Panic Symptom Scale Research Articles

Impact of Panic Attacks on Bronchoconstriction and Subjective Distress in Asthma Patients With and Without Panic Disorder.

Panic disorder (PD) is common among asthma patients and is associated with worse asthma outcomes. This may occur because of psychophysiological factors or cognitive/affective factors. This study evaluated the impact of panic attacks (PAs) on bronchoconstriction and subjective distress in people who have asthma with and without PD. A total of 25 asthma patients (15 with PD who had a PA [PD/PA], 10 without PD who did not have a PA [no PD/no PA]) were recruited from an outpatient clinic. They underwent a panic challenge (one vital capacity inhalation of 35% carbon dioxide [CO2]) and completed the Panic Symptom Scale, the Subjective Distress Visual Analogue Scale, and the Borg Scale before and after CO2. Forced expiratory volume in 1 second was assessed pre- and post-CO2; respiratory (i.e., CO2 production, minute ventilation, tidal volume) was continuously recorded, and physiological measures (i.e., systolic and diastolic blood pressure [SBP/DBP]) were recorded every 2 minutes. Analyses adjusting for age, sex, and provocative concentration of methacholine revealed no significant differences between groups in forced expiratory volume in 1 second change after CO2 inhalation (F(1, 23) < 0.01, p = .961). However, patients with PD/PA reported more panic (F(1, 22) = 18.10, p < .001), anxiety (F(1, 22) = 21.93, p < .001), worry (F(1, 22) = 26.31, p < .001), and dyspnea (F(1,22) = 4.68, p = .042) and exhibited higher levels of CO2 production (F(1, 2843) = 5.89, p = .015), minute ventilation (F(1, 2844) = 4.48, p = .034), and tidal volume (F(1, 2844) = 4.62, p = .032) after the CO2 challenge, compared with patients with no PD/no PA. Results, presented as hypothesis generating, suggest that asthma patients with PD/PA exhibit increased panic-like anxiety, breathlessness, and a respiratory pattern consistent with hyperventilation that was not linked to statistically significant drops in bronchoconstriction.

Do asthma patients with panic disorder really have worse asthma? A comparison of physiological and psychological responses to a methacholine challenge

BackgroundPanic disorder (PD) has been linked to worse asthma outcomes. Some suggest that asthmatics with PD have worse underlying asthma; others argue that worse outcomes are a result of their tendency to over-report symptoms. This study aimed to measure physiological and psychological responses to a simulated asthma attack (methacholine challenge test: MCT) in asthmatics with and without PD. MethodsAsthmatics with (n = 19) and without (n = 20) PD were recruited to undergo a MCT. Patients completed subjective symptom questionnaires (Panic Symptom Scale, Borg Scale) before and after a MCT. Physiological measures including heart rate (HR), and systolic and diastolic blood pressure (SBP/DBP) were also recorded. ResultsAnalyses, adjusting for age and sex, revealed no difference in methacholine concentration required to induce a 20% drop in forced expiratory volume in one second (FEV1: F = 0.21, p = .652). However, PD patients reported worse subjective symptoms, including greater ratings of dyspnea (F = 8.81, p = .006) and anxiety (F = 9.44, p = .004), although they exhibited lower levels of physiological arousal (i.e., HR, SBP/DBP). An interaction effect also indicated that PD, relative to non-PD, patients reported more panic symptoms post-MCT (F = 5.05, p = .031). ConclusionsAsthmatics with PD report higher levels of subjective distress, despite exhibiting lower levels of physiological arousal, with no evidence of greater airway responsiveness. Results suggest that worse outcomes in PD patients may be more likely due to a catastrophization of bodily symptoms, rather than worse underlying asthma. Interventions designed to educate patients on how to distinguish and manage anxiety in the context of asthma are needed.

Neuropeptide S receptor gene variation modulates glutamatergic anterior cingulate cortex activity during CCK-4 induced panic

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S(NPS)system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time x genotype interaction was detected (p = .008), with significantly lower anterior cingulate Glx/Cr levels in T allele carriers as compared to AA homozygotes 5 minutes after injection (p = .003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate glutamatergic activity in the ACC during acute states of stress and anxiety, with blunted, i. e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers.

Neuropeptide S receptor gene variation modulates anterior cingulate cortex Glx levels during CCK-4 induced panic

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans.Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment.CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned.The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.

EPA-1581 - Anxiety-related neuronal responses in phobic postural vertigo

Vertigo and anxiety are frequent symptoms in both psychiatric and vertigo patients, especially in those with phobic postural vertigo (PPV). The aim of this study was the investigation of anxiety-associated functional responses in PPV patients compared to healthy controls. For that purpose cholecystokinin tetrapeptide (CCK-4), a valid model to experimentally induce anxiety symptoms, was used. 15 PPV patients and 15 matched healthy controls underwent challenges with CCK-4. During the paradigm, participants did not know the exact time point of the injection in order to separate the anticipatory and CCK-4 induced anxiety. The panic symptom scale score was assessed before and after the injection. During anticipatory anxiety healthy controls showed functional responses mainly in fronto-temporal regions. Patients suffering from PPV showed pronounced BOLD responses in the (ventral) anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and precuneus. In healthy subjects, CCK-4 induced anxiety was accompanied by activations in the medial and inferior frontal cortex. In PPV, the CCK-4 injection led to increased activities particularly in the ACC, the cuneus, the cerebellum, the amygdala and fronto-temporal regions. Given the fact of increased neuronal responses in emotion-related brain areas in patients with anxiety disorders these findings could provide evidence for common aspects of phobic postural vertigo and anxiety disorders.

Anxiety-related neuronal responses in phobic postural vertigo

Vertigo and anxiety are frequent symptoms in both psychiatric and vertigo patients, especially in those with phobic postural vertigo (PPV). The aim of this study was the investigation of anxiety-associated functional responses in PPV patients compared to healthy controls. For that purpose cholecystokinin tetrapeptide (CCK-4), a valid model to experimentally induce anxiety symptoms, was used. 15 PPV patients and 15 matched healthy controls underwent challenges with CCK-4. During the paradigm, participants did not know the exact time point of the injection in order to separate the anticipatory and CCK-4 induced anxiety. The panic symptom scale score was assessed before and after the injection. During anticipatory anxiety healthy controls showed functional responses mainly in fronto-temporal regions. Patients suffering from PPV showed pronounced BOLD responses in the (ventral) anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and precuneus. In healthy subjects, CCK-4 induced anxiety was accompanied by activations in the insula, the medial and inferior frontal cortex. In PPV, the CCK-4 injection led to increased activities particularly in the ACC, the insula, the cuneus, the cerebellum, the amygdala and fronto-temporal regions. Given the fact of increased neuronal responses in emotion-related brain areas in patients with anxiety disorders these findings could provide evidence for common aspects of phobic postural vertigo and anxiety disorder. This study was supported by BBF.

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate+glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17)=149.41; p<0.0001; PSS: F(1,17)=88.03; p<0.0001) and heart rate (HR: F(1,17)=72.79; p<0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17)=15.94; p=0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11)=8.68; p=0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both APImax (r=0.598; p=0.009) and maximum heart rate (HR(max)) during challenge (r=0.519; p=0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

Glyoxalase-I mRNA expression and CCK-4 induced panic attacks

Rationale There is evidence that the anti-glycation enzyme glyoxalase-1 (GLO1) may play a role in anxiety-related behaviour. However, discordant findings between GLO1 expression and anxiety-related behaviour have been observed in animal models. Because no data are available on the relation between GLO1 mRNA expression and human anxiety so far, we investigated the expression of GLO1 mRNA in peripheral blood cells in relation to cholecystokinin-tetrapeptide (CCK-4) induced panic anxiety in healthy subjects as an established model of human anxiety in healthy volunteers. Methods Twenty-three healthy subjects underwent challenge with CCK-4. GLO1 mRNA expression was assessed by quantitative real-time polymerase chain reaction prior to CCK-4 injection. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI) and panic response was measured with the Panic Symptom Scale (PSS). Results CCK-4 elicited a marked anxiety response accompanied by a significant increase in heart rate. GLO1 mRNA expression did not correlate with state or trait anxiety nor with severity of CCK-4 induced anxiety. Conclusions The lack of correlation between GLO1 mRNA expression and CCK-4 induced panic severity suggests that GLO1 is not involved into the acute panic response to CCK-4 in healthy volunteers. Therefore, further studies are needed to clarify the involvement of GLO1 in anxiety disorders at baseline and in anxiety challenge paradigms to resolve the apparent contradictions of preclinical studies concerning the relationship between GLO1 expression and anxiety.

One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: Investigation of neural correlates with BOLD MRI

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

PW01-44 - Impact of glyoxalase-1 mRNA expression on CCK-4 induced anxiety

ObjectivesThere is evidence that the antioxidant enzyme glyoxalase-1 (Glx-1) may play a role in anxiety-related behaviour. However, discordant findings between Glx-1 expression and anxiety-related behaviour have been observed in animal models. Because no data are available on the relation between Glx-1 mRNA expression and human anxiety so far, we investigated the expression of Glx-1 mRNA in peripheral red blood cells in relation to cholecystokinin-tetrapeptide (CCK-4) induced anxiety in healthy subjects.MethodsTwenty-three healthy subjects underwent challenge with CCK-4. Glx-1 mRNA expression was assessed by quantitative real-time polymerase chain reaction prior to CCK-4 injection. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI) and panic response was measured with the Panic Symptom Scale (PSS).ResultsCCK-4 elicited a marked anxiety response accompanied by a significant increase in heart rate. Glx-1 mRNA expression correlated significantly with severity of CCK-4 induced anxiety. In contrast, Glx-1 activity did not correlate with state or trait anxiety.ConclusionsThe positive correlation between Glx-1 mRNA expression and CCK-4 induced panic severity suggests that Glx-1 is involved into the acute anxiety response to CCK-4. Our preliminary findings support preclinical findings and point towards a role of Glx-1 for human anxiety.

Impact of loudness dependency of auditory evoked potentials on the panic response to CCK-4

Rationale Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder. In line with the serotonin (5-HT)-hypothesis of panic disorder it has been suggested that the panicogenic effects of CCK-4 are mediated in part through the 5-HT system. The analysis of the loudness dependency of the auditory evoked potentials (LDAEP) is a valid non-invasive indicator of central serotonergic activity. Methods We investigated the correlation between LDAEP and behavioral, cardiovascular and neuroendocrine panic responses to CCK-4 in 77 healthy volunteers and explored whether differences in LDAEP paralleled subjective panic severity. Behavioral panic responses were measured with the panic symptom scale (PSS). Heart rate and ACTH/cortisol plasma concentrations were assessed concomitantly. Results LDAEP did not differ between panickers and nonpanickers. Furthermore, LDAEP did not correlate with the behavioral panic response. However, a significant positive correlation between LDAEP and CCK-4 induced HPA-axis activation, which was uniform in panickers and nonpanickers, could be detected. Conclusions The psychological effects of CCK-4 rather are mediated by neurotransmitters others than the endogenous 5-HT system. However, the extent of the neuroendocrine activation related to the CCK-4 panic provocation was correlated with the LDAEP, thereby suggesting that central 5-HT mechanisms are involved in the HPA-axis activation during this challenge paradigm.

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules. To provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection. We assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly. The API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers. The panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective "read out". The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.

Effects of repetitive transcranial magnetic stimulation (rTMS) on panic attacks induced by cholecystokinin-tetrapeptide (CCK-4)

Low-frequency (LF) rTMS shows beneficial effects in patients with depression and anxiety disorders. To explore its anxiolytic properties we investigated the effects of rTMS on experimentally induced panic attacks. Eleven healthy subjects underwent 1 Hz rTMS or sham rTMS over the right dorsolateral prefrontal cortex in a randomized cross-over protocol. Panic induction with 50 mug CCK-4 was carried out immediately after rTMS. Response to CCK-4 was assessed using the Acute Panic Inventory and the Panic Symptom Scale and measurements of heart rate, plasma ACTH and cortisol. All subjects reported a marked panic response following CCK-4 administration after both real and sham rTMS. Moreover, injection of CCK-4 induced a marked increase in heart rate, cortisol and ACTH concentrations. However, ANOVA showed no significant differences in any of the measures between both conditions. In contrast to the effects of pretreatment with alprazolam on CCK-4-induced panic in healthy subjects LF rTMS does not affect CCK-4-induced panic and cortisol or ACTH release.

Response to flumazenil in the late luteal phase and follicular phase of the menstrual cycle in healthy control females

Animal studies of short-term progesterone administration and withdrawal model the natural increase and abrupt decrease in progesterone levels which occur in the late luteal phase (LP) of the human menstrual cycle (MC). Previously, studies in animals have shown that abrupt cessation of chronic or short-term progesterone administration results in pharmacological changes at the GABAA receptor, resulting in altered sensitivity to GABAA receptor neuromodulators such as benzodiazepines and flumazenil, a GABAA receptor antagonist. This study's goal was to compare the response to flumazenil in the follicular phase (FP) and late LP in female healthy controls (HCs). We postulated that HC females would exhibit a greater psychological and somatic response to flumazenil in the late LP, a period of progesterone withdrawal, compared to the FP. Twelve healthy females, without history of psychiatric disorder, were randomized to receive two injections of a 2 mg bolus injection of flumazenil (one in the late LP and one in the FP) and two injections of placebo (one in the late LP and one in the FP). Following injection, subjects were asked to rate the occurrence and intensity of panic symptoms on the panic symptom scale (PSS). A main treatment effect was detected for the PSS score response after flumazenil injection (P=0.008). However, there was no significant treatment-by-phase interaction observed (P=0.449). These findings indicate that MC phase did not affect the response to flumazenil in HC females. This result is contrary to our hypothesis of altered sensitivity to flumazenil in the late LP.

Central and peripheral chemoreflexes in panic disorder

Klein (Arch Gen Psychiatry, 50, 1993, 306–317) has suggested that panic disorder patients have a false suffocation alarm that may be associated with a lowered threshold for carbon dioxide detection. We compared the thresholds and sensitivities of the central and peripheral chemoreflexes between panic disorder patients and age- and sex-matched healthy volunteers to test this aspect of the hypothesis. We used a modified version of Read's rebreathing technique in 11 panic disorder patients and 10 healthy volunteers to examine the peripheral and central chemoreflex characteristics in these two populations. Subjects were examined during three rebreathing tests: training, hyperoxic (central chemoreflex alone) and hypoxic (combined central and peripheral chemoreflex). Panic symptoms were retrospectively assessed between groups using a DSM-IV derived Panic Symptom Scale. Comparisons of panic disorder patients with agoraphobia and healthy volunteers showed no significant differences in sensitivities or thresholds. Klein's hypothesis is not supported by these data. If a false suffocation alarm exists, its triggering may not be implemented within the respiratory chemoreflexes.

Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients

Background: Alteration in noradrenergic regulation as well as alteration in the hypothalamic—pituitary—adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. Methods: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. Results: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. Conclusions: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.

Vigabatrin Decreases Cholecystokinin-Tetrapeptide (CCK-4) Induced Panic in Healthy Volunteers

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4–induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 μg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4–induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4–induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD.

Effect of ethinyl estradiol on the panic response to the panicogenic agent pentagastrin

Background: Panic disorder (PD) symptomatology has been reported to be altered by hormonal events or treatments which affect estrogen levels. Coryell et al. [Arch. Gen. Psychiatry, 39 (1982) 701–703; Am. J. Psychiatry, 143 (1986) 508–510] have suggested that the increased cardiovascular risk associated with PD is significantly greater in males, alluding to a potential cardioprotective effect of female hormones in the context of panic attacks. In the present study, we were, therefore, interested in elucidating the role of estrogen in modulating the behavioural and cardiovascular responses induced by the panicogenic agent pentagastrin, a cholecystokinin-B (CCK B) receptor agonist. Methods: A double-blind cross-over placebo-controlled design with randomization of the order of a 3-day pretreatment of ethinyl estradiol (EE) (50 μg/day) or placebo was used to assess the effect of a 30-μg i.v. bolus injection of pentagastrin on panic symptom intensity and on increases in heart rate (ΔHR), systolic (ΔSBP) and diastolic (ΔDBP) blood pressure following each pretreatment. Subjects were 9 male healthy controls and 11 male PD patients. Results: EE pretreatment did not significantly reduce the pentagastrin-induced panic symptom scale (PSS) scores and had no effect on ΔDBP or ΔSBP. EE did, however, attenuate the pentagastrin-induced increase in HR in both PD patients and healthy controls. Limitations: Only male subjects were included in the present study, however, we are currently investigating the influence of female gonadal hormones on the panic response to pentagastrin in female PD patients and healthy controls. Conclusion: Our results suggest that estrogens may display cardioprotective effects in the context of panic attacks.

Effects of Cholecystokinin Tetrapeptide on Respiratory Function in Healthy Volunteers

The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

The panic-inducing properties of the cholecystokinin tetrapeptide CCK 4 in patients with panic disorder

We studied the effect of the cholecystokinin tetrapeptide (CCK 4), a potent CCK B antagonist, in patients with panic disorder. Two different dosages (25 and 50 μg) of CCK 4 and saline were tested in 12 patients who were randomly allocated to 2 of the 3 possible treatment groups. Patients were tested on 2 separate occasions, 1 week apart, using an unbalanced single-blind incomplete block design. A total of 24 intravenous injections were carried out. The panic rate with 25 μg CCK was 44% (4/9) and 71% (5/7) with 50 μg. None of the patients panicked with saline (0/8). Patients' symptom responses were very similar to their spontaneous panic attacks. Taking the Panic Symptom Scale (PSS) as outcome variable, we found that CCK 4 provoked symptoms of panic in a dose-dependent fashion. The behavioral response to CCK 4 was not accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis as measured by the prolactin and cortisol responses. Moreover, CCK 4-induced panic symptoms were not correlated with plasma increases in the principal noradrenergic metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG), suggesting that activation of the locus coeruleus may not be critical for CCK 4-induced panic.