Plasma cortisol and neuropeptide Y in female victims of intimate partner violence

Psychoneuroendocrinology 28 (2003) 796–808 www.elsevier.com/locate/psyneuen

Plasma cortisol and neuropeptide Y in female victims of intimate partner violence S. Seedat a, M.B. Stein a,b,∗, C.M. Kennedy b, R.L. Hauger a,b a

Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA b VA San Diego Healthcare System, USA Received 4 January 2002; received in revised form 29 July 2002; accepted 9 August 2002

Abstract Background: The experience of intimate partner violence (physical and sexual violence) has been linked to psychiatric disorders such as posttraumatic stress disorder, yet data on the neuroendocrine profile in this population is sparse. This study sought to examine baseline plasma cortisol and neuropeptide Y (NPY) levels in female victims of intimate partner violence (IPV). Methods: Morning plasma samples were collected for cortisol and NPY determination in 22 women with histories of IPV (10 with current PTSD, 12 without current or lifetime PTSD) and 16 non-abused controls. Results: Mean cortisol levels were significantly lower in IPV subjects compared with controls, but did not distinguish IPV subjects with and without PTSD. There were no significant differences in mean NPY levels between the groups. Neither cortisol nor NPY levels were significantly correlated with PTSD symptoms. Conclusions: These preliminary findings suggest that victims of IPV, like women traumatized by childhood abuse, may be characterized by alterations in hypothalamic-pituitary-adrenal axis functioning, however, further study is needed to identify specific stress system disturbances in this group.  2003 Elsevier Science Ltd. All rights reserved. Keywords: Domestic violence; Women; Posttraumatic stress disorder; Cortisol; Neuropeptide Y

∗

Corresponding author. Tel.: +1 858 622 6124; fax: +1 858 450 1491. E-mail address: [email protected] (M.B. Stein).

0306-4530/03/$ - see front matter  2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-4530(02)00086-0

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1. Introduction There is compelling evidence that the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic system are essential components of the human stress response. While the acute response is characterized by cortisol release from the adrenals and raised plasma cortisol concentrations (Selye, 1956; Munck et al., 1984; Chrousos and Gold, 1992; Morgan III et al., 2000a); cortisol findings in trauma victims (e.g. combat veterans, sexual abuse victims) with posttraumatic stress disorder (PTSD) have been mixed, with studies indicating high (Pitman and Orr, 1990; Liberzon et al., 1999), normal (Baker et al., 1999) and low levels (Mason et al., 1986; Yehuda et al., 1991, 1995a). For example, lower plasma cortisol levels have been reported in rape victims (n = 37) with histories of prior assault compared with recently assaulted women (Resnick et al., 1995), while high urinary free cortisol levels have been documented in maltreated children (De Bellis et al., 1999) and premenopausal women with PTSD (Lemieux and Coe, 1995; Rasmusson et al., 2001). Neuroendocrine studies conducted in close proximity to trauma suggest that cortisol levels in the immediate aftermath of trauma may predict the later occurrence of PTSD. Delahanty et al. (2000) demonstrated that motor vehicle accident victims (n = 99) diagnosed with PTSD had lower urinary cortisol levels in the first 15 hours post-trauma than did victims who did not go on to meet diagnostic criteria. Low urinary cortisol levels were significantly correlated with intrusive and avoidant symptoms at one month follow-up, suggesting that initial cortisol per se may contribute, in part, to subsequent PTSD (Anisman et al., 2001). In contrast, Resnick et al. (1997) found an association between higher mean cortisol levels and PTSD symptom distress in rape victims at three months’ follow-up, while Hawk and colleagues (2000) found elevated urinary cortisol levels in PTSD-symptomatic men, but not women, one month after involvement in serious motor vehicle accidents. Several mechanisms have been postulated for abnormal cortisol levels in PTSD, including (i) increased sensitivity of the HPA axis to feedback inhibition by cortisol (as evidenced by cortisol hypersuppression in response to dexamethasone in combat veterans and women with childhood sexual abuse) or (ii) decreased adrenocortical responsiveness (Yehuda et al., 1995b; Stein et al., 1997; Yehuda, 1997; Heim et al., 1998, 2001; Kanter et al., 2001). In contrast to the pattern seen in major depression, patients with PTSD appear to have increased sensitivity of hippocampal glucocorticoid receptor signaling to circulating levels of cortisol, consonant with the hypothesis that increased sensitivity may be critical in mediating hippocampal toxicity in PTSD (Yehuda et al., 1995b; Sapolsky, 2000). However, recent findings of relatively low density glucocorticoid receptors in the primate hippocampus suggest that the stress-neurodegenerative effects of glucocorticoids may in fact be mediated by high density glucocorticoid receptors in neocortical and hypothalamic areas (Sanchez et al., 2000). Sympathetic nervous system activation associated with trauma exposure also results in norepinephrine and epinephrine release (Tanaka et al., 2000). Neuropeptide Y (NPY), a neurohormone- and neurotransmitter-polypeptide, closely involved in the regulation of both central and peripheral noradrenergic system functioning, is

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densely concentrated in brain regions known to be activated by stress, e.g., amygdala and hypothalamus (Renshaw and Hinson, 2001). Several lines of evidence in animal models of anxiety indicate that the stress-buffering effects of NPY following central administration are mediated by Y1 and Y2 receptors (Sajdyk et al., 1999, 2002), both of which are abundant in the amygdala. NPY appears to inhibit the release of norepinephrine and the firing of locus ceruleus neurons involved in hyperarousal states (Illes and Regenold, 1990). These findings have provided a rationale for studying the role of NPY in PTSD (Heilig et al., 1989; Heilig and Widerlov, 1990; Griebel, 1999). Significantly increased levels of plasma NPY, cortisol, and norepinephrine have been observed in active-duty soldiers exposed to acute, uncontrollable stress during military survival training (Morgan III et al., 2000b, 2001). Furthermore, plasma NPY levels obtained after interrogation stress have been negatively correlated with dissociative symptoms in healthy active-duty military personnel participating in an intense training exercise (Morgan III et al., 2001). In combat veterans with PTSD compared with healthy controls, low baseline and blunted yohimbine-stimulated increases in plasma NPY and negative correlations between baseline NPY, degree of combat exposure, PTSD, and panic attacks, have been reported (Rasmusson et al., 1998, 2000). In military settings, combat-related decreases in NPY may in fact be advantageous in lowering the threshold for fight/flight responses, whereas in individuals with chronic PTSD persistent decreases in NPY may contribute to exaggerated startle reactions and increased vigilance. While it is still unclear if NPY levels measured in plasma parallel levels measured in brain and whether different settings (e.g. military survival training vs chronic PTSD) alter the effects of peripheral and central release, preliminary work suggests that stress-induced alterations may contribute, in part, to PTSD and anxiety. The occurrence of low cerebrospinal fluid (CSF) NPY levels in suicide victims (Widdowson et al., 1992), patient with major depression (Widerlo¨ v et al., 1988) and patients with previous suicide attempts, raises the question of whether or not chronic or repeated stress may, in fact, induce lowering of NPY levels (Westrin et al., 1999). In animal models of anxiety, interactions between NPY, glucocorticoids and CRF (corticotropin-releasing factor) have been demonstrated. Stress (emotional or autonomic) activates the secretion of CRF/cortisol which in turn activates the release of NPY/norepinephrine from neuron populations located in the central nucleus of the amygdala (an area critical to fear conditioning and stress-responding (Gray and Bingaman, 1996; Koob, 1999). CRF and NPY produce reciprocal effects on anxiety in the amygdala and glucocorticoids, like cortisol, can increase the expression of NPY (Heilig et al., 1997; Sheriff et al., 2001). In the aggregate, while studies consistently document long-term dysregulation of both hypothalamic-pituitary-adrenal (HPA) and noradrenergic systems in PTSD (Bremner and Vermetten, 2001; Geriacoti et al., 2001), the pattern of activation in traumatic stress does not appear to be consensual. The trauma associated with intimate partner violence (IPV) encompasses physical and sexual abuse, both of which frequently occur in the context of emotional abuse. Abused women are significantly more likely than non-victims to suffer from psychiatric morbidities, in particular major depression and PTSD (Koss, 1990; Mullen et al., 1988; Bell et al., 1996; Stein and Kennedy, 2001). Based on previous

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findings in female sexual abuse victims, the objective of this investigation was to examine basal plasma cortisol and NPY in women exposed to intimate partner violence (IPV). We hypothesized that there would be evidence of both low cortisol and NPY in women with IPV in comparison with non-abused controls.

2. Methods 2.1. Subjects The sample comprised 22 female IPV subjects (10 with current diagnoses of PTSD, 12 without lifetime/current diagnoses of PTSD) and 16 healthy, non-abused comparison subjects. Intimate partner violence (IPV) was defined by a history of either physical and/or sexual abuse. Subjects were recruited via print advertisements from community organizations providing services for abused women (e.g., YWCA, Women’s Resource Center, Center for Community Solutions). To qualify for inclusion, subjects had to be out of the abusive relationship for at least four months but no longer than two years. Comparison subjects were recruited from the same sources as IPV subjects, but had no lifetime history of exposure to a DSM-IV qualifying (i.e., PTSD criterion A1) traumatic event (APA, 1994) and were case-matched for age and socio-economic status (based on Hollingshead scores) (Hollingshead, 1975). All subjects were able to read and write English at 8th grade level and were free of any psychotic-, bipolar-, substance-, attention deficit-, or neurological-disorder. Use of any psychotropic medications and use of oral/intramuscular steroids within six weeks of assessment, were also exclusions. This study was approved by the local human subjects review board and informed, written consent was obtained prior to administration of study procedures. 2.2. Clinical measures All participants underwent a screening clinical interview (Structured Clinical Interview for DSM-IV Disorders (SCID-P) (First et al., 1997). The SCID-P comprised PTSD (for non-IPV related stressors), major depressive disorder, panic disorder and generalized anxiety disorder modules to assess for the presence of these disorders. In addition, IPV subjects were administered: (1) the Clinician-Administered PTSD Scale [CAPS1] (Blake et al., 1995) and Impact of Event Scale-Revised [IES-R] (Weiss and Marmar, 1997) to assess for the presence and severity of PTSD symptoms (current and lifetime); (2) the Conflict Tactics Scale-Revised [CTS-2], a 39-item self-report instrument with five subscales (Negotiation, Psychological Aggression, Physical Assault, Sexual Coercion, and Injury) (Straus et al., 1996) to assess aspects of IPV; and the (3) Center for Epidemiologic Studies Depression Scale [CES-D] (Radloff, 1977) to measure depressive symptoms over the previous week. Both IPV subjects and controls completed the Childhood Trauma Questionnaire [CTQ] (28item version) (Bernstein et al., 1994; Walker et al., 1999), a self-administered multidimensional measure of childhood interpersonal trauma. The CTQ has dimensions

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reflecting five broad types of trauma: emotional abuse, emotional neglect, physical abuse, physical neglect and sexual abuse. Factor analysis has established the content validity of these five dimensions (Wright et al., 2001). Anxiety symptoms were evaluated using the Beck Anxiety Inventory [BAI] (Beck et al., 1988). 2.3. Cortisol and NPY samples and analysis Plasma samples were collected from subjects and matched controls at similar times of day (between 09h00 and 12h00) and stored at ⫺70 °C from the time of initial collection until assay determination. The same procedures were followed for both the IPV group and controls. Plasma cortisol concentrations were determined using radioimmunoassay kits (obtained from the Diagnostic Products Corporation, Los Angeles, CA) which have an assay sensitivity of 0.3 µg/dL and intra-assay and interassay coefficients of variation of 4 and 6%, respectively. For measurement of neuropeptide Y after plasma extraction, a double antibody radioimmunoassay using 125I-NPY as the tracer was used. This radioimmunoassay has an assay sensitivity of 20 pg/mL and intra-assay and inter-assay coefficients of variation of 8 and 10% respectively (Allen et al., 1991). 2.4. Data analysis First, we determined the relationship of IPV exposure to baseline levels of plasma cortisol and NPY. Second, we examined the relationship of plasma cortisol/NPY to PTSD symptoms specifically in IPV subjects. Third, the relationship of these hormones to psychological indices in IPV subjects (with and without PTSD) was assessed. Demographic variables (ethnicity, marital status) were compared using Pearson Chi Square or Fisher’s Exact Test as appropriate. Clinical and biochemical measures were correlated using Spearman correlation coefficients (r s) and one-way ANOVA (analysis of variance). Independent t-tests were used to test for differences in plasma cortisol and NPY values for the sub-samples (IPV subjects vs controls and IPV subjects with PTSD vs IPV subjects without PTSD) and to compare with mean scores on PTSD, anxiety, depression and abuse dimensions. All significance testing was two-tailed with alpha = 0.05.

3. Results 3.1. Demographic characteristics Table 1 shows the differences in demographic, clinical and biochemical measures between IPV subjects and controls. For both IPV subjects and controls, the majority were of Caucasian origin. More than 90% of IPV subjects (n = 20) were single. separated, or divorced compared with a preponderance of married subjects in the control group (n = 9.56%).

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Table 1 Comparison between IPV subjects and controls on demographic, biochemical and clinical variables Interpersonal violence subjects (N = 22) Mean age in years (SD) 35.6 (9.6) Ethnicity: Caucasian 63.6% Marital status: Single, 90.9% separated or divorced (%) Mean educational level 12.7 (2.5) in years (SD) Plasma Cortisol µg/dL 10.5 (3.1) Mean (SD) Plasma Neuropeptide Y 116.6 (41.3) pg/mL Mean (SD) 56.3 (23.4) CTQa total score Mean (SD) 15.1 (12.1) BAIb total score Mean (SD)

Healthy controls (N = 16)

Statistic (df = 36)

p

40.9 (9.9) 87.5% 43.8%

⫺1.62 χ2=5.8 χ2=10.0

ns ⬍0.02∗ ⬍0.003∗

15.3 (2.4)

⫺3.14

⬍0.004∗

13.4 (4.6)

⫺2.25

⬍0.034∗

100.8 (36.6)

1.25

ns

33.4 (7.4)

4.00

⬍0.001∗

0.8 (1.2)

5.41

⬍0.001∗

a

CTQ, Childhood Trauma Questionnaire BAI, Beck Anxiety Inventory ∗ Denotes statistical significance at p ⬍ 0.05, two-tailed b

3.2. Plasma cortisol and NPY Significantly lower mean cortisol levels were observed in IPV subjects (with and without PTSD) compared with control subjects (10.5 ± 3.1 µg/dL vs 13.4 ± 4.6 µg/dL: df = 36, t = ⫺2.2, p = 0.034), however, NPY levels did not differ significantly between the groups (116.6 ± 41.3 ρg/mL in IPV women vs 100.8 ± 36.6 ρg/mL in controls: df = 36, t = 1.2, p = 0.222). In the IPV group, there were no significant differences in mean plasma cortisol and NPY levels between subjects with and without PTSD. Furthermore, a significant correlation between plasma cortisol and NPY was not demonstrated in the IPV group (r s = ⫺0.18, p ⬍ 0.415, n = 22). 3.3. Clinical measures Significant differences in measures of childhood maltreatment (CTQ total score) and anxiety symptoms (BAI total score) were observed between IPV subjects and controls (CTQ score: 56.3 ± 23.4 vs 33.4 ± 7.4, t = 4.0, p ⬍ 0.001; BAI score: 15.1 ± 12.1 vs 0.8 ± 1.2, t = 5.4, p ⬍ 0.001). Among IPV subjects, women with a diagnosis of PTSD (as determined on the SCID-P) had significantly higher scores on all three CAPS subscales [intrusive, avoidance, hyperarousal symptoms] and on the IES-R compared with women without PTSD. Differences in depression (CESD) and anxiety (BAI) scores between subjects with and without PTSD were also

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significant. However, any differences in severity of IPV (as measured on CTS-2 total scores and subscores) between subjects with PTSD and without PTSD did not reach significance (Table 2). 3.4. Relationship between plasma cortisol, NPY and clinical measures in IPV subjects There were no significant correlations between plasma cortisol and NPY values and the following baseline clinical measures: CAPS, IES-R, CES-D, or BAI total scores. There were also no significant correlations between plasma cortisol/NPY and CAPS subscale scores. A significant negative correlation was observed between Table 2 Comparison of IPV subjects with and without PTSD on biochemical and clinical measures IPV subjects with PTSD (N = 10) Plasma Cortisol µg/dL Mean (SD) Plasma Neuropeptide Y pg/mL Mean (SD) CAPSa total score Intrusion Avoidance Hyperarousal CTS-2b total score Negotiation Psychological aggression Physical assault Sexual coercion Injury CTQc total score Emotional abuse Emotional neglect Physical abuse Physical neglect Sexual abuse CES-Dd total score IES-Re total score BAIf total score a

IPV subjects without PTSD (N = 12)

P

10.3 (3.1)

10.6 (3.2)

0.22

ns

111.9 (37.7)

120.4 (45.3)

0.48

ns

67.5 (14.1) 19.6 (8.1) 23.2 (5.1) 24.7 (6.9) 276.9 (227.9) 35.3 (37.3) 93.3 (68.4)

25.4 (12.9) 7.0 (5.4) 7.2 (4.2) 11.2 (6.9) 171.4 (51.7) 39.6 (34.7) 85.9 (63.1)

⫺6.76 ⫺4.04 ⫺7.48 ⫺4.21 ⫺0.76 0.28 ⫺0.26

⬍0.001∗ ⬍0.002∗ ⬍0.001∗ ⬍0.002∗ ns ns ns

87.0 (88.3) 29.0 (34.8) 32.3 (40.5) 67.7 (25.8) 15.9 (7.5) 16.0 (6.2) 12.8 (5.6) 9.9 (4.4) 12.3 (7.2) 36.0 (7.5) 51.0 (9.9) 23.7 (13.0)

54.3 (76.5) 15.3 (42.0) 14.3 (17.5) 47.8 (17.9) 12.1 (5.6) 10.6 (5.1) 8.2 (3.9) 7.5 (3.3) 9.4 (5.8) 15.3 (11.6) 21.7 (15.2) 8.8 (6.1)

⫺0.90 ⫺0.82 ⫺1.30 ⫺1.98 ⫺1.27 ⫺2.12 ⫺2.13 ⫺1.43 ⫺1.03 ⫺5.05 ⫺5.35 ⫺3.18

ns ns ns ⬍0.07 ns ⬍0.04∗ ⬍0.06 ns ns ⬍0.001∗ ⬍0.001∗ ⬍0.0001∗

CAPS, Clinician Administered PTSD Scale CTS-2, Conflict Tactics Scale-Revised c CTQ, Childhood Trauma Questionnaire d CES-D, Center for Epidemiologic Studies Depression Scale e IES-R, Impact of Event Scale-Revised f BAI, Beck Anxiety Inventory ∗ Denotes statistical significance at p ⬍ 0.05, two-tailed b

Independent t tests (df = 20)

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plasma NPY and mean total CTQ score (r s = ⫺0.482, p ⬍ 0.028, n = 22). When the data were examined for each of the five CTQ dimensions, only the dimension of physical neglect was significantly correlated with plasma NPY. IPV subjects who had higher scores on the physical neglect subscale had lower NPY (r s = ⫺0.655, p ⬍ 0.002, n = 22). Correlations between CTQ total score and NPY (partial correlation coefficient = ⫺0.598, p ⬍ 0.001) CTQ-physical neglect subscore and NPY (partial correlation coefficient = ⫺0.523, p ⬍ 0.03), remained significant when severity of IPV (CTS-2 total score) and PTSD were controlled for.

4. Discussion The main findings of this investigation were as follows: (i) women with IPV trauma had significantly lower plasma cortisol compared with control subjects, (ii) plasma NPY levels did not differ significantly between the groups, and (ii) neither cortisol nor NPY levels were significantly correlated with PTSD symptom measures. We found no differences in cortisol and NPY levels between IPV subjects with and without PTSD suggesting, perhaps, that cortisol and NPY are markers of trauma exposure rather than PTSD per se. Although not a finding here, it has been suggested that differential patterns of cortisol regulation in abused women and children may be related to differences in the type of abuse experience (e.g. physical, sexual) For example, a recent study of salivary cortisol levels in maltreated children did not find significant group differences between maltreated and nonmaltreated children, but did find significant variations based on the type of abuse that maltreated children had experienced (Cichetti and Rogosch, 2001). In terms of cortisol levels in women with and without a PTSD diagnosis, the lack of significant difference is consistent with findings of a recent study in trauma-exposed children. While diurnal salivary cortisol levels were elevated in the clinical group compared with the control group, no differences were observed between children with PTSD and children with subthreshold diagnostic criteria (Carrion et al., 2002). We also failed to find group differences in baseline NPY levels. In the absence of a provocative challenge (e.g. yohimbine or stress) (Rasmusson et al., 1998), it may be somewhat premature to conclude that NPY release is not abnormal in IPVrelated PTSD. As our findings do not replicate findings of decreased baseline and stimulated plasma NPY levels in combat veterans with PTSD (Rasmusson et al., 2000), this raises the question of whether NPY levels might in some way reflect individual genetic-environmental variations in NPY release, type of current and previous trauma exposure in this population, and/or subjective perceptions of distress (Corder et al., 1992; Kallio et al., 2001; Morgan III et al., 2002). The relationship between childhood trauma (as determined on the CTQ) and NPY in IPV subjects was negative and significant. While the severity of self-reported childhood trauma did not differ between women with and without PTSD, higher levels of childhood trauma were significantly correlated with lower NPY levels after controlling for the degree of IPV and PTSD. These findings suggest that that chronic or repeated stress (e.g., previous physical or sexual abuse) may in fact induce lower-

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ing of NPY (Corder et al., 1992). With respect to the type of trauma exposure, the finding that the highest and only statistically significant correlation was with physical neglect is difficult to explain, and bears further investigation. It must also be remembered that the findings observed here are purely cross-sectional in nature and, as such, may not reflect patterns of neuroendocrine abnormality or adaptation over time. The need for longitudinal studies is apparent. The presence of depressive symptoms was not significantly correlated with cortisol and NPY in IPV subjects, consistent with recent studies in combat-related PTSD, where low cortisol (Kanter et al., 2001) and NPY (Rasmusson et al., 2000) were not related to the presence or absence of depression. Heim et al. (2001) recently showed that abused women, with and without major depression, both demonstrated lower basal and stimulated cortisol responses to exogenous CRF and ACTH compared with healthy women without childhood abuse. Furthermore, the blunted ACTH response observed in abused depressed women (14 of 15 women had PTSD) resembled that of depressed women without histories of childhood abuse. Some studies have shown blunted ACTH/ normal cortisol response to CRF in PTSD subjects compared with control subjects, arguing for ‘sensitization’ of the hypothalamic-pituitary-adrenal axis (Smith et al., 1989; Yehuda, 1997). In contrast, other studies have reported increased ACTH and cortisol responses to exogenous CRF in traumatized women with PTSD (Rasmusson et al., 2001), women with major depression and childhood abuse (11 with PTSD) (Heim et al., 2000), and depressed abused children (eight with PTSD) (Kaufman et al., 1997), suggesting a pattern of enhanced pituitary and adrenal reactivity in PTSD. Although the extant literature on the neuroendocrine profile of PTSD in adults suggests a model of enhanced cortisol negative feedback inhibition, with predominantly low plasma levels, many of the earlier studies were conducted in combat veteran populations. Studies of the neuroendocrine profile of women, particularly abused women, have been largely restricted to women with histories of childhood sexual abuse (CSA). This study has looked at a new trauma population: women with IPV. While our findings do not indicate reliable differences in neuroendocrine measures between IPV women with and without PTSD, the study has several limitations. The small sample, the relatively few participants meeting PTSD diagnostic criteria, the single rather than repeated sampling of cortisol/NPY, and the variation in sampling time between subjects (resulting in possible circadian fluctuations in cortisol even within the 3-hour window employed here) are variables which may have decreased the probability of detecting group differences. The precise relationship between cortisol and NPY in mediating anxiety and PTSD in different populations of trauma survivors is an area that warrants exploration in future studies.

Acknowledgements This study was supported by VA Merit Review grants to Dr Stein and Dr Hauger, the VA Mental Illness Research, Education and Clinical Center (MIRECC) of VISN 22, and the NIMH Mental Health Clinical Research Center (PHS MH-20914-14).

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The authors are grateful to Leila Tarokh for assistance with data management and to Traci Bergthold, M.A. for assistance with diagnostic interviews. We also wish to express our appreciation to the San Diego YWCA and the San Diego Center for Community Solutions for their assistance with this project.

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