Neuroendocrine Study of Serotonin Function in Female Borderline Personality Disorder Patients: A Pilot Study

Johanne Martial, Joel Paris, Marco Leyton, Hallie Zweig-Frank, George Schwartz, Eric Teboul, Joseph Thavundayil, Suzanne Larue, NMK Ng Ying Kin, and NP Vasavan Nair
Key Words: Borderline personality, fenfluramine, cortisol, prolactin, serotonin BIOL PSYCHIATRY 1997;42:737739

Introduction
Preliminary findings suggest that patients with borderline personality disorder (BPD) have disturbed serotonin (5-hydroxytryptamine (5HT) neurotransmission. At least some patients have decreased cerebrospinal fluid (CSF) concentrations of the 5HT metabolite, 5-hydroxyindoleacteic acid (5HIAA) (Gardner et al 1990), decreased prolactin responses to both fenfluramine (Coccaro et al 1989), and meta-chlorophenylpiperazine (mCPP) (Hollander et al 1994), and increased cortisol release following mCPP (Hollander et al 1994). Serotonergic disturbances in BPD patients might be different in men and women. Hollander et al (1994) reported that men, but not women patients differed from healthy controls in their mCPP-stimulated release of prolactin and cortisol. As the authors noted, a gender difference might be attributable to circulating ovarian hormones. Perhaps related to this hypothesized difference, prepubertal boys (males who might be hormonally more similar to women than men) with attention deficit hyperactivity

disorder (ADHD) plus aggressive features have increased, rather than decreased, prolactin responses to fenfluramine (Halperin et al 1994). The possibility of a gonadal hormone mediated difference in 5HT function among BPD patients indicated the need for an explicit test. Moreover, the relative absence of physiologic studies of BPD women is striking given that the majority of patients are women. Therefore, we investigated 5HT functioning in BPD women as assessed by fenfluramine stimulated pituitaryadrenal activity, and all were tested during their luteal phase. We hypothesized that, if women BPD patients have disturbed serotonergic activity, then, compared to healthy controls, they would have different plasma levels of prolactin and cortisol following the administration of fenfluramine.

Methods
Five healthy women patients (aged 20 40 years) were recruited from a clinic run by one of the authors (JP). Diagnosis was based on the Diagnostic Interview for Borderlines-Revised (DIB-R 8/10). Current state was determined with the Hamilton-Depression scales (HAM-D; 5 on a 17-item scale) and Hamilton Anxiety scales (HAM-A; 7 on a 14-item scale), and all were free of current DSM-III-R Axis I psychopathology. All patients had been medication-free for at least 2 months, and a urinary screen confirmed that they had not recently used standard drugs of abuse. Six DSM-III-R psychopathology-free, age-matched, and
0006-3223/97/$17.00 PII S0006-3223(97)00295-3

From the Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Verdun, Que bec, Canada (JM, GS, ET, JT, SL, NMKNYK, NPVN); Institute of Community and Family Psychiatry, Sir Mortimer B. Davis-Jewish General Hospital, Montre al, Que bec, Canada (JP, HZ-F); and Allan Memorial Institute, Department of Psychiatry, McGill University, Montre al Que bec, Canada (ML). Address reprint requests to Johanne Martial, Douglas Hospital Research Centre, Department of Psychiatry, McGill University, 6875 LaSalle Blvd., Verdun, Que bec, Canada H4H 1R3. Received May 20, 1996; revised April 1, 1997.

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weight-matched healthy women served as comparison subjects, and each was rated on the DIB-R 4/10). Neither patients nor controls had used hormonal preparations within 6 months of the test; all were in the luteal phase of their menstrual cycle when circulating levels of estrogens are low and less likely to alter 5HT transmission. All subjects were requested to abstain from alcohol for 2 weeks. All were in good physical health as determined by a physical examination and laboratory workup. For 3 days before the test, subjects followed a low monoamine diet. On the test day, they fasted from midnight and arrived at the hospital at 7:30 A.M. From 7:30 A.M. 8:00 A.M., HAM-A and HAM-D scores were determined. At 8:00 A.M., subjects adopted a supine position and a heparinized catheter was inserted into an antecubital vein. At 9:00 A.M., a blood sample was taken for measuring baseline levels of prolactin and cortisol. At 9:10 A.M., fenfluramine hydrochloride (Pondimin, Ayerst) (60 mg) was administered orally. During the next 4 hours, vital signs and serial blood samples were taken at 30-minute intervals. Selfrating scales for physical side effects were completed hourly. The collected blood samples were stored and centrifuged at 4C. Sera were stored 80C in polypropylene tubes until used for the assays. Serum levels of cortisol and prolactin were determined by radioimmunoassay (RIA), using the corresponding RIA kits from Kodak Clinical Diagnostics Ltd. (Amersham, UK). The study was approved by the Ethics Committees of Douglas Hospital and the Jewish General Hospital. All subjects gave written, informed consent.

Figure 1. Plasma levels of cortisol (g/dL SEM) before, during, and after oral administration of fenfluramine hydrochloride (60 mg). or peak magnitude [18.5 4.4 versus 16.5 5.1; F(1,9) .0877, p .75] were not significant.

Discussion
Fenfluramine did not significantly alter mood or vital signs but in both groups it increased plasma levels of prolactin and cortisol. In the patients group, the prolactin response was accelerated, beginning sooner, whereas the cortisol response was abbreviated, ending sooner. The direction of these effects was the opposite to those seen in two studies of BPD men. (Coccaro et al 1989; Hollander et al 1994) though similar to those seen in a study of aggressive ADHD boys (Halperin et al 1994).

Results
Cortisol
The two groups did not have different plasma levels of cortisol at baseline (mean SEM patients: 12.8 2.8 versus controls: 11.3 1.4 g/dl; p .05). Nor were the two groups significantly different for the test as a whole (F(1,9) .617, p .40). However, there was a significant group time interaction (F(8,72) 2.405, p .03) reflecting a faster return to baseline in the patient group, and this difference was significant at the 3.5 hour sample (F(1,22) 4.571, p .05) (Figure 1). In comparison, there were no group differences in area under the curve (43.6 11.4 versus 51.0 7.1; F(1,9) .642, p .40), peak magnitude [18.2 2.5 versus 17.3 3.1; F(1,9) .0416, p .80], or latency to peak magnitude [2.6 3 versus 2.2 2 hours; F(1,9) 1.199, p .30).

Prolactin
Baseline levels of prolactin did not differ significantly between the two groups (patients: 4.5 0.4 versus controls: 4.1 0.9 ng/ml p .05). Nor were the two groups significantly different for the test as a whole [F(1,9) .560, p .45], although there was a weak nonsignificant group time interaction [F(8,72) 1.678, p .12]. However, patients, compared to controls, reached peak response significantly sooner [2.2 .3 versus 3.25 .2 hours; t(9) 3.53, p .007] (Figure 2). Group differences in area under the curve [40.9 7.7 versus 30.8 7.2; F(1,9) .930, p .35],

Figure 2. Plasma levels of prolactin (ng/ml SEM) before, during, and after oral administration of fenfluramine hydrochloride (60 mg).

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The different direction of effect for prolactin and cortisol is consistent with evidence that, in humans, the release of the two hormones is regulated by different 5HT receptor subtypes (Cowen et al 1990). Therefore, one interpretation is that the increased prolactin response reflects increased 5HT2 receptor activity (Prescott et al 1984), the decreased cortisol response altered 5HT1A activity (Lowy and Meltzer 1988; Lesch et al 1990). Interactions between these receptor subtypes have also been suggested (Meltzer and Maes 1995). If women BPD patients have increased 5HT2 receptor activity, it might be consequent to decreased synaptic levels of 5HT. Consistent with this interpretation, patients with BPD display high rates of self-injury and poor impulse control, and across diagnostic boundaries these behaviors are associated with de-

creased neuroendocrine responses to 5HT agonists (Coccaro 1989), decreased CSF levels of 5HIAA (sberg et al 1976), and increased 5HT2 receptor densities in frontal cortex (Stanley and Mann 1983). In conclusion, our findings suggest that the serotonergic regulation of HPA axis activity is disturbed in women BPD patients. However, additional studies will be necessary before gonadal hormone modulated differences in 5HT function in BPD patients can be declared unequivocally; the differences seen so far might only reflect the small number of tested subjects.
We thank Mr. Dhunraj Ramdoyal for technical assistance and Mrs. Joan Oppenheimer for assisting in the recruitment of subjects.

References
sberg M, Tra skman L, Thore n P (1976): 5-HIAA in the cerebrospinal fluid: a biochemical suicide predictor? Arch Gen Psychiatry 33:11931197. Coccaro EF (1989): Central serotonin and impulsive aggression. Br J Psychiatry 155(Suppl 8):52 62. Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB, Mohs RC, Davis KL (1989): Serotonergic studies in patients with affective and personality disorders: correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry 46:587599. Cowen PJ, Anderson IM, Gartside SE (1990): Endocrinological responses to 5-HT. Ann N York Acad Sci 600:250 257. Gardner DL, Lucas PB, Cowdry RW (1990): CSF metabolites in borderline personality disorder compared with normal controls. Biol Psychiatry 28:247254. Halperin JM, Sharma V, Siever LJ, Schwartz ST, Matier K, Wornell G, Newcorn JH (1994): Serotonergic function in aggressive and non-aggressive boys with attention deficit hyperactivity disorder. Am J Psychiatry 151:243248. Hollander E, Stein DJ, DeCaria CM, Cohen L, Saoud JB, Skodol AE, Kellman D, Rosnick L, Oldham JM (1994): Serotonergic sensitivity in borderline personality disorder: preliminary findings. Am J Psychiatry 151:277280. Lesch K-P, So hnle K, Poten B, Schoellnhammer G, Rupprecht R, Schulte HM (1990): Corticotropin and cortisol secretion after central 5-hydroxytryptamine-1A (5-HT1A) receptor activation: effects of 5-HT receptor and -adrenoceptor antagonists. J Clin Endocrinol Metab 70:670 674. Lowy MT, Meltzer HY (1988): Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist. Biol Psychiatry 23:818 828. Meltzner HY, Maes M (1995): Effect of pindolol pretreatment on MK-212-induced plasma cortisol and prolactin responses in normal men. Biol Psychiatry 38:310 318. Prescott RWG, Kendall-Taylor P, Weightman DR, Watson MJ, Ratcliffe WA (1984): The effect of ketanserin, a specific serotonin antagonist on the PRL, GH, ACTH and cortisol responses to hypoglycaemia in normal subjects. Clin Endocrinol 20:137142. Stanley M, Mann JJ (1983): Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1:214 216.