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Journal of Psychiatric Research 44 (2010) 874e880

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Journal of Psychiatric Research

journal homepage: www.elsevier .com/locate/psychires

Cortisol responses to ipsapirone challenge correlate with aggression, whilebasal cortisol levels correlate with impulsivity, in personality disorderand healthy volunteer subjects

Marcela Almeida, Royce Lee, Emil F. Coccaro*

Clinical Neuroscience & Psychopharmacology Research Unit, Department of Psychiatry and Behavioral Neuroscience, Division of Biological Sciences and thePritzker School of Medicine, The University of Chicago, Chicago, IL, USA

a r t i c l e i n f o

Article history:Received 9 January 2010Received in revised form13 February 2010Accepted 16 February 2010

Keyword:Serotonin aggressionImpulsivityPersonality Disorder5-HT-1a Receptors

* Corresponding author. Clinical Neuroscience & PUnit, Department of Psychiatry and Behavioral NeuroSciences and the Pritzker School of Medicine, MC 307of Chicago, 5841 South Maryland Avenue, Chicago, IL4083; fax: þ1 773 834 7427.

E-mail address: ecoccaro@yoda.bsd.uchicago.edu (

0022-3956/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.jpsychires.2010.02.012

a b s t r a c t

Background: This study was performed to test the hypothesis that 5-HT-1a receptors, as assessed by thecortisol (post-synaptic) and temperature (pre-synaptic) responses to the 5-HT-1a agonist, Ipsapirone(IPSAP), play a role in the regulation of impulsive aggressive behavior in human subjects.Methods: Fifty-two healthy subjects (28 with Personality Disorder: PD; 24 Healthy Volunteers: HV)underwent acute challenge with the selective 5-HT-1a agonist, ipsaprione (IPSAP: .3 mg/kg po). ResidualPeak Delta Cortisol (DCORT[IPSAP]-R; after removal of Basal CORT and IPSAP plasma levels) was used asthe primary 5-HT-1a post-synaptic receptor variable. Residual Nadir Delta Temperature (DTEMP[IPSAP]-R; after removal of Basal TEMP) was used as the primary 5-HT-1a somatodendritic (pre-synaptic)receptor variable. Measures of trait aggression included the Aggression scales of the BusseDurkeeHostility Inventory (BDHI) and the Life History of Aggression (LHA); trait impulsivity was assessed withthe Impulsivity scale of the Eysenck Personality Questionnaire (EPQ-II).Results: Correlations between DCORT[IPSAP]-R responses and BDHI Aggression scores varied by group.Specifically, BDHI Aggression correlated inversely with DCORT[IPSAP]-R values in PD subjects but directlyin HV subjects. While EPQ-II Impulsivity did not correlate with DCORT[IPSAP]-R responses, this measureof impulsivity correlated directly with Basal CORT levels in all subjects. DTEMP[IPSAP]-R responses didnot correlate with measures of trait aggression or trait impulsivity.Conclusion: Physiologic responses of 5-HT-1a post-synaptic receptors may be reduced as a function oftrait aggression, but not impulsivity, in PD subjects. In contrast, pre-synaptic 5-HT-1a receptors may notplay a role in the regulation of aggression or impulsivity in human subjects.

� 2010 Elsevier Ltd. All rights reserved.

1. Introduction

Impulsive aggressive behaviors, in lower mammals, non-humanprimates, and humans, have been associated with impairments incentral serotonergic (5-HT) function for more than thirty years(Coccaro and Siever, 2002). Studies of the role of specific 5-HTreceptors, particularly in humans, are less frequent. For example,inverse correlations betweenmeasures of aggression and hormonalresponses to fenfluramine (e.g., Coccaro et al., 1989; Dolan et al.,2001; New et al., 2004), and to m-CPP (Coccaro et al., 1997a;

sychopharmacology Researchscience, Division of Biological7, Room B330, The University60637, USA. Tel.: þ1 773 834

E.F. Coccaro).

All rights reserved.

Handelsman et al., 1996; Moss et al., 1990), suggest a role inhuman aggression for both 5-Ht-1a and 5-HT-2 (most likely 5-HT-2c; Coccaro et al., 1997a) receptors in humans. While no specificprobes for 5-HT-2 receptors are available for human use, highlyselective 5-HT-1a probes (e.g., 8-OH-DPAT) are available for use inlower mammals and relatively selective 5-HT-1a probes (e.g., bus-pirone, flesinoxan, gepirone, ipsapirone) are available for use inhumans.

Administration of selective 5-HT-1a receptor agonists leads todecreased aggressive behavior in rodent models of aggression (Belland Hobson, 1994; Olivier et al., 1995). While similar anti-aggres-sive effects of 5-HT-1a probes have not been tested in humans,measures of aggression (and related traits) have been reported tocorrelate with hormonal responses to 5-HT-1a probes in somestudies. In personality disordered subjects, aggressiveness has beeninversely correlated with the prolactin response to buspirone(Coccaro et al., 1990) and with the cortisol response to ipsaprione

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880 875

(Coccaro et al., 1995). Behavioral irritability has also been reportedto correlate inversely with the cortisol response to ipsapirone inhealthy volunteers (Cleare and Bond, 2000). In addition, “experi-ence seeking” has been associated with blunted cortisol responsesto ipsapirone in healthy subjects (Netter et al., 1996), and theprolactin response to flesinoxan has been shown to be bunted inpatients with borderline personality disorder (Hansenne et al.,2002), a disorder typically characterized by high levels of impul-sivity and aggression. More recently, Minzenberg et al. (2006)reported that the cortisol response to ipsapirone correlatedinversely with a measure of impulsivity in subjects with borderlinepersonality disorder but not in subjects with other personalitydisorders. In contrast, other investigators report no relationshipbetween aggression and the cortisol response to ipsapirone inrelation to either measures of “anger” (Klaasen et al., 2002),“disinhibition” (Netter et al., 1996), or “aggressive responding” in ananalog model of aggression in the laboratory (Moeller et al., 1998)in other human subjects. Lastly, one study reports a positive rela-tionship between cortisol responses to ipsapirone and aggressionin healthy volunteers (Netter et al., 1999).

In this human subject study, we used ipsapirone as a 5-HT-1aagonist probe. Ipsapirone is a relatively selective 5-HT-1a agentwith both antidepressant and anxiolytic properties (Glaser, 1988).Its affinity for the 5-HT-1a receptor is much greater than that for the5-HT-1d, or 5-HT-2a/2c, receptor by 1000 fold and does not appearto bind to 5-HT-3 receptors. Its selectively for 5-HT-1a, compared toother Non-5-HT, receptors is as follows: a) greater than CholinergicM1 and M2 receptors by 1000 fold; b) greater than D1 and sigmareceptors by 100 fold; c) greater than alpha-2, D2, and alpha-1receptors by 87, 67, and 48 fold, respectively, though physiologicaleffects at these receptors only occur at high doses of Ipsapirone(Hamon et al., 1988). Ipsapirone, also, does not appear to bind toBenzodiazepine, GABA, Opioid, or Phencyclidine receptors. Ipsa-pirone's effect on the firing of 5-HT cells is consistent with theprofile of a full agonist at somatodendritic 5-HT-1a autoreceptors(Sprouse and Aghajanian, 1986) and a partial agonist (with 77%efficacy compared with endogenous 5-HT) at post-synaptic 5-HT-1a receptors (DeVry et al., 1991). Based on our knowledge of the roleof 5-HT in stimulating the release of cortisol in humans (e.g.,Coccaro and Kavoussi, 1994), the cortisol response to ipsapirone isthought to reflect activation of post-synaptic 5-HT-1a receptors.The hypothermic response to ipsapirone is thought to reflect acti-vation of pre-synaptic 5-HT-1a receptors at somatodendritic 5-HTautoreceptors (Lesch et al., 1990a). Both cortisol and temperatureresponses to ipsapirone can be blocked by 5-HT receptor antago-nists and by the noradrenergic beta, and 5-HT-1a antagonist, pin-dolol, but not by betanoxol which has only noradrenergic betaantagonist properties (Lesch et al., 1990a,b). Accordingly, cortisoland temperature responses to ipsapirone appear to reflect thesensitivity of central 5-HT-1a receptors in the limbic-hypothal-amusepituitaryeadrenal axis.

The purpose of this investigation was to study the relationshipbetween cortisol responses to acute challenge with ipsapirone andmeasures of impulsivity, aggression, and related behaviors ina sample of medication free adults with and without personalitydisorder. We hypothesized that both cortisol and temperatureresponses to ipsapironewould correlate inversely with measures ofaggression and impulsivity in healthy volunteer, and/or personalitydisordered, subjects. This is one of the few studies on 5-HT-1areceptor responsiveness to ipsapirone in personality disorderedsubjects and healthy volunteers. Its novel findings are the differ-ential correlations between cortisol responses to ipsapirone andaggression in personality disordered (inverse) vs. healthy volun-teers (positive) and the positive correlations between basal cortisoland impulsivity in both types of subjects.

2. Subjects & methods

2.1. Subjects

Twenty-eight subjects (n ¼ 22 male) with personality disorderand twenty-four healthy control volunteer subjects (n ¼ 22 male)participated in this study. All subjects were medically healthy andwere systematically evaluated in regard to impulsive, aggressive,suicidal, and other behaviors as part of a larger program designed tostudy the biological correlates of impulsive aggressive, and otherpersonality-related, behaviors in personality disordered subjects.Personality disordered subjects were recruited by newspaper andpublic service announcements seeking subjects with, and without,self-reported problems of personality disorder. Healthy controlsubjects were recruited by newspaper and public serviceannouncements by seeking out subjects interested and willing toparticipate in biological studies of personality traits. All subjectsgave informed consent and signed the informed consent documentapproved by our Institutional Review Board (IRB) before engagingin any of the studies. Medical health of all subjects was documentedby medical history, physical examination, electrocardiogram, andblood hematology, chemistry (including hepatic profile), thyroidfunction tests, pregnancy tests, and urinalysis, including a urinescreen for drugs of abuse.

2.2. Diagnostic assessment

Axis I and Axis II Personality Disorder (PD) diagnoses weremadeaccording to DSM-IV criteria (American Psychiatric Association,1994); the diagnosis of Intermittent Explosive Disorder (IED) wasmade by Integrated Research Criteria (IED-IR; Coccaro, 2003) forIED.

All diagnoses were made using information from: (a) semi-structured interviews conducted by trained masters, or doctoral,level clinicians using the Structured Clinical Interview for DSMDiagnoses (SCID-I; First et al., 1997) for Axis I disorders, and theStructured Interview for the Diagnosis of DSM-IV PersonalityDisorder (SIDP-4; Pfohl et al., 1997) for Axis II disorders; (b) clinicalinterview by a research psychiatrist; and, (c) review of all otheravailable clinical data. Final diagnoses were assigned by team best-estimate consensus procedures (Klein et al., 1994; Leckman et al.,1982) involving at least two research psychiatrists and two clin-ical psychologists. This methodology has previously been shown toenhance the accuracy of diagnosis over direct interview alone(Kosten and Rounsaville, 1992). Subjects with a life history ofBipolar disorder, Schizophrenia (or other psychotic disorder), ormental retardation were excluded from this study.

By definition, Healthy Volunteer (HV) subjects (n ¼ 24) werefree of current or lifetime history of Axis I or II disorder. Personalitydisordered (PD) subjects (n ¼ 28) were without a life history ofmania/hypomania, schizophrenia, or delusional disorder or currentalcohol or drug use disorders; other Axis I disorders were notexclusionary. Eleven of the PD subjects met DSM-IV criteria fora specific personality disorder as follows: (a) Cluster A (n ¼ 4), i.e.,paranoid (n ¼ 3), schizoid (n ¼ 1); (b) Cluster B (n ¼ 7), i.e.,narcissistic (n ¼ 3); antisocial (n ¼ 2), borderline PD (n ¼ 2),histrionic (n ¼ 1) and, (c) Cluster C (n ¼ 6), i.e., obsessive-compulsive (n ¼ 3), avoidant (n ¼ 3). The remaining PD subjectsmet criteria for personality disorder-not otherwise specified (PD-NOS). These subjects met criteria for multiple personality disordertraits and had evidence of diminished psychosocial function asso-ciated with their personality pathology (mean GAF score ¼ 59.7 �7.8). While most PD subjects had a life history of at least one Axis Idisorder (22 of 28: 79%; Mean � SD: 2.1 � 1.8 disorders), less thanhalf had a current history of at least one Axis I disorder (11 of 28:

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880876

39%Mean� SD: .6� 1.0 disorders). Current Axis I disorders were asfollows: (a) mood disorder of any type (n ¼ 1), one subject withmajor depression and dysthymia; (b) anxiety disorder of any type(n ¼ 3), i.e., social phobia (n ¼ 2) and specific phobia (n ¼ 1);intermittent explosive disorder (n ¼ 8); kleptomania (n ¼ 1);adjustment disorder (n ¼ 1). Lifetime Axis I disorders were asfollows: (a) mood disorder of any type (n¼ 9), i.e., major depression(n ¼ 6), dysthymia (n ¼ 1), mood disorder-NOS (n ¼ 3); (b) anxietydisorder of any type (n ¼ 3), i.e., social phobia (n ¼ 2); specificphobia (n ¼ 1); alcohol dependence (n ¼ 6); drug dependencedisorder (n ¼ 4); intermittent explosive disorder (n ¼ 10); patho-logical gambling (n ¼ 1); kleptomania (n ¼ 1); pyromania (n ¼ 1);adjustment disorder (n ¼ 4); eating disorder (n ¼ 1).

2.3. Assessment of aggression and impulsivity

Psychometric assessments for selected measures of aggressionand impulsivity were available in almost all subjects. Aggressionwas assessed dimensionally by use the Aggression score from theBusseDurkee Hostility Inventory (BDHI; n ¼ 45; Buss and Durkee,1957) and the Aggression score from the Life History of Aggres-sion (LHA; n ¼ 41; Coccaro et al., 1997b). Impulsivity was assessedusing the Impulsivity scale of the Eysenck Personality Question-naire-II (EPQ-II; n ¼ 35; Eysenck and Eysenck, 1977). Otherassessments used in this study included the original EysenckPersonality Questionnaire (EPQ I: n ¼ 45; Neuroticism, Psychoti-cism, Extraversion; Eysenck and Eysenck, 1975) as control dimen-sions of personality. An assessment for history of suicide attempt(Coccaro et al., 1989) was made during the diagnostic assessmentbut only one subject in the PD group had this history. Globalfunction of subjects was assessed by the global assessment offunction scale (GAF).

2.4. General preparation for study

Only 4 of the 52 subjects (all PD) had any lifetime history ofexposure to psychotropic agents. In order of frequency, these agentsfell into the following classes: antidepressants (n¼ 3), stimulants (n¼ 2), anxiolytics (n ¼ 2), antipsychotics (n ¼ 1) and, sedatives (n ¼1). Subjects were instructed to remain drug-free for at least twoweeks prior to study and no subject was taking any psychotropicagent for at least two weeks at time of study. Subjects were alsoinstructed to followa lowmonoamine diet for at least three (3) daysprior to study. Subjects were informed that initial and follow-upurine toxicology would be performed randomly just prior to study;illicit drug use was not detected in any subject reported herein.Females were all studied within the first ten days of the follicularphase of the menstrual cycle.

2.5. Ipsapirone (IPSAP) challenge

Subjects reported to the Clinical Research Procedure Unit(where pharmaco-challenge studies are performed in an outpa-tient setting) at approximately 8:00 AM after an overnight fast. AnIV was inserted in a forearm vein and kept open by normal salineat a slow drip. Baseline blood samples for cortisol (CORT) werecollected in an EDTA tube at 9:45 AM and at 9:55 AM (Basal CORT).Ipsapirone (@ .3 mg/kg) was given orally at 10:00 AM. Post-chal-lenge CORT levels were collected at þ15, þ30, þ45, þ60, þ75, þ90,þ120 þ 150, and at þ180 min (from 10 AM to 1 PM). Post-Chal-lenge samples for plasma ipsapirone levels were collected inpotassium oxylate coated tubes at þ30, þ90, and þ180 min.Whole blood for plasma CORT and IPSAP levels was spun imme-diately in a refrigerated centrifuge. Plasma was separated off andplaced in sample tubes into dry ice within 15e20 min and then,

after frozen, were transferred to a �20� freezer and stored untilassay. Plasma cortisol levels were assayed by RIA (laboratory ofRichard L. Hauger, M.D. at U.C. San Diego). This assay had a sensi-tivity of .3 mg/dl and intra- and inter-assay coefficients of variationof 4% and 6%, respectively. Temperature was assessed using anIVAC electronic temperature probe; inter-assay coefficient ofvariation < .7%. Plasma ipspairone levels were determined by gaschromatography with electrochemical detection (laboratory ofThomas B. Cooper, M.A. at the Nathan Kline Institute). This assayhad a sensitivity of 3 ng/ml and intra-/inter-assay coefficients ofvariation <7%.

2.6. Statistical analysis

Statistical analysis included Chi-Square, t-test (with correctionfor unequal variances where necessary), Pearson Correlation,Analysis of Variance, and Multiple Regression where appropriate.Plasma cortisol (CORT), rather than plasma adrenocorticotropichormone (ACTH), was used as a primary outcomemeasure because,in human subjects, plasma CORT responses to ipsapirone are morereliable than comparable plasma ACTH responses (Kahn et al.,1994). CORT values demonstrated a normal distribution in allsubjects. Peak Delta CORT[ISPAP] (i.e., Peak CORT after IPSAP minusBasal CORT)was initially selected to represent the CORT response toIPSAP. Closer analyses revealed that this measure was correlatedinversely with Basal CORT (r ¼ �.41, n ¼ 52, p ¼ .003) and directlycorrelated with the Peak Plasma IPSAP levels (r ¼ .41, n ¼ 52, p <

.003); no correlations were noted with other variables (e.g., age,gender). A multiple regression analysis, with Peak Delta CORT[IPSAP] as dependent variable, and Basal CORT and Peak PlasmaIPSAP Levels as independent values, was performed. This analysis (F[2,49]¼ 12.49, p< .001) revealed that both Basal CORT (b¼�.417, p¼ .001) and Peak Plasma IPSAP levels (b ¼ .413, p ¼ .001) contrib-uted significantly to Peak Delta CORT[IPSAP] responses. Accord-ingly, a standardized residual variable produced by this analysis(i.e., DCORT[IPSAP]-R) was then used in all CORT[IPSAP] analyseswhen a single variable was necessary. DCORT[IPSAP]-R responseswere normally distributed. Nadir Delta TEMP[IPSAP] (i.e., NadirTEMP after IPSAP minus Basal TEMP) was initially selected torepresent the temperature response to IPSAP. Nadir Delta TEMP[IPSAP] responses were normally distributed. Closer analysesrevealed that Nadir Delta TEMP[IPSAP] responses were correlatedinversely with Basal TEMP (r ¼ �.46, n ¼ 44, p ¼ .002), though notwith Peak Plasma IPSAP levels (r ¼ �.15, n ¼ 44, p ¼ .33); nocorrelations were noted with other variables (e.g., age, gender). Amultiple regression analysis, with Nadir Delta TEMP[IPSAP]response as dependent variable, and Basal TEMP as the indepen-dent variable, was performed in order to produce a standardizedresidual variable (i.e., DTEMP[IPSAP]-R) to use in TEMP[IPSAP]analyses when a single variable was necessary. DTEMP[IPSAP]-Rresponses were normally distributed. A two-tailed alpha value of.05 was used in the study to reject the null hypothesis.

3. Results

Demographic, functional, and behavioral data for the PD and HVsubjects are displayed in Table 1. While the two groups displayeda small, though significant difference in age (PD > HV), the twogroups did not differ significantly in the distribution of gender, race,or in socioeconomic class. As expected, however, PD subjects hadlower global functioning scores and higher scores on BDHIAggression and LHA Aggression, compared with the HV subjects.PD subjects had higher scores than HV subjects on EPQ Impulsivitybut this difference was not statistically significant.

Table 1Demographic, functional, and behavioral data: PD vs. HV subjects.

Variable PD subjects(n ¼ 28)

HV subjects(n ¼ 24)

Statistic p

DemographicAge 35.5 � 10.2 29.1 � 7.2 t50 ¼ 2.56 <.02Gender (M/F) 18/6 26/2 Fishers Exact Test .123Race (white/non-white)

17/11 18/6 Fishers Exact Test .376

SES (I/II/III/IV/V) 0/1/8/12/7 0/5/6/10/3 X2 ¼ 4.45, df ¼ 3 .217FunctionalGAF 56.1 � 10.6 84.4 � 3.2 t36 ¼ 13.67 <.001

BehavioralBDHI Aggression 26.3 � 10.0 13.3 � 5.4 t43 ¼ 4.08 <.001LHA Aggression 9.6 � 6.4 5.0 � 4.4 t35.1 ¼ 2.72 .01EPQ Impulsivity 5.3 � 3.5 4.2 � 3.9 t33 ¼ 0.93 .361

10 15 20 25 30 35 40 45

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Fig. 2. (a) Inverse Correlation of Peak CORT[IPSAP]-R Response with BDHI AggressionScores in Personality Disorder Subjects, (b) Direct Correlation of Peak CORT[IPSAP]-RResponse with BDHI Aggression Scores in Normal Control Subjects.

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880 877

3.1. Plasma IPSAP levels

The Mean � SD values for Plasma IPSAP at t ¼ þ30, þ90, andþ180 min were as follows: 49.4 � 67.5 ng/ml, 46.8 � 22.2 ng/ml,and 32.9� 19.7 ng/ml, respectively. There was no difference amongPD and HV subjects in plasma IPSAP levels at any time point. Thehighest Plasma IPSAP level was most frequently observed at þ90min (50% of subjects; 36.5% of subjects had highest levels at þ30min; 13.5% had highest levels at þ180 min). Mean � SD for PeakPlasma IPSAP levels were 72.8 � 56.9 ng/ml in all subjects and didnot differ among PD (76.5 � 58.4 ng/ml) and HV subjects (68.5 �56.0 ng/ml; t50 ¼ .50, p ¼ .62).

3.2. CORT[IPSAP], and DCORT[IPSAP]-R, responses in PD and HVsubjects

Repeated Measures ANOVA revealed a significant effect of Time(F[1,50] ¼ 38.69, p < .001), but not for Group � Time (F[1,50] ¼ .00,p¼ .99) on CORT[IPSAP] responses over time (Fig.1). Therewas alsono difference between the groups in DCORT[IPSAP]-R values (PD ¼�.02 � 1.05 vs. HV ¼ .02 � .91, t50 ¼ .13, p ¼ .90).

3.3. CORT[IPSAP]-R response and aggression

No correlation was observed between DCORT[IPSAP]-Rresponses and BDHI Aggression scores in all subjects (r ¼ �.05, n ¼45, p ¼ .741). However, when examined separately, a statisticallysignificant inverse correlation was observed between DCORT[IPSAP]-R responses and BDHI Aggression scores in PD subjects (r¼�.52, n ¼ 22, p ¼ .014; Fig. 2a) and a positive correlation was

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0 +15 +30 +45 +60 +75 +90 +120 +150 +180

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Fig. 1. Time Course of Cortisol Response to Ipsapirone Challenge in Normal Control andPersonality Disorder Subjects.

observed in HV subjects (r ¼ .51, n ¼ 23, p ¼ .013; Fig. 2b). Corre-lations between DCORT[IPSAP]-R responses and LHA Aggressionwere not significant (all subjects: r ¼ �04, n ¼ 44, p ¼ .799; PD: r ¼�.13, n ¼ 21, p ¼ .576; HV: r ¼ .06, n ¼ 23, p ¼ .778).

3.4. DCORT[IPSAP]-R response and impulsivity

As with BDHI Aggression, no correlation was noted betweenDCORT[IPSAP]-R responses and EPQ Impulsivity scores in allsubjects (r¼�.03, n¼ 35, p¼ .868). Examined separately, a modestinverse, correlation was observed between DCORT[IPSAP]-Rresponses and EPQ Impulsivity scores in PD subjects. However,despite a positive correlation between BDHI Aggression scores andEPQ Impulsivity scores among PD subjects (r ¼ .51, n ¼ 18, p ¼ .03),the correlation between DCORT[IPSAP]-R response and EPQImpulsivity was not statistically significant (r ¼ �.27, n ¼ 18, p ¼.289). A similar, though positive and non-significant, correlation,was observed in HV subjects (r ¼ .19, n ¼ 17, p ¼ .465).

3.5. Basal CORT, aggression, and impulsivity

The relationship between Basal CORT levels and aggression andimpulsivity (i.e., BDHI Aggression and EPQ Impulsivity) was alsoexplored. While Basal CORT and BDHI Aggression scores were not

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Fig. 3. Direct Correlation of Basal Cortisol with EPQ Impulsivity Scores in All Subjects,PD Subjects, and NC Subjects.

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Fig. 4. Time Course of Temperature Response to Ipsapirone Challenge in NormalControl and Personality Disorder Subjects.

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880878

significantly correlated (all subjects: r ¼ �.04, n ¼ 45, p ¼ .784; PDsubjects: r ¼ �.10, n ¼ 22, p ¼ .669; HV subjects: r ¼ .10, n ¼ 23, p ¼.658), Basal CORT and EPQ Impulsivity scores were significantly,and directly, correlated in all subjects (r¼ .41, n¼ 35, p¼ .013). Thiscorrelationwas also statistically significant in PD subjects (r¼ .49, n¼ 18, p ¼ .038). While the correlation in HV subjects did not reachstatistical significance (r¼ .33, n¼ 17, p¼ .201), the magnitude, andslopes, of these two correlations were not significantly differentfrom each other (Fig. 3).

3.6. DCORT[IPSAP]-R responses, Basal CORT values, generalpersonality traits and Axis I and II variables

DCORT[IPSAP]-R responses did not correlate significantly withEysenck Neuroticism, Psychoticism, or Extraversion in any analysis(e.g., range for all subjects: r ¼ �.07e.04, n ¼ 45, p > .67). BasalCORT, also, did not correlate with Eysenck Neuroticism, Psychoti-cism, or Extraversion (e.g., range for all subjects: r¼ .03e.15, n¼ 45,p> .33). Neither DCORT[IPSAP]-R responses, nor Basal CORT values,differed as a function of current history of mood disorder, anxietydisorder or of IED. The same was true for both variables as a func-tion of a life history of mood disorder, anxiety disorder, IED,alcohol/drug dependence or Cluster A, B, or C Personality Disorder.

3.7. TEMP[IPSAP] and DTEMP[IPSAP]-R responses in PD and HVsubjects

Repeated Measures ANOVA revealed a significant within subjecteffect of Time (F[9226] ¼ 5.41, p < .001), but not a between-subjecteffect (Group � Time: F[1,42] ¼ .14, p ¼ .71) on TEMP[IPSAP]responses over time (Fig. 4). There was no difference between thegroups in DTEMP[IPSAP]-R responses (PD ¼ �.02 � 1.05 vs. HV ¼.02 � .93, t42 ¼ .11, p ¼ .91). Finally, there were no significantcorrelations between TEMP[IPSAP]-R responses and anymeasure ofaggression, impulsivity, or general personality traits in thesesubjects.

4. Discussion

This study found a significant inverse correlation between traitaggressiveness and the cortisol response to ipsapirone (after

removal of the influences of basal cortisol and plasma ipsapironelevels, see below) in PD subjects and a similar, though positive,correlation in HV subjects. In contrast, no relationship was notedwith the temperature response to ipsapirone. This suggests thatwhile there may be a relationship between aggressiveness andpost-synaptic 5-HT-1a receptor responsiveness, no such relation-ship may exist with pre-synaptic 5-HT-1a receptor responsive-ness. Finally, this study also found a direct relationship betweenbasal cortisol and trait impulsiveness in all subjects, notably PDsubjects.

The relationship between basal cortisol and ipsapirone levelsand cortisol responses to ipsapirone is noteworthy. First, it appearsthat as basal cortisol levels increase, cortisol responses to ipsapir-one are dampened. This is consistent with data from human studiesdemonstrating that corticosterone administration blunts 5-HT-1amediated hormonal responses (Porter et al., 1998). Second, vari-ability in cortisol responses to ipsaprione also appear to be due tovariations in plasma levels of ipsapirone. Since it is important tostudy an ipsapirone-related outcome variable that reflectsprimarily the effect of the challenge agent, removal of the influenceof both these factors is necessary.

In this study, BDHI Aggression, but not LHA Aggression, scorescorrelated in with cortisol responses to ipsapirone. While bothmeasures are correlated in subjects they do not fully overlap (e.g., r2

¼ .24, p < .001, in this study) and do not reflect the same exactaspects of aggression. Accordingly, it may be the case that thetendency to respond aggressively to possible outside events(reflected by BDHI Aggression scores: e.g., “Someone who pestersyou is asking for a punch in the nose”), but not history of actualaggressive behavior (reflected by LHA Aggressive scores; e.g., “Howmany times have you actually hit someone?”), is related to reducedpost-synaptic 5-HT-1a receptor responsiveness in PD subjects. If so,this is an interesting diversion in the relationships betweenmeasures of aggression and biological variables as both BDHI andLHA variables have been shown to correlate similarly in otherstudies of PD subjects (e.g., Coccaro et al., 1989).

The inverse correlation between cortisol responses to ipsapir-one and aggression in PD subjects is consistent with some, but notall, previous studies involving 5-HT-1a challenge probes. Aggres-siveness has been inversely correlated, in small numbers of PDsubjects, with the prolactin response to buspirone (Coccaro et al.,1990) and with the cortisol response to ipsaprione (Coccaro et al.,1995). Aggressiveness has also been associated with reducedprolactin response to flesinoxan patients with borderline

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880 879

personality disorder (Hansenne et al., 2002). More recently,Minzenberg et al. (2006) reported that the cortisol response toipsapirone correlated inversely with a measure of impulsivity, butnot aggressiveness, in subjects with borderline personalitydisorder; this finding did not extend to subjects with otherpersonality disorders. Other studies, involving Non-PD subjectsreport no relationship between aggression and the cortisolresponse to ipsapirone in relation to either measures of “anger”(Klaasen et al., 2002) in mood and anxiety disordered subjects,“disinhibition” in healthy volunteers (Netter et al., 1996), or“aggressive responding” in an analog model of aggression in thelaboratory in subjects with, and without, histories of drug abuse(Moeller et al., 1998). It is possible that some of these differencesmay be accounted for by the fact that we controlled for plasmaipsaprione levels and other studies did not.

The positive correlation between cortisol responses to ipsapir-one and aggression in HV subjects was unexpected. This resultruns counter to the findings of Cleare and Bond (2000) whoreported an inverse correlation between aggression and cortisolresponses to ipsapirone, but not to a similar study of healthyvolunteers (Netter et al., 1999) that reported a positive relationshipbetween cortisol responses to ipsapirone and aggression. Accord-ingly, this finding in healthy volunteers must be taken aspreliminary.

The finding that Basal CORT values were directly correlated withEPQ Impulsivity scores is noteworthy. Overall, cortisol levels havebeen reported as variably correlating with impulsive aggression.Three studies report an inverse correlation with impulsiveaggression in disruptive behavior disorder (Scerbo and Kolko,1994), psychopathic (Dolan et al., 2001), and violent alcoholic(Adler et al., 1997), subjects. Three studies report no correlationwith impulsive aggression in adolescent prisoners (Dabbs et al.,1991), delinquents (Banks and Dabbs, 1996), and in alcoholrelated aggressiveness (Von der et al., 2002). On the other hand,two studies report a positive correlation between plasma CORT andimpulsive aggression in healthy volunteers (Gerra et al., 1996) andin Vietnam Veterans (Mazur, 1995). A third study reports highercortisol levels in patients with borderline personality disordercompared with controls (Lieb et al., 2004) e patients known to behighly impulsive and aggressive. In addition, two other studiesreport a positive correlation between plasma ACTH and impulsiveaggression in conduct disordered individuals (Dmitrieva et al.,2001) and in a mixed group of healthy volunteers and aggressivesubjects (Gerra et al., 1998). If so, this study is consistent with thelatter five cited studies in this regard but, possibly, more specific inthat the Basal CORT levels are correlated with a well validatedpersonality assessment of trait impulsivity. Finally, plasma cortisolmay also be elevated in subjects with a current depression orsubjects with a life history of childhood trauma (Lee et al., 2005;using the Childhood Trauma Questionnaire: Bernstein et al., 1994).However, no subject in this analysis had a current depressivesyndrome (of any type) and there was no correlation notedbetween Basal CORT levels and history of childhood trauma usingthe Childhood Trauma Questionnaire.

It is notable that none of the correlations seen in this study weregeneralized to other non-aggression/non-impulsivity measures (e.g.,global personality traits). This suggests that the findings noted arenot an epiphenomenon of relationships between DCORT[IPSAP]-R orBasal CORT and other non-aggressive/non-impulsivity variables.

Limitations of this study include the cross-sectional nature ofthis project; modest sample size and the fact that not all subjectscompleted all the dimensional behavioral measures; use of plasmacortisol, as opposed to ACTH, as an outcome measure; limitednumber of samples for basal cortisol levels; and the ascertainmentof subjects and the nature of the subjects.

First, the cross-sectional nature of this study does not allow toan examination of the developmental aspects of 5-HT-1a receptors,or of basal cortisol, and aggression/impulsivity over time. Unfor-tunately, no studies in humans have yet been performed that allowthis kind of examination. Second, the modest sample size and thefact that not all subjects completed all behavioral measures limitsthe power to reject the null hypothesis in the cases of the negativefindings. This study had only 44e53% power to detect statisticallysignificant correlations of moderate effect size (r ¼ .30) in the caseof the primary behavioral measures studied. In fact, the effect sizesnoted in this studywere large inmagnitude (r ~ .50) and the samplesize needed to detect large correlations with 80% power was 26subjects for each behavioral measure, which was close to thesample sizes in this study. To detect moderate sized (r ¼ .30), andsmall sized (r ¼ .10) correlations with 80% power would haverequired 81, and 770, subjects for each behavioral measurewith thelatter proposed sample being far more than could be studied at ourcenter. Third, the use of plasma cortisol, as opposed to ACTH, asa primary outcome measure leaves open the possibility ofpathology at the level of the peripheral adrenal cortex rather thanat the level of the central hypothalamus. While ACTH is directlyreflective of CRF responses in the hypothalamus, plasma ACTH is anextremely variable measure and studies in healthy volunteersdemonstrate more reliable results with cortisol instead (Kahn et al.,1994). Fourth, our assessment of Basal CORT was based only on twosamples within 10 min of each other (i.e., before administration ofipsaprione) is a limitation because it is possible that these BasalCORT data were unstable. Recent work, however, by Brown et al.(2008) suggests that a single sample for cortisol at 8 AM is rela-tively stable measure of cortisol over a period of weeks. While oursamples were obtained at 10 AM (rather than 8 AM), we assume theBasal CORT samples in this study (based on two separate samplesobtained 10 min apart) are comparably stable based on the studiesof Brown et al. (2008). Plasma cortisol data on a corresponding (e.g.,placebo) day, could have provided a replication of this relationshipwith EPQ Impulsivity. However, these data were not available.Finally, the ascertainment of subjects may limit the generalizabilityof these findings since the subjects in this study represent thosewho volunteered for research studies. Accordingly, these data maynot fully generalize to a population based sample or to individualsin current psychiatric treatment.

Finally, for the purposes of this study, personality disorder wastreated as a unitary construct. However, it is possible that aggres-sion (and other behavioral variables of interest) may differ acrossvarious Axis II disorders. Thus, it is possible that within differentpersonality disorders the relationships, and the direction of theserelationships, between biological variables and behavior coulddiffer (as seen for PD vs. controls in this study). This should befollowed up as a direction for future research in this area.

Conflict of interest statement

There are no conflicts of interest regarding this work.

Role of funding source

This work was supported by NIMH Grants RO1MH46948 andKO2MH00951 (Dr. Coccaro).

Acknowledgements

We thank Richard L. Hauger, M.D. for the RIA CORT assays of theplasma samples and we thank Thomas B. Cooper, M.A. for theanalyses of plasma ipsapirone levels.

M. Almeida et al. / Journal of Psychiatric Research 44 (2010) 874e880880

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