You are on page 1of 6

Psychiatry Research 178 (2010) 342–347

Contents lists available at ScienceDirect

Psychiatry Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s

Associations between personality traits and CCK-4-induced panic attacks in

healthy volunteers
Innar Tõru a,⁎,1, Anu Aluoja a,1, Ülle Võhma b, Mait Raag c, Veiko Vasar a, Eduard Maron a,b,e, Jakov Shlik d
Department of Psychiatry, University of Tartu, Tartu, Estonia
North Estonia Medical Centre Foundation, Psychiatry Clinic, Tallinn, Estonia
Department of Public Health, University of Tartu; Tartu, Estonia
Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada
Department of Neuropsychopharmacology and Molecular Imaging, Imperial College London, London, UK

a r t i c l e i n f o a b s t r a c t

Article history: In this study we examined how personality disposition may affect the response to cholecystokinin
Received 24 September 2009 tetrapeptide (CCK-4; 50 μg) challenge in healthy volunteers (n = 105). Personality traits were assessed with
Received in revised form 30 March 2010 the Swedish universities Scales of Personality (SSP). Statistical methods employed were correlation analysis
Accepted 1 April 2010
and logistic regression. The results showed that the occurrence of CCK-4-induced panic attacks was best
predicted by baseline diastolic blood pressure, preceding anxiety and SSP-defined traits of lack of
assertiveness, detachment, embitterment and verbal aggression. Significant interactions were noted between
Anxiety the abovementioned variables, modifying their individual effects. For different subsets of CCK-4-induced
symptoms, the traits of physical aggression, irritability, somatic anxiety and stress susceptibility also
appeared related to panic manifestations. These findings suggest that some personality traits and their
interactions may influence vulnerability to CCK-4-induced panic attacks in healthy volunteers.
© 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction response through mainly biological mechanisms, the somewhat

contradictory data suggest that cognitive appraisal, fear of anxiety
In the past decades several neurobiological and psychological sensations, some personality traits and baseline anxiety may have at
factors have been identified to play a crucial role in the pathophys- least some role (Koszycki et al., 1993, 1996; Flint et al., 1998; Aluoja
iology of panic disorder (PD). As the experimental induction of panic et al., 1997). Koszycki et al. (1996) found that in patients with PD
attacks offers a unique opportunity to study the core symptoms of PD (n = 29), anxiety sensitivity, a trait characterized by the propensity to
under controlled conditions, several panic challenge procedures have appraise symptoms of anxiety as threatening, correlated significantly
been established to investigate the mechanisms of panic attacks and with cognitive, but not with somatic or affective, response to CCK-4.
anxiolytic treatments. Panic induction with cholecystokinin-tetra- Radu et al. (2003) demonstrated that in healthy volunteers (n = 20),
peptide (CCK-4) or pentagastrin (CCK-5) has been established as a the Anxiety Sensitivity Index scores correlated with ratings of anxiety
valid experimental model of human panic attacks. CCK-4 and CCK-5 and discomfort following the administration of pentagastrin. Howev-
are synthetic analogues of the endogenous neuropeptide cholecysto- er, several studies have observed that anxiety sensitivity did not
kinin (CCK) acting as agonists of the central subtype of CCK receptors predict panic response to CCK-4 in healthy subjects (Koszycki et al.,
to induce panic attacks in patients with PD and, to a lesser extent, in 1993 (n = 36); Flint et al., 1998 (n = 80)). Furthermore, Van Megen
healthy subjects (Bradwejn et al., 1991; Abelson and Nesse, 1994). et al. (1994) found no association between the fear of anxiety-related
The CCK-induced panic symptoms resemble spontaneous panic symptoms and response to pentagastrin in patients with PD (n = 30).
attacks in PD patients (Bradwejn et al., 1991; Abelson and Nesse, The associations between baseline state or trait anxiety and response
1994), suggesting the suitability of such experimental challenge to CCK-4 also vary from study to study. While Radu et al. (2003)
setting to clinical investigation of panic phenomena. The mechanisms showed that in healthy volunteers, baseline state anxiety correlated
underlying panic induction by CCK-4 are not yet fully understood. with anxiety/discomfort reaction after the administration of penta-
Although previous studies have accounted for CCK-4-induced panic gastrin, Aluoja et al. (1997) in their study on healthy volunteers
(n = 14) found that state/trait anxiety predicted the reaction to
placebo, but not to CCK-4. Also, Eser et al. (2008), studying the impact
⁎ Corresponding author. University of Tartu, Department of Psychiatry, Raja 31,
50417 Tartu, Estonia. Tel.: +372 7 318812; fax: +372 7 318801.
of state and trait anxiety on CCK-4-induced panic in healthy
E-mail address: (I. Tõru). volunteers (n = 33), found no significant differences between the
Joint first authors. groups of panickers and non-panickers.

0165-1781/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
I. Tõru et al. / Psychiatry Research 178 (2010) 342–347 343

Among basic personality traits, introversion and neuroticism may structure similar to the original version (Aluoja et al., 2009). The subjective effects of
CCK-4 challenge were assessed by Visual Analogue Scales (VAS), based on scales of Bond
have some relationships with CCK-4-induced panic. Koszycki et al.
et al. (1974), consisting of 100 mm lines for the dimensions of anxiety (VAS-A) and
(1996) found significant correlations between the scores of Minne- discomfort (VAS-D). CCK-4-induced symptoms were rated on the Panic Symptom Scale
sota Multiphasic Personality Inventory (MMPI) Social Introversion (PSS; Bradwejn et al., 1991) assessing the intensity of 18 symptoms derived from the
scale and somatic, cognitive, and affective response to CCK-4 in DSM-III-R/IV criteria for panic attack from 0 (not present) to 4 (extremely severe). The
patients with PD. Koszycki and Bradwejn (1997) also found an inverse main outcome variable was occurrence of a panic attack. The a priori criteria to define
the panic attack were a sudden onset of at least 4 PSS symptoms of at least moderate
relationship between the scores of extraversion on the Eysenck intensity (score ≥2) and anxiety/apprehension/fear PSS item scored as at least 3 (severe
Personality Questionnaire and baseline nervousness in healthy males or extreme). Other measures derived from the PSS were the number of symptoms
(n = 40). Extraversion scores correlated positively with the onset of (number of items scored ≥1), sum intensity score (the sum of all individual item
CCK-4-induced symptoms and some physiological indices. The same ratings), and subscale scores for somatic and cognitive symptoms. Arterial blood
pressure (BP) and heart rate (HR) were measured with an automatic sphygmoma-
study showed that neuroticism correlated positively with pre-
nometer (Dinamap Pro 100, Criticon, Tampa, FL, USA). Maximum changes in the studied
challenge self-rated nervousness, the number of CCK-4-induced parameters were calculated by subtracting baseline scores from the highest values
symptoms, and post-challenge self-rated anxiety, nervousness and obtained within 90 s after injection.
fearfulness. Predisposing influence of negative affect on panic reaction
in response to a biological challenge was further supported by Radu 2.3. Procedures
et al. (2003), showing that Karolinska Scales of Personality subscales
The subjects arrived at the research unit on the challenge day at about 10:00 am.
of Muscular Tension, Indirect Aggression, Verbal Aggression and Upon arrival, they completed the EST-Q and HAS. Then, an intravenous cannula was
Suspicion were associated with the anxiety reaction to pentagastrin. inserted into an antecubital vein and saline infusion was started to keep the cannula
This brings attention to the possible role of aggression-related traits in open. The subjects stayed in the same room resting. At 11 am, after the registration of
panic reaction to CCK-4. However, the predictive value of personality baseline values of BP, HR and VAS-A, a bolus injection of 50 µg of CCK-4 (Clinalfa, Merck
Biosciences AG, Switzerland) diluted in 2.5 ml of normal saline solution was given
traits in CCK-4 challenge studies has been equivocal. Eser et al. (2007) through the cannula (during ca 3 s). The subjects were asked to describe any symptoms
studying healthy males (n = 85) found no correlation between CCK-4- they experienced after the injection. The BP, HR and VAS-A were registered every 30 s
induced panic symptom severity and any of the revised Minnesota for 2 min, then at 5 and 15 min. After the CCK-4-induced symptoms had abated, the
Multiphasic Personality Inventory (MMPI-2) subscales. Furthermore, subjects were assessed on PSS and rated VAS-A and VAS-D for the peak symptoms. After
completion of the last measurements the cannula was removed and the subject was
the MMPI-2 clinical scales did not correlate with panic status
allowed to leave when comfortable with an option of phone contact over the next 24 h.
according to either panic criterion posed by the authors. These
discrepancies warrant further exploration of the role of personality in 2.4. Data analysis
laboratory panic, especially in larger samples, which could yield more
reliable results compared with the relatively small samples of For comparison of the groups with and without panic reaction we used t-tests for
normally distributed data and Mann–Whitney U tests for the rest of the variables.
previous studies.
Correlation analysis was done to investigate the relationships between the continuous
We aimed to test the hypothesis that susceptibility to CCK-4- or nearly continuous variables. A logistic model was developed to determine the
induced panic attacks in healthy subjects is influenced by anxiety- variables possibly predicting the occurrence of panic attack. All possible main-effect
related personality traits. Based on the findings outlined above, we models that did not contain interaction terms with up to 10 parameters (out of 23
possible) were created. After excluding the models with the parameters resulting in
hypothesized that (a) higher pre-challenge anxiety will be associated
multicollinearity, three models with the least Akaike's information criterion (AIC) were
with a stronger panic reaction to CCK-4 challenge; (b) some SSP chosen for detailed investigation. Adding quadratic terms did not decrease AIC. The
anxiety-related traits will predict the emergence and magnitude of interaction terms which improved AIC were added to the models. For easier
the panic reaction—specifically, somatic trait anxiety will predict interpretation of interactions, the models were fitted to standardised data. Finally, to
somatic symptoms and psychic trait anxiety will predict cognitive find out if the model with better AIC was also significantly better by likelihood, the log-
likelihood chi-squared tests were performed. Correlation analysis was conducted to
symptoms of panic; and (c) SSP detachment and trait aggression
examine how personality traits were associated with the number of panic symptoms,
scores will predict CCK-4-induced panic reaction. self-assessed discomfort and anxiety. In addition to investigating predictive values of
personality traits, regression models were developed for the PSS total, somatic and
2. Methods cognitive scores, number of panic symptoms, and VAS-A and VAS-D by stepwise
regression towards minimizing AIC. For PSS symptoms, Poisson regression was used; in
2.1. Subjects other cases, response variables (or suitably transformed response variables) followed
normal distribution and ordinary linear regression models were developed. The data
A total of 105 healthy volunteers (mean age 22.4, range 18–49, 55% females) were were controlled for multiple testing where appropriate and power analyses were
recruited by flyer advertisements. All subjects gave written informed consent after performed ad hoc. The R and Stata statistical software were used for the data analysis.
learning about the study aims and procedures. The study protocol and informed
consent form were approved by the Human Studies Ethics Committee of the University
3. Results
of Tartu, Estonia. The inclusion criteria were age between 18 and 50 years, no personal
or family (first degree relatives) psychiatric history, negative urine drug screen and
good physical health. Pregnancy was excluded with a urine pregnancy test. Forty seven subjects (45%) met the study definition for a CCK-4-
induced panic attack. Panic rate was not different between male and
2.2. Assessments females. The comparison of mean values and predictor variables
between panic and non-panic groups is presented in Table 1. Among
The diagnostic assessment was done using the Estonian translation of the Mini all variables only age and the scores on Verbal Trait Aggression
International Neuropsychiatric Interview (M.I.N.I. 5.0.0; Sheehan et al., 1998). Baseline
anxiety and depression were measured by the clinician-rated Hamilton Anxiety Scale
subscale were significantly different between the groups. After Holm–
(HAS; Hamilton, 1969) and two subscales of the self-rated Emotional State Bonferroni correction for multiple testing none of the comparisons
Questionnaire (EST-Q; Aluoja et al., 1999) measuring the symptoms of depression retained significant difference. None of the pairwise comparison tests
and anxiety during past four weeks. Personality traits were assessed with the Swedish achieved 80% power (min 5%, max 62%). The sample sizes required to
universities Scales of Personality (SSP; Gustavsson et al., 2000; Aluoja et al., 2009), a self-
achieve 80% power with the observed effect sizes assuming similar
rated questionnaire based on the Karolinska Scales of Personality (Schalling, 1978). The
SSP comprises 91 items grouped into 13 scales: Somatic Trait Anxiety (STA), Psychic panic attack rates are shown in Table 1.
Trait Anxiety (PsTA), Stress Susceptibility (SS), Lack of Assertiveness (LA), Impulsive- The comparison of logistic regression models indicated that the
ness (I), Adventure Seeking (AS), Detachment (D), Social Desirability (SD), Embitter- best set (by AIC) of variables predicting the occurrence of PA included
ment (E), Trait Irritability (TI), Mistrust (M), Verbal Trait Aggression (VTA), and Physical baseline diastolic blood pressure (RRD-0; lower values result in higher
Trait Aggression (PhTA). Each scale is formed by 7 items rated on a scale of 1 (does not
apply at all) to 4 (applies completely). Factor analysis suggested that SSP scales measure
chance of PA), baseline anxiety (EST-Q-A; higher scores give higher
three broad constructs: neuroticism, extraversion and aggressiveness (Gustavsson et al., chance of PA), SSP Lack of Assertiveness (LA; higher scores result in
2000). The Estonian translation of SSP has previously been validated showing a factor higher chance of PA), SSP Verbal Trait Aggression (VTA; higher scores
344 I. Tõru et al. / Psychiatry Research 178 (2010) 342–347

Table 1
Means, standard deviations and tests for difference between CCK-4-induced panic and non-panic groups.

Group Types of achieved Sample size

needed to achieve
Panickers Non-panickers

Mean S.D. Median Mean S.D. Median P-value Analysis Power 80% power

Age 23.17 6.04 21 21.47 4.31 20 0.021 (a) 0.36 311

HAS 2.4 2.4 2 3.17 4.04 2 0.425 (a) 0.16 567
RRS-0 122.9 9.87 122.5 123.6 10.61 125 0.708 (b) 0.06 6756
RRD-0 73.79 7.49 73.5 71.4 7.68 70 0.112 (b) 0.36 322
fr-0 76.57 19.62 72 77.19 22.54 74 0.872 (a) 0.05 36′419
VAS-A-0 8.19 8.25 5 10.66 10.4 9 0.295 (a) 0.25 451
EST-Q-D 2.93 3.04 2 3.7 3.36 3 0.219 (a) 0.22 547
EST-Q-A 2.48 2.23 2 3.77 3.36 3 0.068 (a) 0.61 152
STA 1.58 0.36 1.57 1.65 0.39 1.57 0.43 (a) 0.15 889
PsTA 1.88 0.48 1.86 1.94 0.46 2 0.561 (b) 0.1 1950
SS 2.03 0.46 2 2.17 0.53 2.14 0.183 (a) 0.29 391
LA 2.18 0.43 2.14 2.29 0.43 2.29 0.208 (b) 0.24 487
I 2.43 0.41 2.43 2.46 0.47 2.43 0.861 (a) 0.06 6829
AS 2.84 0.44 2.86 2.85 0.49 3 0.877 (b) 0.05 67′173
D 2.09 0.39 2.14 2.09 0.4 2 0.995 (b) 0.05 –
SD 3.03 0.31 3 2.97 0.32 3 0.309 (b) 0.16 849
E 1.82 0.4 1.79 1.84 0.37 1.86 0.438 (a) 0.06 12′073
TI 2.18 0.48 2.14 2.25 0.51 2.29 0.479 (b) 0.11 1557
M 1.93 0.47 1.86 2.04 0.37 2.14 0.056 (a) 0.25 487
VTA 2.43 0.49 2.43 2.65 0.49 2.71 0.024 (b) 0.62 159
PhTA 2.09 0.5 2 2.24 0.57 2.29 0.155 (b) 0.29 398

PA—panic attack, (a) Mann–Whitney U test, (b) t-test, HAS—Hamilton's anxiety scale, RRS-0—baseline systolic blood pressure, RRD-0—baseline diastolic blood pressure, fr-0—
baseline heart frequency, VAS-A-0—baseline anxiety on VAS, EST-Q-D—EST-Q depression score, EST-Q-A—EST-Q anxiety score, SSP scales: STA—somatic trait anxiety score, PsTA—
psychic trait anxiety, SS—stress susceptibility, LA—lack of assertiveness, I—impulsiveness, AS—adventure seeking, D—detachment, SD—social desirability, E—embitterment, TI—trait
irritability, M—mistrust, VTA—verbal trait aggression, PhTA—physical trait aggression. Data in bold: significant on significance level P b .05.

result in higher chance of PA), SSP Detachment (D; lower scores predicted higher PSS cognitive subset scores, total PSS scores, and the
predict higher chance of PA), and SSP Embitterment (E; lower scores number of PSS symptoms. Higher EST-Q anxiety scores predicted
result in higher chance of PA) (Table 2). The best predictive model did higher PSS total and somatic scores. Higher Physical Trait Aggression
not include age, although Mann–Whitney U-test showed that it was was linked to higher PSS total, somatic and cognitive scores, and the
significantly different between the groups of panickers and non- number of PSS symptoms. Higher Stress Susceptibility was associated
panickers. Notably, significant interactions influencing the effect of with higher PSS cognitive scores. Higher Lack of Assertiveness
the individual factors emerged. For instance, a higher RRD-0 was predicted higher PSS somatic scores, number of PSS symptoms, and
associated with lower chance of PA, but this effect was weaker when maximum post-challenge discomfort. Higher Embitterment predicted
Verbal Trait Aggression scores were lower. Similarly, higher scores on lower PSS somatic scores. Higher Trait Irritability was linked to higher
Lack of Assertiveness predicted greater risk of PA, but lower scores on maximum post-challenge discomfort.
Detachment as well as higher scores on Embitterment decreased the
effect of Lack of Assertiveness. Furthermore, higher scores on
4. Discussion
Embitterment generally lowered the risk of PA, but a high score on
Lack of Assertiveness decreased this effect. For the logit model for PA,
The 45% panic rate in our study was similar to the earlier findings
the sample size required to achieve 80% power in testing the
in healthy volunteers (e.g. 47% in the study of Bradwejn et al., 1991).
significance should have been 247 for RRD-0, 87 for EST-Q-A, 90 for
In our sample, the panickers were significantly younger than non-
LA, 331 for D, 164 for E, 95 for VTA, 166 for RRD-0 VTA, 114 for LA D,
panickers. Although the age range in our study was narrower, this
and 244 for LA E.
observation is in parallel with the data of Flint et al. (1998) showing
Correlations between personality traits and the number of panic
that older subjects (age 65 and older vs. 20–35 years) had less
symptoms, and self-assessed discomfort and anxiety are presented in
pronounced panic response to CCK-4. The occurrence of CCK-4-
Table 3. Regression models developed for the PSS total, somatic and
induced panic attack was best predicted by the EST-Q assessed
cognitive scores, number of panic symptoms, and VAS-A and VAS-D
anxiety, SSP subscales of Lack of Assertiveness, Detachment, Embit-
are presented in Table 4. We observed that higher HAS scores
terment and Verbal Trait Aggression, and baseline diastolic blood
The effect of baseline anxiety on susceptibility to panic challenge
Table 2 has been a subject of some contradictions. Studies in patients with PD
The best predictive logistic regression model for CCK-4-induced PA.
have shown that the subjects with a higher level of baseline anxiety
Model for logit(PA) Df Deviance, Gen. R2 AIC LR-X2 P were more likely to react with panic symptoms to provocation with
−0.36 − 0.36·RRD-0 + 0.62· 9 117.2 0.305 137.2 27.19 0.0013 sodium lactate and hyperventilation (Aronson et al., 1989; Spinhoven
EST-Q-A + 0.82·LA − 0.46· et al., 1993). In healthy volunteers, Radu et al. (2003) have found that
D − 0.62·E + 0.57·VTA − 0.58· the pre-challenge HAS scores correlated positively with the ratings of
anxiety and discomfort following administration of pentagastrin
+ 0.43·LA·D-0.56·LA·E
(0.05 µg and 0.2 µg/kg). Eser et al. (2007) have found that the
Df—degrees of freedom of the model; Gen. R2—Nagelkerke's generalised R2, AIC—Akaike's panickers reported higher baseline panic scores on two panic rating
information criterion, LR-X2—model likelihood chi-squared statistic, P—model's P-value.
RRD-0—standardised baseline diastolic blood pressure (ratio of centred baseline diastolic
scales used, although the difference reached a statistical significance
blood pressure, EST-Q-A—EST-Q anxiety score, LA—SSP lack of assertiveness, E—SSP only with one of the two applied panic definitions. On the other hand,
embitterment score, D—SSP detachment score, VTA—SSP verbal trait aggression score. Aluoja et al. (1997) have shown that in healthy volunteers baseline
I. Tõru et al. / Psychiatry Research 178 (2010) 342–347 345

Table 3
Pearson correlations between variables measured before injection of CCK and PSS-scores and VAS-based discomfort and anxiety scores.


Age −0.045 −0.139 −0.004 −0.023 −0.023 −0.155 −0.129

HAM-anx 0.309** 0.205* 0.305** 0.279** 0.013 0.020 −0.070
RRS-0 0.013 0.042 0.001 −0.015 0.009 −0.080 −0.118
RRD-0 −0.173 −0.137 −0.163 −0.141 0.034 −0.115 −0.077
fr-0 −0.062 0.006 −0.079 −0.100 −0.065 −0.023 −0.034
VAS-A-0 0.077 0.157 0.037 0.030 0.171 0.182 −0.248*
EST-Q-D 0.238* 0.137 0.243* 0.220* 0.144 0.095 −0.003
EST-Q-A 0.324*** 0.249* 0.307** 0.241* 0.123 0.129 0.026
STA 0.276** 0.233* 0.255** 0.245* 0.182 0.231* 0.121
PsTA 0.172 0.079 0.183 0.182 0.230* 0.136 0.004
SS 0.229* 0.226* 0.200* 0.241* 0.244* 0.233* 0.108
LA 0.099 −0.041 0.136 0.151 0.245* 0.089 0.005
I 0.051 0.070 0.037 −0.011 0.108 0.053 −0.021
AS 0.062 0.150 0.022 0.021 0.159 0.182 0.114
D 0.082 −0.081 0.130 0.149 0.077 −0.042 −0.079
SD −0.156 −0.071 −0.166 −0.216* −0.148 −0.053 −0.012
E 0.085 0.115 0.063 0.065 0.193* 0.112 −0.010
TI 0.227* 0.235 0.193* 0.179 0.223* 0.093 0.016
M 0.118 0.155 0.089 0.146 0.166 0.165 0.060
VTA 0.208* 0.136 0.207* 0.187 0.157 0.119 0.095
PhTA 0.265** 0.297** 0.217* 0.212* 0.086 0.038 −0.013

*P b 0.05, **P b 0.01, ***P b 0.001. HAS—Hamilton's anxiety score, RRS-0 baseline systolic blood pressure, RRD-0—baseline diastolic blood pressure, fr-0—baseline heart frequency, VAS-A-0—
baseline anxiety on VAS, EST-Q-D—EST-Q depression score, EST-Q-A—EST-Q anxiety score, STA—SSP somatic trait anxiety score, PsTA—SSP psychic trait anxiety score, SS—SSP stress
susceptibility score, LA—SSP lack of assertiveness score, I—SSP impulsiveness score, AS—SSP adventure seeking score, D—SSP detachment score, SD—SSP social desirability score, E—SSP
embitterment score, TI—SSP trait irritability score, M—SSP mistrust score, VTA—SSP verbal trait aggression score, PhTA—SSP physic trait aggression score. PSS-TOT—sum of all PSS item
scores, PSS-COG—sum of cognitive PSS item scores, PSS-SOM—sum of somatic PSS item scores, PSS-NrS—Number of PSS symptoms, VAS-D—maximum discomfort score on VAS, VAS-A-
max—maximum anxiety score on VAS, VAS-A-dif—difference between baseline and maximum anxiety scores on VAS. Data in bold: significant on significance level P b .05.

anxiety, as well as anxiety sensitivity, did predict reactions to placebo, challenge increase in RRD with a trend for dose–response effect.
but not to CCK-4. Also, Koszycki et al. (1998) observed no association Koszycki et al. (1998) reported no differences between panickers and
between pre-challenge VAS measurements of subjective arousal and non-panickers in RRD-0 but noted differences between the groups in
anxiety and susceptibility to CCK-4-induced panic in healthy controls. RRD response to CCK-4. Koszycki et al. (1998) have suggested that an
In the present study, higher levels of anxiety as assessed by the HAS augmented diastolic blood pressure response may be explained by the
and EST-Q predicted the occurrence of panic attack, as well as higher augmented parasympathetic activation by CCK-4 or a blunted
PSS total scores and somatic intensity scores. Higher PSS cognitive neuronal influence of vagal afferents, both of which might be linked
subscores were predicted by higher scores on the HAS, but not by to some personality characteristics. Pertinently, Koszycki and Brad-
higher EST-Q anxiety, probably reflecting contextual differences wejn (1997) have shown that in healthy volunteers, extraversion
between these two scales. Thus, our data support the assumption scores correlated negatively with CCK-4-induced increase in RRD. In
that baseline anxiety has at least some role in determining the the present study, the mean RRD-0 did not differ between the groups
reaction to a panic challenge agent. of panickers and non-panickers, yet lower RRD-0 predicted the
The predictive effect of RRD-0 in our study is difficult to explain. In occurrence of panic attack. The contradiction, however, might
other studies, the data concerning relationship between RRD-0 and dissipate if the modulating influence of other factors was considered.
CCK-4-induced symptoms, as well as the effect of CCK-4 on RRD, have In particular, the predictive effect of RRD-0 was lessened by the lower
been equivocal. Eser et al. (2007) reported no difference between Verbal Trait Aggression score. In addition, many other moderating
panickers and non-panickers in RRD-0 and no effect of CCK-4 on RRD. factors not assessed in the present study may exist.
Bradwejn et al. (1992), in a dose-ranging study, observed no influence We identified four personality traits as potential predictors of CCK-4-
of RRD-0 on post-challenge variables but found a consistent post- induced panic attack: higher Lack of Assertiveness and Verbal Trait

Table 4
Predictive regression models for number of CCK-4-induced panic symptoms, somatic reactions, and self-assessed discomfort and anxiety.

Model Gen. R2 Model characteristics AIC

PSS-TOT = 8.40 + 0.57·HAS + 0.57·EST-Q-A + 3.73·PhTA 0.184 SE: 8.126 on 101 df; F(3,101): 7.564, P b 0.001 743.86
(PSS-COG)0.5 = 0.65 + 0.30·SS + 0.29·PhTA 0.151 SE: 0.5827 on 102 df; F(2,102): 7.473, P b 0.001 189.53
PSS-SOM = 3.64 + 0.44·HAS + 0.56·EST-Q-A + 3.39·LA − 0.201 SE: 6.593 on 99 df; F(5,99): 4.971, P b 0.001 701.86
3.11·E + 3.41·PhTA
ln(PSS-NrS) = 1.50 + 0.02·HAS + 0.14·LA + 0.16·PhTA 0.138 Null deviance: 113.970 on 104 df, Residual deviance: 527.76
98.452 on 101 df
(VAS-D)1.8 = −98.6 + 526.7·LA + 464.5·TI 0.111 SE: 927.9 on 102 df, F(2,102): 6.35, P = 0.003 1737.85
(VAS-A-max)1.7 = 650.0 + 418.8·STA 0.061 SE: 618.1 on 103 df, F(1,103): 6.641, P = 0.011 1651.55
(VAS-A-dif)1.5 = 322.2 − 8.3·VAS-A-0 + 129.2·STA 0.071 SE: 224.2 on 102 df, F(2,102): 6.638, P = 0.002 1439.57

Gen. R2—Nagelkerke's generalised R2; AIC—Akaike's information criterion; SE—residual standard error; PSS-TOT—sum of all PSS item scores; PSS-COG—sum of cognitive PSS item
scores; PSS-SOM—sum of somatic PSS item scores; PSS-NrS—number of PSS symptoms; VAS-D—maximum discomfort score on VAS; VAS-A-max—maximum anxiety score on VAS;
VAS-A-dif—difference between baseline and maximum anxiety scores on VAS; HAS—Hamilton Anxiety Scale score; EST-Q-A—EST-Q anxiety score; PhTA—SSP physical trait
aggression; SS—SSP stress susceptibility; LA—SSP lack of assertiveness; E—SSP embitterment; TI—SSP trait irritability; STA—SSP somatic trait anxiety; VAS-A-0—baseline anxiety on
346 I. Tõru et al. / Psychiatry Research 178 (2010) 342–347

Aggression as well as lower Detachment and Embitterment. We did not nounced in cases of PD with agoraphobia and affective co-morbidity
confirm our assumption that higher Detachment is associated with (Võhma et al., 2010).
panic reaction. Nevertheless, we found an association of panic attack Our hypothesis that some SSP anxiety-related traits will predict
with Lack of Assertiveness. Higher Lack of Assertiveness was also the emergence and magnitude of the panic reaction was only partially
associated with a greater number of panic symptoms, higher scores of supported. Although anxiety-related traits did not predict the
PSS somatic symptoms, and higher maximum discomfort during the occurrence of panic attack, we still found that stress susceptibility
provocation. Lack of Assertiveness in SSP is a trait resembling social had significant associations with cognitive panic symptoms. The SSP
anxiety. Katzman et al (2004) have shown a trend for CCK-4-induced Stress Susceptibility denotes sensitivity to situational pressure and
panic to occur more frequently in patients with Social Phobia (SP) as easy fatigability. According to Abelson et al. (2007), heightened
compared to healthy controls. Patients with SP also reported a greater reactivity to novel and uncontrollable situations may be a vulnera-
number and intensity of panic symptoms as compared to the patients bility factor for PD and can account for reactivity in panic challenge
with Obsessive–Compulsive Disorder and control subjects in both CCK- experiments. Somatic trait anxiety predicted increase of subjective
4 and placebo challenge conditions. This suggests a higher non-specific anxiety during the CCK provocation. Stress susceptibility and somatic
responsiveness in SP. Socially anxious subjects may have additional trait anxiety are part of the broader neuroticism construct; thus, our
sensitivity to the interpersonal aspects of the CCK-4 provocation study supports the findings of Koszycki and Bradwejn (1997) on the
procedure. The panic-predicting role of low detachment is also in converging relationship of neuroticism and number of CCK-4 induced
agreement with social sensitivity hypothesis. It has been argued that symptoms and self-rated anxiety. Our results did not confirm the
besides mental and physical catastrophes panic subjects fear social specific hypotheses that somatic trait anxiety will predict somatic
humiliation while experiencing arousal symptoms (Austin and symptoms and that psychic trait anxiety will predict cognitive
Richards, 2001). Individuals who isolate less from social environment symptoms of panic. The interaction of personality traits in predicting
could be more sensitive to the reactions of others and therefore respond occurrence of panic showed a complex nature of associations between
with heightened anxiety to the challenge. At the same time low personality characteristics and panic reaction. Most studies so far have
assertiveness may inhibit direct communication of discomfort and lead looked at the associations of single personality traits or dimensions
to higher anxiousness and panic symptoms. In the presence of higher with panic reaction without considering the influence of combina-
detachment, the communication-blocking role of low assertiveness may tions of traits. Our results suggest that the effect of a certain
be enhanced, as indicated by the interaction between SSP Detachment personality trait on panic reaction can be enhanced or decreased by
and the Lack of Assertiveness subscales. Detachment has been the presence of other traits.
conceptualized as part of a broader extraversion–introversion construct When interpreting the results of the present study in the context
(Gustavsson et al., 2000). Other studies have shown associations of earlier and future studies, one needs to bear in mind that different
between higher introversion and aspects of CCK-4-induced panic in personality scales assessing slightly or even robustly diverse para-
healthy volunteers (Koszycki and Bradwejn, 1997) and patients with PD meters have been used across the various studies, making direct
(Koszycki et al 1996). This is in contrast to our findings of higher comparisons difficult and possibly explaining some inconsistencies.
detachment predicting a lower chance of panic attack. Notably, the Also, variations in challenge settings used in different laboratories
constructs in these two studies were measured by different instruments may have played a role in amplifying or attenuating the impact of
and it is not known how much the MMPI Social Introversion and SSP certain personality traits. Some other limitations of our study have to
Detachment may overlap. The inverse relationship between embitter- be considered. As we did not have a placebo control for CCK-4, it
ment and CCK-4-induced panic was a counterintuitive finding. SSP remains uncertain whether the results are specific to CCK-4 or can be
Embitterment, which is associated with neuroticism and aggression, attributed to non-specific factors of challenge procedure. Our model
indicates general dissatisfaction, feelings of injustice, and resentment predicted the occurrence of PA with moderate accuracy. To increase
and, therefore, may be expected to heighten propensity to panic. At the the model's precision, additional potentially relevant factors may
same time embitterment can be conceptualized as a habitual way of need to be included. For example, the effect of menstrual cycle phase
stress management; blaming others and expecting the worst, which can in females suggested by Le Melledo et al. (1999) was not taken into
reduce the reactivity to sudden uncontrollable acute stress encountered account in our protocol. Also, we did not assess all the personality
in panic provocation situation. characteristics that have been shown to influence CCK-4-induced
In accordance with our hypothesis we found that personality traits panic reaction in earlier studies. The effect of different personality
reflecting aggressive tendencies were associated with CCK-4-induced traits on panic reaction seems to be of a small statistical magnitude
panic. Verbal trait aggression predicted the occurrence of panic attack, and to involve complex interactions between traits; therefore, and
whereas physical trait aggression predicted all aspects of panic based on power calculations, it is obvious that for reliable evaluation
symptoms. Previously it has also been indicated that the tendency to of the associations between personality traits and experimentally
be verbally aggressive was associated with panic response to induced anxiety much larger sample sizes are necessary (see Table 1).
pentagastrin administration (Radu et al., 2003). The association In conclusion, challenge studies with CCK-4 seem productive in
between aggressiveness and provoked panic response is further uncovering the role of individual psychological characteristics in
supported by George et al. (2000), who showed that persons vulnerability to panic attacks. Our results suggest that neuroticism and
exhibiting high rate of physical aggression in domestic relationships aggressiveness predispose to a greater panic reaction in laboratory
react with more panic symptoms to sodium lactate provocation. The challenge in healthy volunteers, but the relevance of these findings to
exact nature of these associations is unclear. A Radu et al. (2003) clinical aspects of PD is not clear. The influence of personality traits on
finding that personality emerges as a significant predictor of panic susceptibility to panic attacks requires more extensive research using
reaction only with a lower dose of pentagastrin suggests rather non- different challenge and treatment approaches in the individuals
specific stress reactivity. It is possible that certain personality traits affected by PD and those at risk to develop PD.
heighten an individual's reactivity to different kinds of stressors,
including panic-provoking agents. On the other hand, the anxiety and Acknowledgements
aggression are known to share underlying neurobiology, including
aspects of CCK neurotransmission and pharmacotherapy approaches This study was supported by Estonian Science Foundation grant 7034 (EM) and by
target grants SF0182590As03 (VV) and SF0180125s08 (VV) from the Ministry of Education
(Siegel et al., 2007). Of note, our preliminary study in patients with of Estonia. The authors thank study subjects for their participation, the nurses Katri Sööt,
PD, also using SSP, indicated an increased aggressiveness in the Jane Puusepp, Birgit Aumeste, Merle Taevik and Ketlin Veeväli for their dedicated assistance
patients as compared to healthy controls, which was more pro- and Emilie Chan, MSc, for careful proofreading.
I. Tõru et al. / Psychiatry Research 178 (2010) 342–347 347

References Gustavsson, J.P., Bergman, H., Edman, G., Ekselius, L., von Knorring, L., Linder, J., 2000.
Swedish universities Scales of Personality (SSP): construction, internal consistency
Abelson, J.L., Nesse, R.M., 1994. Pentagastrin infusion in patients with panic and normative data. Acta Psychiatrica Scandinavica 102, 217–225.
disorder. I. Symptoms and cardiovascular responses. Biological Psychiatry 36, Hamilton, M., 1969. Diagnosis and rating of anxiety. British Journal of Psychiatry 76–79
73–83. Special publication.
Abelson, J.L., Khan, S., Liberzon, I., Young, E.A., 2007. HPA axis activity in patients with Katzman, M.A., Koszycki, D., Bradwejn, J., 2004. Effects of CCK-tetrapeptide in patients
panic disorder: review and synthesis of four studies. Depression and Anxiety 24, with social phobia and obsessive–compulsive disorder. Depression and Anxiety 20,
66–76. 51–58.
Aluoja, A., Shlik, J., Vasar, V., Kingissepp, P.H., Jagomagi, K., Vasar, E., Bradwejn, J., 1997. Koszycki, D., Bradwejn, J., 1997. Personality correlates of response to CCK-4 in healthy
Emotional and cognitive factors associated with response to CCK-4 in healthy males. Biological Psychiatry 42 (1S–297S), 18S.
volunteers. Psychiatry Research 66, 59–67. Koszycki, D., Cox, B., Bradwejn, J., 1993. Anxiety sensitivity and response to
Aluoja, A., Shlik, J., Vasar, V., Luuk, K., Leinsalu, M., 1999. Development and cholecystokinin-tetrapeptide in healthy volunteers. American Journal of Psychiatry
psychometric properties of the Emotional State Questionnaire, a self-report 150, 1881–1883.
questionnaire for depression and anxiety. Nordic Journal of Psychiatry 53, 443–449. Koszycki, D., Bradwejn, J., Zacharko, R.M., 1996. Influence of personality on behavioral
Aluoja, A., Voogne, H., Maron, E., Gustavsson, J.P., Võhma, Ü., Shlik, J., 2009. Personality response to cholecystokinin-tetrapeptide in patients with panic disorder. Psychi-
traits measured by the Swedish universities Scales of Personality: factor structure atry Research 62, 131–138.
and position within the five-factor model in an Estonian sample. Nordic Journal of Koszycki, D., Zacharko, R.M., Le Melledo, J.M., Bradwejn, J., 1998. Behavioral, cardiaovas-
Psychiatry 63, 231–236. cular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: a
Aronson, T.A., Whitaker-Azmitia, P., Caraseti, I., 1989. Differential reactivity to lactate comparison of panickers and nonpanickers. Depression and Anxiety 8, 1–7.
infusions: the relative role of biological, psychological and conditioning variables. Le Melledo, J.M., Merani, S., Koszycki, D., Palmour, R., Gutkowska, Y., Bellavance, F.,
Biological Psychiatry 25, 469–481. Steinberg, S.I., Bichet, D.G., Bradwejn, J., 1999. Influences of the menstrual cycle and
Austin, D.W., Richards, J.C., 2001. The catastrophic misinterpretation model of panic premenstrual dysphoric disorder on the response to CCK-4. Neuropsychopharma-
disorder. Behaviour Research and Therapy 39, 1277–1291. cology 20, 81–91.
Bond, A.J., James, D.C., Lader, M.H., 1974. Physiological and psychological measures in Radu, D., Ahlin, A., Svanborg, P., Lindefors, N., 2003. Pentagastrin test for anxiety—
anxious patients. Psychological Medicine 4, 364–373. psychophysiology and personality. Psychopharmacology 166, 139–145.
Bradwejn, J., Koszycki, D., Shriqui, C., 1991. Enhanced sensitivity to cholecystokinin Schalling, D., 1978. Psychopathy-related personality variables and the psychophysiol-
tetrapeptide in panic disorder. Clinical and behavioral findings. Archives of General ogy of socialization. In: Hare, R.D., Schalling, D. (Eds.), Psychopathic Behaviour.
Psychiatry 48, 603–610. Approaches to Research. John Wiley and Sons, Chichester, pp. 85–106.
Bradwejn, J., Koszycki, D., Annable, L., Couėtoux du Tetre, A., Reines, S., Karkanias, C.A., 1992. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta,
Dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview
panic disorder. Biological Psychiatry 32, 903–912. (MINI): the development and validation of a structured diagnostic psychiatric
Eser, D., Schüle, C., Baghai, T., Floesser, A., Krebs-Brown, A., Enunwa, M., de la Motte, S., interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59, 22–33.
Engel, R., Kucher, K., Rupprecht, R., 2007. Evaluation of the CCK-4 model as a Siegel, A., Bhatt, S., Bhatt, R., Zalcman, S.S., 2007. The neurobiological bases for
challenge paradigm in a population of healthy volunteer within a proof-of-concept development of pharmacological treatments of aggressive disorders. Current
study. Psychopharmacology 192, 479–487. Neuropharmacology 5, 135–147.
Eser, D., Wenninger, S., Baghai, T., Schüle, C., Rupprecht, R., 2008. Impact of state and Spinhoven, P., Onstein, E.J., Sterk, P.J., Le Haen-Versteijnen, D., 1993. Discordance
trait anxiety on the panic response to CCK-4. Journal of Neural Transmission 115 between symptom and physiological criteria for the hyperventilation syndrome.
(6), 917–920. Journal of Psychosomatic Research 37, 281–289.
Flint, A.J., Koszycki, D., Vaccarino, F.J., Cadieux, A., Boulenger, J.P., Bradwejn, J., 1998. Van Megen, H.J.G.M., Westenberg, H.G.M., den Boer, J.A., Haigh, J.R., Traub, M., 1994.
Effect of aging on cholecystokinin-induced panic. American Journal of Psychiatry Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients.
155, 283–285. Psychopharmacology 114, 449–455.
George, D.T., Hibbeln, J.R., Ragan, P.W., Umhau, J.C., Phillips, M.J., Doty, L., Hommer, D., Võhma, Ü., Aluoja, A., Vasar, V., Shlik, J., Maron, E., 2010. Evaluation of personality traits
Rawlings, R.R., 2000. Lactate-induced rage and panic in a select group of subjects in panic disorder using Swedish universities Scales of Personality. Journal of
who perpetrate acts of domestic violence. Biological Psychiatry 47, 804–812. Anxiety Disorders 24, 141–146.