSF metabolites in bordeflir ~ patients with a current major depression (n = 8) compared with borderline patients without a major depression (n = 9), between borderline patients with a history of physical selfinjury (.- - 12) and those patients without such a history (n = 5), or between borderline patients with a history of physical violence directed toward another person (n = 9) and those without such a history (n = 6) (the data were not adequate for an accurate assessment in 2 patients).
250
D.L. Gardner et al.
BIOL PSYCHIATRY 1990;28:247-254
Table 2. CSF Metabolites in Subgroups of Borderline Patients Major depression
MHPG (pmol/ml) 5-HIAA (pmc,~',rtl) HVA (pmol/ml) HVA/5-HIAA HVAJMHPG 5-HiAA/~PG
Violence
Self-injury
Suicide attempts
None (n = 9 )
Current (n = 8)
No (n = 5)
Yes (n = 12)
No (n = 5)
Yes (n = 12)
No (n = 6)
Yes (n = 9)
45.10 ( I2. I0) 106.44 (25.48) 201.29 (69.20) 1.87 (0.35) 4.64 (1.56) 2.52 (0.8'7)
41.54 (6.16) 100.44 (39.60) 167.85 (62.66) 1.74 (0.57) 4.09 (1.49) 2.47 (1.15)
41.46 (5.77) 123.54' (43.43) 177.84 (34.04) 1.51 (0.29) 4.31 (0.83) 3.03" (1.27)
44.24 (10.99) 95.32" (23.29) 188.77
45.64 (6.73) 99.66 (19.19) 193.64 (64.99)
42.50 (10.77) 105.27 (36.61) 182.18 (69.52)
39.75 (11.42) 100.87 (32.72) 177.83 (88.61) ~_.72 (0.40) 4.64 (1.98) 2.66 (0.92)
45.43 (8.51) 110.36 (34.37) 200.77 (55.44) 1.89 (0.55) 4.49 (1.27) 2.54 (1.11)
(77.15) 1.93 (0.46) 4.41 (1.75) 2.27" (0.78)
1.94
1.76
(0.52) 4.28 (1.46) 2.2(~ (0.3"•)
(0.44) 4.43 (I .59) 2.62 (1.13)
°p < 0.05, Wilcoxon, one-tailed test.
200
A
,ml
o
,<
2,~7
CSF Metabolites in Borderline Personality Disorder Compared with Normal Controls David L. Gardner, Peter B. Lucas, and Rex W. Cowdry
Cerebrospinal metabolites were measured in 17 patients with borderline personality disorder and 17 normaI consols. There were no significant differences between the two groups in levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), or 3-methoxy-4-hydroxyphenylglycol (MHPG). Within the borderline group, lower levels of CSF 5-HIAA were significantly associated with a history of genuine suicide attempts, but were not associated with violence, self-mutilation, or with the presence of major depression. Thus, CSF 5-HIAA levels are not distinctively low in a diagnostic group characterized by impulsivity and suicidal behavior, but within that group may be associated with genuine suicide attempts.
Introduction Violence and suicide in human beings are complex and mu!tidetermined behaviors, which may be linked to a variety of situational stresses, psychodynamic mechanisms, and sociological factors. It has become increasingly clear that there are also biological factors that may predispose to violent or suicidal behavior. Animal research has identified relationships between aggressive behavior and central Jiervous system neurotransrnitters, including the catecholamines, serotonin, and gamma-amino butyric acid (Eichelman 1979; Garattini et al. 1969; Welch and Welch 1969). Human studies have found a strong association of both aggressive behavior and suicide with the serotonergic system. Violent or suicidal behavior has been linked to low concentrations of the serotonin metabolite 5hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) across a variety of diagnostic groups (Asbe~ et al. 1987). Preliminary. studies also suggest an association of suicidal behavior with abnormal serotonin-mediated platelet aggregation (McBride et al. 1987) and with reduced (Coccaro et al. 1989) or exaggerated (Fishbein et al. 1989) neuroendocrine responses to the serotonergic challenge agent fenfluramine. Borderline personality disorder (BPD) involves both affective dysreguiation and behavioral dyscontrol. The affective dysregulation is characterized by mood lability with episodes of rage and/or dysphoria superimposed on a chronic depression. Additionally, episodes of major depression occur in 40%-60% of patients with BPD (Carroll and Greden 1981; Sdoff et al. 1982; Baxter et a_i. 1984; Pope et al. 1983; Beeber et al. 1984;
From the Cl~aical and Research Services Branch, National Institute of Mental Health, Washington, DC (D.L.G., R.W.C.), and the Clinical Neuroscieact, s Branch, Nationa~ Institute of Mental Health, Bethesda, ~ (P.B.L.). Dr. Lucas is now with the Department of Psychiatry, Veterans .~.dministration Hospital, Sepulveda, CA. Address reprint requests to David L. Gardner, M.~., NqMH Neurosciences Center at ~t~ Elizabeths, WashingWn, DC 20032. Received November 7, 1989; revised January 11, 1990. Published 1990 by Elsevier Science Publishing Co., Inc.
0006-3223/~/$00:q0
248
BIOL PSYCHIATRY 1990;28:247-254
D.L. Gardner et al.
Steiner et al. 1984; Torgerson 1984; Grunhaus et al. 1985). The behavioral dyscontrol is characterized by impulsivity, violence, self-destructive behavior (including drugs and alcohol abuse, self-injury, and overdoses), ar. ,,;enuine suicide attempts. BPD thus presents an oppowanity to examine whether ~ diagnostic group characterized by impulsivity and behavioral dyscontrol demonstrates abnormalities in CSF monoamine metabolites compared with normal controls, and whether, within the group, CSF monoamine metabolites are correlated with depression, the frequency of self-injury, or the occurrence of genuine suicide attempts. Subjects a n d M e t h o d s Fem,~le patients with BPD were referred to the National Institute of Mental Health for evalua~'ion and possible participation in biological and pharmacological studies of BPD. They were interviewed by two members of the research team and were offered the opportunity to participate in the research program if they met the following criteria: (1) had met at least five of eight DSM-IH criteria (American Psychiatric Association 1980) for BPD; (2) had a duration of illness of at least 2 years since age 18 years; (3) had no history of schizophrenia; (4) had no alcohol or substance dependence or prolonged abuse within the past 2 years; (5) had no serious cardiovascular, renal, hepatic, or neurological disorder; (6) were able to be medication free for at least 2 weeks before entry into the study. I n f o ~'~dconsent for participation was obtained through extensive discussions and through detailed consent documents. Seventeen female patients participated in this study. Nine of the patients were participants in a 3-week inpatient evaluation, and 8 participated in an outpatient evaluation with a brief hospitalization for the lumbar puncture (LP). Extensive clinical histories were taken to identify current or past episodes of DSM-III major mood disorder, suicidal or parasuicidal behavior, and violent acts. Using a previously described approach to classification (Gardner and Cowdry 1985), suicidal and parasuicidal behavior were identified either as genuine suicide attempts (high risk/low rescue act with an expressed intent to die) or as parasuicidal behavior (overdose or intentional physical self-injury such as wristcutting, clinically determined to be primarily an attention-seeking, ragcful, or dysphoriarelieving act). Individuals were then classified according to whether they had had a current episode of major depression, had ever made a genuine suicide attempt, had ever intentionally injured themselves physically, or had ever intentionally harmed another person physically. Metabolite values for normal controls were obtained from the pool of normal control values from the Intramural Research Program, National Institute of Mental Health by selecting the female normal control closest in age to each patient. The normal controls had been recruited through the normal volunteer office at the National Ir -titute of Mental Health, Bethesda, MD. All had no personal history of a psychiatric disorder and no history of a psychiatric disorder in any first-degree relative. All subjects had normal physical examinations, were free of medication for at least 2 weeks prior to the LP, and followed a low-monoamine, alcohol-free, and caffeine-restricted diet for at least 5 days prior to the LP. Lumbar punctures were performed on an inpatient unit. All subjects fasted and remained at bedrest after midnight prior to the LP. The lumber punctures were performed between 8:30 AM and 9:00 AM with the subject in the lateral decubitus position. The first 12 ml
CSF Metabolites in BPD
toOL PSYCHIATRY 1990;28:247-254
249
Table 1. CSF Metabolite Levels in Borderline Patients and Normal Controls CSF metabolites MHPG (pmol/ml) 5-HIAA (pmol/ml) HVA (pmolhrd) HVA/5-HIAA HVA/MHPG 5-HIAA/MHPG
Normal controls n = 17 47.53 88.14 180.57 2.17 3.92 !.85
(11.99) (33.79) (60.79) (0.71) (1.48) (0.52)
Borderline pts n = 17 43.42 103.62 185.55 1.81 4.38 2.50
(9.65) (31.94) (66.39) (0.46) (1.51) (0.97)"
Values are mean (SD). °p < 0.02, Wileoxon, 2-tailed test.
of CSF was collected as a pool and placed on ice at the bedside. It was then aliquoted and frozen at - 8O°C for subsequent analysis. Levels of CSF 5-HIAA, homovanillic acid (HV.a0, and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured using high-pressure liquid chromatography ~,~, ~,~ptuDt e-,~ with ,,,,,,.,,.,,,,,,,,,,~,,,,,"l°,'-"-"s'°"'~"ol ~,,,,,,,.u,,,,a°*°"a'"(Scheiaia et al. 1983; Seppala et al. 1984).
Results The mean ages of the normal controls and borderline patients were 28.71 years and 31.12 years, respectively [analysis of variance (ANQVA), F = 1.02, p = ns]. The mean values of CSF metabolites are shown in Table 1. There were no significant differences between the normal controls and the borderline patients on measures of CSF MHPG (47.53 versus 43.42) (pmol/ml), 5-HIAA (88.14 versus 103.62) (pmol/ml), or HVA (180.57 versus 185.55) (pmol/ml). The ratio of 5-HIAAJMHPG is significantly lower in the normal controls than in the borderline patients. Within the group of patients with BPD, we examined the association of CSF metabolites with current major depression, past history of genuine suicide attempts, past history of physical self-injury (e.g., self-mutilation), and past history of physical violence toward other people (see Table .9). Borderline patients with a past history of genuine suicide attempts in addition to parasuicidal behavior (n = 12) have significantly lower levels of CSF 5-HIAA tha~, those bordedine patients who have only shown parasuicidal behavior (n = 5) [95.32 versus 123.54 (pmol/ml), Wilcoxon p < 0.05, one-tailed test]. There are no significant differences for levels of MHPG or HVA between the two suicide groups. Three of the 17 patients, denoted by solid circles in Figure 1, had attempted suicide by violent means (two attempts by hanging and one completed suicide with a self-inflicted gunshot). The use of violent m e ~ s in these patients does not appear to be associated with particularly low concentrations of CSF 5-HIAA. There are no significant differences in levels of CSF metabolites in bordeflir ~ patients with a current major depression (n = 8) compared with borderline patients without a major depression (n = 9), between borderline patients with a history of physical selfinjury (.- - 12) and those patients without such a history (n = 5), or between borderline patients with a history of physical violence directed toward another person (n = 9) and those without such a history (n = 6) (the data were not adequate for an accurate assessment in 2 patients).
250
D.L. Gardner et al.
BIOL PSYCHIATRY 1990;28:247-254
Table 2. CSF Metabolites in Subgroups of Borderline Patients Major depression
MHPG (pmol/ml) 5-HIAA (pmc,~',rtl) HVA (pmol/ml) HVA/5-HIAA HVAJMHPG 5-HiAA/~PG
Violence
Self-injury
Suicide attempts
None (n = 9 )
Current (n = 8)
No (n = 5)
Yes (n = 12)
No (n = 5)
Yes (n = 12)
No (n = 6)
Yes (n = 9)
45.10 ( I2. I0) 106.44 (25.48) 201.29 (69.20) 1.87 (0.35) 4.64 (1.56) 2.52 (0.8'7)
41.54 (6.16) 100.44 (39.60) 167.85 (62.66) 1.74 (0.57) 4.09 (1.49) 2.47 (1.15)
41.46 (5.77) 123.54' (43.43) 177.84 (34.04) 1.51 (0.29) 4.31 (0.83) 3.03" (1.27)
44.24 (10.99) 95.32" (23.29) 188.77
45.64 (6.73) 99.66 (19.19) 193.64 (64.99)
42.50 (10.77) 105.27 (36.61) 182.18 (69.52)
39.75 (11.42) 100.87 (32.72) 177.83 (88.61) ~_.72 (0.40) 4.64 (1.98) 2.66 (0.92)
45.43 (8.51) 110.36 (34.37) 200.77 (55.44) 1.89 (0.55) 4.49 (1.27) 2.54 (1.11)
(77.15) 1.93 (0.46) 4.41 (1.75) 2.27" (0.78)
1.94
1.76
(0.52) 4.28 (1.46) 2.2(~ (0.3"•)
(0.44) 4.43 (I .59) 2.62 (1.13)
°p < 0.05, Wilcoxon, one-tailed test.
200
A
,ml
o
,<
