tetragastrin and Panic-Disorder

Experimental neurochemical provocation of panic attacks in susceptible human subjects has considerably expanded our knowledge of the pathophysiology and psychopharmacology of panic disorder. Some panicogens also elicit short-lived panic-like states in healthy man. This offers the opportunity to assess the anti-panic action of drugs in proof-of-concept studies. However, from current data it is still unclear whether experimental panic in healthy man is a valid translational model. Most such studies in healthy volunteers have been performed using a cholecystokinin tetrapeptide (CCK-4) challenge. While CCK-4 panic was blocked by alprazolam pretreatment, escitalopram showed negative results in healthy man. Preliminary findings on novel investigational drugs and a few problematic results will be reviewed. Small sample sizes in many panic provocation studies, lack of dose-response aspects, and still-insufficient knowledge about the biological underpinning of experimental and spontaneous panic limit the interpretation of existing findings and should inspire further research.

Topics: Alprazolam; Anti-Anxiety Agents; Clinical Trials as Topic; Drug Design; Humans; Panic Disorder; Tetragastrin; Translational Research, Biomedical

The involvement of cholecystokinin (CCK) in human anxiety is well documented. Exogenous administration of CCK-2 receptor agonists, such as cholecystokinin-tetrapeptide and pentagastrin, provoke panic attacks in man. Patients with panic disorder (PD) are hypersensitive to CCK-2 receptor stimulation compared to healthy volunteers and patients with other anxiety disorders, and they differ from healthy subjects in CCK metabolism and genetic characteristics of the CCK-2 receptor system. This article reviews the corpus of work supporting the role of CCK in anxiety and suggests three research approaches which can further enhance our understanding of the CCK-2 system in PD. These approaches include: i) searching for a specific anomaly of the CCK-2 receptor system, ii) establishing a relationship between CCK-2 receptor polymorphism and vulnerability to pharmacologically-induced or spontaneous panic attacks, and iii) evaluating the therapeutic efficacy of CCK-2 receptor antagonists which possess adequate pharmacokinetic properties.

Topics: Cholecystokinin; Humans; Panic Disorder; Pentagastrin; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Research Design; Tetragastrin

The serendipitously discovered panicogenic effect of the cholecystokinin fragment, the C-terminal tetrapeptide amide (CCK-4), has suggested that the widespread network of CCK neurons and corresponding CCK-B receptors in the brain are in some way involved in pathogenesis panic disorders in man. Two decades of research have now established that exogenous CCK-4 in a reproducible, dose-dependent and sensitive manner indeed evokes panic attacks in both healthy subjects and at even lower doses in anxiety patients. But several questions about the molecular mechanisms by which endogenous CCK peptides may precipitate panic attacks remain to be answered. This review focuses on three immediate questions. (1) Does endogenous CCK-4 exist? (2) Is the panicogenic effect mediated only through CCK-B receptors? (3) Are measurements of CCK peptides in cerebrospinal fluid of use in elucidating the pathogenesis and/or diagnosis? This review concludes that the answers to these questions may further the understanding of panic disorder substantially, and hence contribute to improved diagnosis and therapy of the disease.

Topics: Amino Acid Sequence; Animals; Cholecystokinin; Humans; Molecular Sequence Data; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin

Topics: Animals; Anxiety; Anxiety Disorders; Cholecystokinin; Humans; Panic Disorder; Receptors, Cholecystokinin; Tetragastrin

Cholecystokinin (CCK) is a neurotransmitter found in high density in the brains of mammals. Microiontophoretic studies showing that benzodiazepines selectively antagonized CCK-induced excitation of rat hippocampal neurons have led to the hypothesis that CCK is an anxiogenic peptide. The hypothesis was supported by demonstrations that CCK-tetrapeptide (CCK4) induces panic attacks in humans. This paper reviews phases of investigations which studied the validity of CCK4 as a panicogenic agent and research strategies for the study of panic disorder using CCK4 as an investigative tool.

Topics: Amino Acid Sequence; Base Sequence; Benzodiazepines; Brain; Cerebrovascular Circulation; Cholecystokinin; Female; Hippocampus; Humans; Imipramine; Male; Molecular Sequence Data; Neurotransmitter Agents; Panic Disorder; Sincalide; Tetragastrin

Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 μg CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.

Topics: Adaptation, Psychological; Adult; Biomarkers; Female; Glycopeptides; Healthy Volunteers; Humans; Male; Panic; Panic Disorder; Secretory Pathway; Sex Characteristics; Tetragastrin; Young Adult

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.

Topics: Adrenocorticotropic Hormone; Adult; Creatine; Functional Neuroimaging; Glutamic Acid; Glutamine; Gyrus Cinguli; Heart Rate; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Panic Disorder; Pituitary-Adrenal System; Psychiatric Status Rating Scales; Tetragastrin

Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5 ± 5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 μg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p = 0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies.

Topics: Adult; Citalopram; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Polymorphism, Genetic; Selective Serotonin Reuptake Inhibitors; Serotonin Plasma Membrane Transport Proteins; Tetragastrin

The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psychovegetative symptoms pointing to different subtypes of panic disorder patients have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder.. We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinine tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and matched healthy control subjects. Psychophysiological changes were measured using the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal.. In patients with panic disorder 18 out of 25 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4 induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder.. The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges.

Topics: Adult; Case-Control Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Sodium Lactate; Tetragastrin

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.

Topics: Adult; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attention; Cerebral Cortex; Cross-Over Studies; Gyrus Cinguli; Heart Rate; Humans; Lorazepam; Magnetic Resonance Imaging; Male; Panic; Panic Disorder; Psychiatric Status Rating Scales; Tetragastrin; Young Adult

Cholecystokinin-tetrapeptide (CCK-4) is an established model to generate subjective panic anxiety. CCK-4 injection also results in consistent and dose-dependent rise of stress hormones. Effects other than upon subjective panic and stress hormone activity have barely been examined. The purpose of the study was to investigate CCK-4 effects on emotional facial expression and especially on fear relevant facial muscles establishing therewith a more objective method to measure subjective panic anxiety.. 20 healthy male subjects were randomly and double-blindedly assigned in two groups (dose groups), each of which was investigated three times once with placebo and twice with 25 μg or 50 μg CCK-4 respectively. Subjects of each group were randomly assigned in two different balanced orders of investigations: CCK-CCK-Placebo vs. Placebo-CCK-CCK. Facial muscle and hypothalamo-pituitary-adrenocortical (HPA)-axis activity were recorded.. CCK-4 led dose-dependently to an increase of panic anxiety, an activation of fear relevant facial muscles and a rise of stress hormones. Whereas placebo administration before CCK-4 revealed no significant panic and stress response, during placebo following CCK-4 stimulations a psychophysiological conditioning effect could be observed without rise in HPA-axis activity.. Our findings indicate the possibility to measure different intensities of panic anxiety and conditioning effects with a facial EMG method. Dissociation of HPA-activity and fear relevant facial muscle activity is in accordance with former results about spontaneous panic attacks.

Topics: Adrenocorticotropic Hormone; Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Electromyography; Facial Muscles; Humans; Male; Pain Measurement; Panic Disorder; Radioimmunoassay; Tetragastrin; Time Factors; Young Adult

There is evidence that gamma-amino-butyric acid type A (GABA(A))-receptor modulating neuroactive steroids play a role in the pathophysiology of panic disorder. Antidepressant treatment has been suggested to stabilize the concentrations of neuroactive steroids. In this pilot study we investigated neuroactive steroid concentrations during GABAergic treatment, which might represent an alternative anxiolytic pharmacotherapeutic strategy. Neuroactive steroid concentrations were determined in 10 healthy subjects treated with tiagabine. To evaluate the anxiolytic effects of tiagabine a cholecystokinin-tetrapeptide (CCK-4) challenge was performed before and after treatment. Treatment with tiagabine led to a significant increase in 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) from 0.49 to 1.42 nmol/l (Z=-2.80, p=.005), which was significantly correlated with a decrease of panic symptoms in the CCK-4 challenge. Thus, it might be hypothesized that the anxiolytic effects of GABAergic treatment might in part be mediated by their influence on 3alpha,5alpha-THDOC concentrations.

Topics: Adult; Desoxycorticosterone; Female; GABA Uptake Inhibitors; Humans; Male; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Panic Disorder; Pilot Projects; Tetragastrin; Tiagabine

Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

Topics: Adult; Alprazolam; Animals; Anti-Anxiety Agents; Benzodiazepines; Cell Line; Drug Tolerance; gamma-Aminobutyric Acid; Humans; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Neurotransmitter Agents; Panic Disorder; Purines; Rats; Rats, Sprague-Dawley; Receptors, GABA; Receptors, GABA-A; Substance Withdrawal Syndrome; Tetragastrin

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.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Blood Pressure; Heart Rate; Humans; Hydrocortisone; Male; Models, Biological; Models, Psychological; Panic Disorder; Personality Inventory; Reference Values; Tetragastrin

Data by [Bell et al. J Psychopharmacol (2002) 16:5-14] suggest that a decrease in 5-HT neurotransmission predisposes to panic attacks and that the antipanic effect of SSRIs depends upon the availability of 5-HT in the brain.. Our aim was to assess the effect of acute tryptophan depletion (TD) on cholecystokinin-tetrapeptide (CCK-4)- induced symptoms in patients with panic disorder (PD) who had responded to a 10-week treatment with a selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram.. A total of 18 patients (6 males and 12 females, mean age 34.5 years) received a tryptophan-free amino acid drink and a control drink, each followed by a CCK-4 challenge (25 microg), 1 week apart in a double-blind crossover design.. The results showed no significant differences in response to the CCK-4 challenge between the TD and the control conditions. Panic rate after the CCK-4 challenge was 27.8% after depletion and 33.3% after control drink (chi2=0.13, p=0.72). No significant effects of TD were observed in panic intensity scores, subjective anxiety, or cardiovascular indices.. This study demonstrates that an acute lowering of brain 5-HT availability with TD does not affect response to a CCK-4 challenge in PD patients successfully treated with citalopram. Thus, the reduction of CCK-4 sensitivity following SSRI-treatment in patients with PD may be related to mechanisms other than 5-HT availability in the brain, possibly to a reduction in brain cholecystokinin receptor sensitivity.

Topics: Adult; Citalopram; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Selective Serotonin Reuptake Inhibitors; Tetragastrin; Tryptophan

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.

Topics: Adolescent; Adult; Anxiety; Arousal; Brain; Brain Mapping; Dominance, Cerebral; Heart Rate; Humans; Image Processing, Computer-Assisted; Injections, Intravenous; Magnetic Resonance Imaging; Male; Panic Disorder; Tetragastrin

The present study was designed to examine the efficacy and tolerability of the non-peptide neurokinin-3 (NK3) receptor antagonist SR142801 in outpatients suffering from panic disorder.. In a pilot study, 52 patients who were responders to a cholecystokinin tetrapeptide (CCK-4) challenge were randomized to four weeks of treatment with SR142801 (n = 36) or placebo (n = 16). Panic symptoms were assessed on weekly visits and a second CCK-4 challenge was performed at the end of the double-blind placebo controlled treatment period. Tolerability of SR142801 was generally good.. The proportion of patients who had at least one adverse event (AE) in the SR142801 group and the placebo group was similar (58.3 and 50 %, respectively). Independent of treatment group, patients' overall panic symptomatology was substantially improved at the end of the treatment.. With regard to efficacy of outcome, the compound was not significantly different from placebo. However, post-CCK-4 plasma prolactin concentrations showed a significant difference between placebo and SR142801.

Topics: Adolescent; Adult; Antipsychotic Agents; Double-Blind Method; Electrocardiography; Endpoint Determination; Female; Humans; Male; Middle Aged; Panic Disorder; Piperidines; Receptors, Neurokinin-3; Tetragastrin

Preclinical findings have repeatedly shown an anxiolytic-like action of agonists at metabotropic glutamate receptors type II, such as LY354740.. We aimed to investigate the effect of LY544344, the prodrug of LY354740, upon experimental panic anxiety in humans.. Twelve healthy human volunteers were treated orally with 80 mg bid LY544344 for 1 week in a randomized placebo-controlled cross-over study before 50 mug cholecystokinin tetrapeptide (CCK-4) was injected intravenously. We assessed CCK-induced panic and anxiety symptoms and measured stress hormone release.. While no significant treatment effect emerged in the entire sample, a significant reduction of the number of CCK-4-induced panic symptoms and of CCK-4-induced subjective anxiety ratings was detected after removing two subjects who did not show decreased CCK-4-elicited adrenocorticotropin (ACTH) release after LY544344 compared to placebo treatment.. Further studies are needed to clarify the potential of LY544344 as a new anxiolytic or antipanic drug.

Topics: Adrenocorticotropic Hormone; Adult; Anxiety; Bridged Bicyclo Compounds; Cross-Over Studies; Double-Blind Method; Excitatory Amino Acid Agonists; Humans; Hydrocortisone; Male; Panic Disorder; Prolactin; Receptors, Metabotropic Glutamate; Tetragastrin

Sensitivity to the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) is enhanced in panic disorder patients relative to normal controls (NC). In the present study, we determined whether sensitivity to CCK-4 is enhanced in patients with major depressive disorder (MDD) with no history of panic attacks. We also determined whether CCK-4 would exacerbate depressive symptoms.. The study used a double-blind, randomized, placebo-controlled design. Behavioral and cardiovascular response to a submaximal dose (20 microg) of CCK-4 was studied in seven patients with MDD and 12 NC subjects.. None of the subjects panicked with placebo, whereas 29% of MDD and 17% of NC subjects panicked with CCK-4. There was no significant difference between groups on the frequency of CCK-4-induced panic or the number and intensity of panic symptoms. No significant difference was detected for cardiovascular response to the CCK-4 challenge. CCK-4 did not worsen depressive symptoms in MDD patients.. Small number of study subjects.. These data indicate that MDD patients show a response to CCK-4 that is comparable to NC. The lack of effect of CCK-4 on depressive symptoms suggest that central CCK receptors may not play an important role in the pathophysiology of MDD.

Topics: Adult; Depressive Disorder, Major; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Injections, Intravenous; Male; Panic Disorder; Receptors, Drug; Severity of Illness Index; Surveys and Questionnaires; Tetragastrin

Previous studies suggest a modulatory role of serotonin (5-HT) in experimentally-induced panic attacks. In the current study, we investigated the acute effects of 5-HT precursor l-5-hydroxytryptophan (5-HTP) on the response to panicogenic challenge with cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Thirty-two subjects were randomized to receive either 200 mg of 5-HTP or placebo with the CCK-4 challenge following in 90 min in a double-blind, parallel-group design. The results showed a nonsignificant difference between the groups in panic rate (19% after 5-HTP and 44% after placebo, p = 0.13) with a trend for lower intensity of symptoms after 5-HTP (p = 0.08). Further analysis by gender revealed that females in the 5-HTP group had a significantly lower panic rate and intensity of cognitive symptoms whereas, in males, the effect of 5-HTP was limited to lowering the intensity of somatic panic symptoms. Thus, an increased availability of 5-HT may have a gender-dependent protective effect in CCK-4-induced panic.

Topics: 5-Hydroxytryptophan; Administration, Oral; Adolescent; Adult; Capsules; Cognition Disorders; Double-Blind Method; Female; Humans; Hypertension; Injections, Intravenous; Male; Panic Disorder; Psychiatric Status Rating Scales; Sex Characteristics; Tachycardia; Tetragastrin; Time Factors

Panicogenic sensitivity to CCK-tetrapeptide (CCK-4) is enhanced in panic disorder patients relative to normal controls (NC). We sought to determine whether CCK-4 sensitivity is augmented in patients with social phobia (SP) (n = 12) and obsessive-compulsive disorder (OCD) (n = 8) versus NC (n = 12). We also determined whether CCK-4 could elicit syndrome-specific symptoms in SP and OCD patients. The study employed a single-blind, placebo-controlled, within-subject design. Behavioral, cardiovascular and hormonal responses to a submaximal dose (20 microg) of CCK-4 were evaluated. Panic frequency after the placebo and CCK-4 challenge varied as a function of diagnosis. Differences in panic frequency between groups and between challenge agents within each group did not, however, reach statistical significance. Further, the number and intensity of panic symptoms, intensity of subjective anxiety, autonomic reactivity and hormonal release after CCK-4 administration did not distinguish the groups. Core symptoms of SP and OCD were unaffected by CCK-4. These data failed to detect significant differences between groups on behavioral, cardiovascular and hormonal response to CCK-4. The lack of effect of CCK-4 on SP and OCD symptoms suggests that this peptide does not play a salient role in the pathophysiology of these disorders.

Topics: Adrenocorticotropic Hormone; Adult; Anxiety; Arousal; Autonomic Nervous System; Female; Human Growth Hormone; Humans; Hydrocortisone; Male; Middle Aged; Obsessive-Compulsive Disorder; Panic Disorder; Phobic Disorders; Prolactin; Reference Values; Single-Blind Method; Tetragastrin

Panic attacks induced by administration of cholecystokinin tetrapeptide (CCK-4) have been evaluated as a valuable tool to investigate the neurobiological mechanisms involved in panic anxiety. The rationale to study the effects of natriuretic peptides on the CCK-4 response is derived from observations that atrial natriuretic peptide (ANP) is released during panic attacks in humans and has anxiolyticlike actions in various animal models.. A double-blind, placebo-controlled design was conducted in 9 patients with panic disorder and 9 similar healthy control subjects. After pretreatment with an infusion of 150 microg of ANP or placebo in random order, each subject received 50 microg of CCK-4. Psychopathological parameters as well as physiological measures were sampled before and after CCK-4 administration.. After pretreatment with ANP, the number of CCK-4-induced panic attacks decreased from 8 to 6 in patients and from 5 to 2 in controls. Acute Panic Inventory ratings were significantly reduced in patients after ANP vs placebo pretreatment. Infusion of ANP significantly curtailed the CCK-4-induced release of corticotropin in patients. Heart rate variability analysis indicated a sympathetic stimulation by CCK-4 that was inhibited by ANP in patients and controls.. The present study indicates that ANP exerts anxiolyticlike effects on CCK-4-stimulated anxiety attacks in patients with panic disorder. In addition, ANP produced an inhibition of the hypothalamopituitary-adrenocortical system and sympatholytic effects.

Topics: Adrenocorticotropic Hormone; Adult; Anti-Anxiety Agents; Anxiety Disorders; Area Under Curve; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Hydrocortisone; Male; Panic Disorder; Placebos; Prospective Studies; Tetragastrin

This study examined the effects of i.v. administration of cholecystokinin-tetrapeptide (CCK-4) on plasma release of arginine vasopressin (AVP) and oxytocin (OT) in women with premenstrual dysphoric disorder (PMDD) and control women, during both the follicular phase and the luteal phase of their menstrual cycle. Plasma AVP and OT concentrations increased following CCK-4 administration. AVP and OT response to CCK-4 was similar for PMDD and control women and unaffected by menstrual cycle phase. AVP and OT may play a role in the hypothalamo-pituitary adrenal (HPA) axis activity associated with the panic response induced by CCK-4.

Topics: Adult; Arginine Vasopressin; Cholecystokinin; Cross-Over Studies; Double-Blind Method; Female; Humans; Oxytocin; Panic Disorder; Peptides; Placebos; Premenstrual Syndrome; Radioimmunoassay; Tetragastrin; Time Factors; Vasoconstrictor Agents

Preclinical evidence exists for the anxiolytic activity of atrial natriuretic peptide, which is released during lactate-induced panic attacks. Atrial natriuretic peptide receptor modulation may have antipanic activity in patients with panic disorder.. The effects of 150 microg of atrial natriuretic peptide and placebo on panic attacks induced by cholecystokinin tetrapeptide (CCK-4) (25 microg) were studied in 10 panic disorder patients. The panicogenic activity of CCK-4 was measured with the Acute Panic Inventory.. Panic attacks occurred in seven patients in the placebo condition and in two patients in the atrial natriuretic peptide condition. CCK-4 administration was accompanied by a significant increase in Acute Panic Inventory scores. Pretreatment with atrial natriuretic peptide resulted in significantly lower Acute Panic Inventory scores than pretreatment with placebo.. The results support the antipanic activity of atrial natriuretic peptide. Nonpeptidergic atrial natriuretic peptide receptor ligands may be ultimately used to treat anxiety disorders.

Topics: Adult; Anti-Anxiety Agents; Atrial Natriuretic Factor; Double-Blind Method; Female; Humans; Male; Panic Disorder; Placebos; Receptors, Atrial Natriuretic Factor; Tetragastrin

Review of the literature equivocally suggests that subjects with Type A behavioral pattern (TABP) compared to subjects with Type B behavioral pattern display an increased sympathetic activity, a condition associated with sudden cardiac death. The objective of this study was to determine whether healthy subjects classified as Type A or Type B differed in their reactivity to the beta 1 and beta 2 receptor agonist isoproterenol and to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4). By comparing reactivity to CCK-4 after pretreatment with placebo or propranolol, a beta 1 and beta 2 receptor antagonist, the role of the beta adrenergic system in the hypothesized increased response of Type A subjects to CCK-4 was also assessed.. The study used a randomized, double-blind, placebo-controlled design. Twenty-seven Type A or B subjects were included in the study. The reactivity to isoproterenol was assessed with the CD25 of isoproterenol (i.e., the intravenous dose of isoproterenol necessary to increase the heart rate of 25 bpm). The panic symptom response and the cardiovascular response to bolus injection of 50 microg of CCK-4 was assessed in subjects pretreated with either propranolol or placebo infusions prior to the CCK-4 challenge. An additional group of subjects was recruited and these subjects received a placebo infusion pretreatment before an injection of placebo.. The CD25 was significantly greater in Type A subjects than in Type B subjects. No difference was found among the groups on behavioral sensitivity to the CCK-4 challenge. However, CCK-4-induced maximum increase in heart rate was greater in Type A subjects.. Our finding that Type A subjects exhibited greater CD25 of isoproterenol and greater increases in heart rate following CCK-4 administration compared to Type B subjects suggests that peripheral beta-receptor sensitivity may be increased in individuals with TABP.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Adult; Blood Pressure; Cardiovascular Physiological Phenomena; Double-Blind Method; Heart Rate; Humans; Isoproterenol; Male; Panic Disorder; Personality; Propranolol; Receptors, Adrenergic, beta; Tetragastrin; Type A Personality

Given the relationship between posttraumatic stress disorder (PTSD) and panic, it was of interest to examine whether panic provoking agents affect PTSD symptoms. We therefore investigated the behavioral and endocrine response of PTSD patients to the panicogen cholecystokinin tetrapeptide (CCK-4).. Eight patients with PTSD (DSM-IV) received 50 micrograms CCK-4 intravenously in a placebo-controlled, double-blind balanced design. Provocation of panic, anxiety, and flashbacks was assessed. Plasma adrenocorticotropin (ACTH) and cortisol levels after CCK-4 were measured and compared to healthy subjects matched for age, gender, and provoked symptoms.. Despite significant effects of CCK-4 on anxiety and panic symptoms, no significant provocation of flashbacks emerged. CCK-4-induced panic symptoms showed an inverse correlation to trait dissociation. The ACTH response after CCK-4 was significantly lower in PTSD patients than in controls. Cortisol was similarly increased in both groups after CCK-4, but PTSD patients showed a more rapid decrease of stimulated cortisol concentrations.. Panic symptoms or heightened anxiety are not necessarily conditioned stimuli for the provocation of posttraumatic flashbacks. Further studies in PTSD with different panicogens should be controlled for the potential interference of trait dissociation. Our hormone data show further evidence for a corticotropin-releasing hormone (CRH) overdrive and enhanced negative glucocorticoid feedback in PTSD patients.

Topics: Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Hydrocortisone; Injections, Intravenous; Male; Middle Aged; Panic Disorder; Stress Disorders, Post-Traumatic; Tetragastrin

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Aged, 80 and over; Aging; Double-Blind Method; Female; Human Growth Hormone; Humans; Hydrocortisone; Male; Panic Disorder; Placebos; Prolactin; Tetragastrin

Sixteen healthy subjects participated in a crossover, double blind, and placebo-controlled study, designed to assess simultaneously the psychological and cardiovascular effects of cholecystokinin tetrapeptide (CCK4). Following an i.v. injection of 25 microg of CCK4, 44 percent of subjects experienced symptoms that fulfilled the DSM-IV criteria for a panic attack while no one panicked with placebo. CCK4 induced a significantly greater number and higher intensity of panic-like symptoms than placebo. A significant increase in state anxiety was observed in the period after CCK4 injection; this increase was significantly larger than the non-specific anxious reaction to placebo. CCK4 also affected cardiovascular signs. Both heart rate and mean blood pressure significantly increased after administration of CCK4. Again, these increases were significantly higher than those seen after placebo injection. We conclude that, in healthy subjects, CCK4 induces panic-like reaction characterized by a number of somatic, cognitive and emotional symptoms, which are accompanied by increases in heart rate and blood pressure.

Topics: Adult; Anxiety; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Heart Rate; Hemodynamics; Humans; Injections, Intravenous; Male; Panic Disorder; Psychiatric Status Rating Scales; Tetragastrin

Cholecystokinin tetrapeptide (CCK4) induces symptoms similar to those of panic attack. The present study investigated the effects of CCK4 administration on catecholaminergic system. In this double blind, randomised, crossover experiment, 16 healthy subjects received injections of either 25 microg of CCK4 or placebo on two separate occasions. Platelet and plasma catecholamine concentrations were assessed before the administration and compared to post-injection values. The results clearly show that both plasma and platelet concentrations of catecholamines are significantly affected by CCK4. Plasma norepinephrine (NE) and epinephrine (EPI) raised significantly above baseline in the immediate post-CCK4 period, while in plasma dopamine (DA), the significant increases were delayed. In the platelets, significant post-CCK4 increases of NE and EPI concentrations were observed with a delay of several minutes. In summary, we have demonstrated that, in healthy subjects, CCK4 increases peripheral concentrations of catecholamines in both plasma and platelets, with the most consistent changes occurring in platelet NE and plasma EPI concentrations.

Topics: Adult; Blood Platelets; Catecholamines; Chromatography, High Pressure Liquid; Cross-Over Studies; Dopamine; Double-Blind Method; Epinephrine; Female; Humans; Male; Norepinephrine; Panic Disorder; Tetragastrin

Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points.. To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis.. The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions.. These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

Topics: Adult; Analysis of Variance; Anxiety; Basal Ganglia; Brain; Cerebral Cortex; Cerebrovascular Circulation; Female; Hormones; Humans; Hypothalamus; Limbic System; Longitudinal Studies; Male; Middle Aged; Oxygen Isotopes; Panic Disorder; Single-Blind Method; Tetragastrin; Time Factors; Tomography, Emission-Computed

1. The purpose of this study was to determine whether a subthreshold dose of CCK-4 would enhance the vulnerability of healthy subjects to a 35% carbon dioxide challenge. 2. 27 subjects, with no prior or present psychiatric disorder and in good physical condition were challenged with a vital capacity breath of a 35% carbon dioxide mixture, immediately after an intravenous injection of 5 micrograms CCK-4 or placebo, according to a random order double blind crossover design. 3. Subjects reported significantly less panic symptoms upon carbon dioxide after premedication with CCK-4 than after placebo. 4. Both CCK-4 and carbon dioxide may act on the same neuronal pathways, but seem to inhibit rather than potentiate each other effects.

Topics: Adult; Carbon Dioxide; Double-Blind Method; Humans; Inhalation Exposure; Panic Disorder; Tetragastrin

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.

Topics: Adult; Double-Blind Method; Female; Humans; Male; Panic Disorder; Placebos; Pulmonary Ventilation; Respiration; Stimulation, Chemical; Tetragastrin; Tidal Volume

Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4).. The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline.. When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects.. This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Infusions, Intravenous; Male; Panic Disorder; Placebos; Tetragastrin

Healthy subjects who panic following systemic cholecystokinin-tetrapeptide (CCK-4) challenge typically exhibit a symptom profile reminiscent of that evident among panic patients. However, the biological concomitants of CCK-4-induced panic in healthy subjects remain obscure. Accordingly, we evaluated the behavioral, cardiovascular, and neuroendocrine effects of CCK-4 in panickers and nonpanickers. Predictably, subjects who panicked with CCK-4 experienced more intense symptoms of panic and greater increases in ratings of fearful and anxious mood than did subjects who did not panic. CCK-4-induced increases in diastolic blood pressure, adrenocorticotropic hormone, prolactin, and growth hormone secretion were also significantly enhanced in subjects who panicked. The results of this study demonstrate that the behavioral experience of CCK-4-induced panic in healthy individuals is accompanied by marked biological changes and provide confirmation that CCK-4 is a useful model of panic for research among nonclinical subjects.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Affect; Analysis of Variance; Behavior; Blood Pressure; Heart Rate; Human Growth Hormone; Humans; Hydrocortisone; Male; Panic; Panic Disorder; Prolactin; Psychiatric Status Rating Scales; Reference Values; Tetragastrin

The authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers.. Subjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms).. Acute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity.. These preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.

Topics: Adult; Humans; Male; Panic Disorder; Propranolol; Receptors, Adrenergic, beta; Tetragastrin

To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men.. Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo.. Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment.. Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.

Topics: Administration, Oral; Adolescent; Adult; Anti-Anxiety Agents; Cholecystokinin; Double-Blind Method; Humans; Male; Middle Aged; Ondansetron; Panic Disorder; Tetragastrin

This article examines the effect of baseline anxiety, anxiety sensitivity and dysfunctional attitudes on the response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. CCK-4 and placebo were administered to 14 subjects in a double-blind manner. Four volunteers experienced a panic attack after CCK-4 administration. Those subjects who panicked had significantly higher baseline scores on dysfunctional attitudes. Dysfunctional thought patterns appeared also to predict number of symptoms and experience of cognitive and affective symptoms during injection. Baseline anxiety as well as anxiety sensitivity predicted reactions to placebo but not panic responses to CCK-4. Results suggest that a general tendency towards erroneous interpretation of information has some role in mediating the panicogenic effects of CCK-4, and also interpersonal sensitivity may constitute a vulnerability factor for panic. Psychological factors that have been considered more specific to panic disorder, namely high state and trait anxiety as well as anxiety sensitivity, appeared mainly to determine general reactions to a threatening situation.

Topics: Adult; Anxiety Disorders; Cognition Disorders; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Panic Disorder; Placebos; Tetragastrin

The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two different dosages of CI-988 (50 mg or 100 mg) or placebo 2 h prior to an IV bolus injection of CCK4 (20 micrograms) on two separate occasions. The primary efficacy parameter was the total intensity score on the Panic Symptoms Scale (PSS). Secondary parameters were the number of panic symptoms, time to and occurrence of the first panic symptoms, duration of symptoms, intensity of apprehension and the percentage of patients who did not have a panic attack. The PSS failed to show a statistically significant treatment effect on any of these outcome measures. The average panic rate was 50%, 14.3% and 37.5% after placebo, 50 and 100 mg CI-988, respectively. The differences in panic rate were not statistically significant. The results of this study suggest that CI-988 in doses up to 100 mg is not effective in reducing symptoms of panic anxiety induced by CCK4.

Topics: Adolescent; Adult; Anti-Anxiety Agents; Cross-Over Studies; Double-Blind Method; Female; Humans; Hydrocortisone; Indoles; Male; Meglumine; Middle Aged; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin; Treatment Outcome

Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT) system. There is increasing evidence that the cholecystokinin-4 (CCK4) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1) to validate this model further and 2) to shed more light on the putative CCK/5-HT interaction. To this end, we studied the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK4-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 micrograms CCK4. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK4 while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when rechallenged with CCK4, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the validity of the CCK4 test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin are implicated in the regulation of anxiety.

Topics: Adult; Female; Fluvoxamine; Humans; Male; Models, Psychological; Neuropsychological Tests; Panic Disorder; Tetragastrin

The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide (CCK-4) was characterized. Patients with panic disorder (DSM-III-R) were given 50 micrograms CCK-4 i.v. at 1100 hours on 2 separate study days. In a randomized double-blind design they were additionally infused with 150 micrograms clonidine or placebo from 1040 to 1110 hours. After CCK-4 all patients experienced symptom attacks. No effects of clonidine on panic psychopathology or blood gas parameters were observed. After CCK-4, in the clonidine condition the pituitary release of adrenocorticotropin (ACTH) and prolactin was seemingly enhanced compared to placebo. Our results suggest that CCK-4-induced panic attacks are not suppressible by presynaptic alpha-2 receptor stimulation. Moreover, they point to a synergistic postsynaptic action of clonidine to CCK-4 upon pituitary hormone secretion. The diverging sites of action might possibly explain the discrepancies of psychopathological alterations and stress hormone secretion.

Topics: Adrenergic alpha-Agonists; Adrenocorticotropic Hormone; Adult; Clonidine; Double-Blind Method; Female; Growth Hormone; Humans; Hydrocortisone; Male; Middle Aged; Panic Disorder; Prolactin; Respiration; Tetragastrin

Topics: Arousal; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Heart Rate; Humans; Panic; Panic Disorder; Pentagastrin; Tetragastrin; Thyrotropin-Releasing Hormone

We studied the effect of the cholecystokinin tetrapeptide (CCK4), a potent CCKB antagonist, in patients with panic disorder. Two different dosages (25 and 50 micrograms) of CCK4 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 micrograms CCK was 44% (4/9) and 71% (5/7) with 50 micrograms. 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 CCK4 provoked symptoms of panic in a dose-dependent fashion. The behavioral response to CCK4 was not accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis as measured by the prolactin and cortisol responses. Moreover, CCK4-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 CCK4-induced panic.

Topics: Adult; Dose-Response Relationship, Drug; Female; Humans; Male; Methoxyhydroxyphenylglycol; Middle Aged; Panic Disorder; Tetragastrin

Topics: Female; Humans; Menstrual Cycle; Panic Disorder; Placebos; Premenstrual Syndrome; Tetragastrin

The authors tested the prediction of temporal cortex activation during experimentally induced anxiety by using positron emission tomography and the [15O]H2O bolus-subtraction method to determine regional cerebral blood flow (CBF) changes in normal volunteers challenged with a bolus injection of cholecystokinin tetrapeptide (CCK4).. Eight right-handed healthy subjects (five male, three female; mean age, 26.4 years) underwent four 60-second [15O]H2O scans separated by 15-minute intervals; each scan followed an intravenous bolus injection of either saline (placebo) or CCK4 (50 micrograms). Each subject received CCK4 once, as the first or second bolus, in a random-order, placebo-controlled, double-blind fashion. Two of the three placebo conditions were nominally identical, and the remaining placebo was used to control for anticipatory anxiety. Magnetic resonance imaging scans were obtained for subsequent anatomical correlation of blood flow changes.. CCK4, but not placebo, elicited a marked anxiogenic response, reflected by robust increases in subjective anxiety ratings and heart rate. CCK4-induced anxiety was associated with 1) robust and bilateral increases in extracerebral blood flow in the vicinity of the superficial temporal artery territory and 2) CBF increases in the anterior cingulate gyrus, the claustrum-insular-amygdala region, and the cerebellar vermis.. Some of the temporopolar cortex CBF activation peaks previously reported in humans in association with drug- and non-drug-induced anxiety, as well as the increase in regional CBF in the claustrum-insular-amygdala region, may be of vascular and/or muscular origin.

Topics: Adult; Anxiety Disorders; Cerebrovascular Circulation; Double-Blind Method; Female; Humans; Magnetic Resonance Angiography; Male; Oxygen Radioisotopes; Panic Disorder; Placebos; Regional Blood Flow; Subtraction Technique; Temporal Lobe; Tetragastrin; Tomography, Emission-Computed

The functional role of cholecystokinin in the central nervous system is unknown. The tetra peptide CCK-4 was previously observed to induce panic attacks in a majority of normal volunteers and patients with panic disorder. Furthermore, it had been demonstrated that pretreatment with 10-50 mg of L-365,260, a selective CCKB antagonist, blocked CCK-4 induced panic in patients with panic disorder. Therefore, the present multicenter, placebo-controlled, double-blind trial was designed to investigate the efficacy of L-365,260, a CCKB antagonist, in patients with panic disorder with or without agoraphobia. Following a 1-week, single-blind placebo period, 88 patients were randomized to double-blind treatment in which they received either L-365,260, 30 mg qid, or placebo for 6 weeks. At the dose tested, there were no clinically significant differences between L-365,260 and placebo in global improvement ratings, Hamilton anxiety rating scale scores, panic attack frequency, panic attack intensity, or disability measures. The possible reasons for lack of effect with L-365,260 are discussed.

Topics: Adult; Agoraphobia; Arousal; Benzodiazepinones; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Personality Inventory; Phenylurea Compounds; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Tetragastrin; Treatment Outcome

The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 micrograms) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.

Topics: Adult; Amino Acid Sequence; Cross-Over Studies; Double-Blind Method; Female; Flumazenil; GABA-A Receptor Antagonists; Humans; Ligands; Male; Molecular Sequence Data; Panic Disorder; Psychiatric Status Rating Scales; Receptors, GABA-A; Tetragastrin

Cholecystokinin (CCK) may mediate human anxiety and animal data suggest that cholecystokinin antagonists could provide an important advance in the treatment of anxiety disorders. The study of CCK receptor systems in psychiatric patients has, however, been severely limited by the lack of available probes. We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls. Pentagastrin produced substantial symptomatology, including anxiety, and increases in heart rate and blood pressure, in both patients and controls. Patients were more sensitive to the panicogenic effects of the pentagastrin. Panic attacks occurred in 70% of patients and 0% of controls. Patients' symptom responses were very similar to their "typical" panic attacks and to symptoms produced by CCK4. Pentagastrin provides a readily available alternative to CCK4 for studying the CCK receptor system and exploring its involvement in human anxiety.

Topics: Adult; Agoraphobia; Arousal; Blood Pressure; Cholecystokinin; Female; Heart Rate; Humans; Male; Norepinephrine; Panic; Panic Disorder; Pentagastrin; Receptors, Cholecystokinin; Single-Blind Method; Tetragastrin

We investigated whether the selective brain cholecystokinin (CCKB) receptor antagonist, L-365,260, could antagonize the panicogenic effects of CCK-tetrapeptide (CCK-4) in patients with panic disorder.. The study employed a double-blind, placebo-controlled, two-period crossover design. Patients (N = 29) received a single oral dose of L-365,260 (10 or 50 mg) or placebo 90 minutes prior to injection of CCK-4. After a 1-week washout period, patients received a different dose of L-365,260 or placebo according to a balanced incomplete block design.. The 50-mg dose of L-365,260 was superior to placebo in reducing the number (P < .01) and sum intensity (P < .001) of symptoms induced with CCK-4. Panic attack frequency following CCK-4 injection was 88% for patients receiving placebo, 33% for those receiving the 10-mg dose, and 0% for those receiving the 50-mg dose. The difference between the effects of the 50-mg dose and placebo was statistically significant (P = .002). Increases in heart rate following CCK-4 injection were markedly reduced with both the 50-mg (P < .0001) and 10-mg (P < .01) doses compared with placebo.. These data suggest that CCKB receptors are an important site of action of exogenous CCK-4. It will be important to determine in future studies the efficacy of CCKB receptor antagonists as antipanic agents.

Topics: Administration, Oral; Adult; Benzodiazepinones; Dose-Response Relationship, Drug; Double-Blind Method; Drug Antagonism; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Panic Disorder; Phenylurea Compounds; Placebos; Psychiatric Status Rating Scales; Receptors, Cholecystokinin; Severity of Illness Index; Tetragastrin

Recent animal studies have shown that pretreatment with centrally active cholecystokinin (CCK) antagonists blocks the anxiogenic effects of CCK-tetrapeptide (CCK-4). In order to determine whether pretreatment with these antagonists can block the anxiogenic effects of CCK-4 in patients with panic disorder, a suitable challenge dose of CCK-4 must be selected. Thus, we conducted a dose range study in which patients with panic disorder (n = 29) were challenged with CCK-4 (10, 15, 20, or 25 micrograms) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 micrograms (n = 12), 15 micrograms (n = 11), 20 micrograms (n = 12), or 25 micrograms (n = 12) of CCK-4 or placebo (n = 11). CCK-4 induced anxiety and panic responses in a dose-dependent fashion. The incidence of panic attacks following the CCK-4 challenge was 17% (10 micrograms), 64% (15 micrograms), 75% (20 micrograms), and 75% (25 micrograms). None of the patients panicked with placebo. Moreover, a strong linear relationship between CCK-4 and increases in heart rate and diastolic blood pressure was found. The findings of this study suggest that a dose of 20 micrograms of CCK-4 (ED75) might be suitable for efficacy studies of CCKB antagonists and other potential antipanic drugs in patients with panic disorder.

Topics: Adolescent; Adult; Arousal; Blood Pressure; Dose-Response Relationship, Drug; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Panic; Panic Disorder; Tetragastrin

The authors determined whether response to cholecystokinin-tetrapeptide (CCK-4) was dose-dependent. Healthy volunteers (n = 36) received double-blind injections of either 9 micrograms, 25 micrograms, or 50 micrograms of CCK-4 and placebo in a randomized sequence of injection. Significant dose-related differences were found for the number of symptoms, sum intensity of symptoms and the time until onset of symptoms, but not for the duration of symptoms. The incidence of panic attacks with CCK-4 was 11%, 17% and 47% for the 9 micrograms, 25 micrograms and 50 micrograms dose, respectively. None of the controls panicked with placebo injections. These results support the notion of a dose-dependent effect of CCK-4-induced panic symptoms. Implications of these findings in the neurobiology of panic attacks are discussed.

Topics: Adult; Analysis of Variance; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Panic Disorder; Random Allocation; Reference Values; Tetragastrin

Peripheral administration of the cholecystokinin (CCK) receptor agonist CCK-4 generates panic and activates the hypothalamic-pituitary-adrenal (HPA) axis. Direct effects at the pituitary and CCK-HPA interactions at higher regulatory sites have been suggested. According to preliminary data, ACTH response to CCK receptor agonists may differ from its response to exogenous CRH by its resistance to cortisol feedback inhibition. To further explore this resistance and to better characterize CCK-4 sites of action, the effects of different glucocorticoid pretreatments on CCK-4-induced panic were compared.. Using a double-blind placebo-controlled design we pretreated healthy males with either dexamethasone (peripheral action) or hydrocortisone (central-peripheral action) each followed by a CCK-4 challenge. Blood levels of ACTH and cortisol were analyzed and panic symptoms were assessed.. We found a blunted response of ACTH release following CCK-4 injection only after hydrocortisone pretreatment. Dexamethasone however did not affect CCK-4-induced ACTH release relative to baseline. In contrast to dexamethasone, hydrocortisone reduced the severity of CCK-4-induced panic as measured by the Acute Panic Inventory on a trend level.. Findings suggest that CCK-4-induced stress hormone release seems susceptible to cortisol-feedback inhibition and argues for a suprapituitary site of CCK action. Effects on panic anxiety were weak but congruent with studies showing that CCK-4-induced HPA axis inhibition is accompanied by a reduction of anxiety after CCK-4.

Topics: Adrenocorticotropic Hormone; Adult; Analysis of Variance; Anti-Inflammatory Agents; Dexamethasone; Double-Blind Method; Humans; Hydrocortisone; Male; Panic Disorder; Psychiatric Status Rating Scales; Severity of Illness Index; Tetragastrin

Recent investigations suggest that genes that confer risk for panic disorder (PD) may moderate response to panicogenic agents in healthy volunteers. Given the potential role of the central cholecystokinin receptor (CCKBR) (CT) polymorphism alleles 26 and 27 in PD, the present study attempted to discern if these alleles moderated panicogenic sensitivity to the CCKBR agonist, CCK-tetrapeptide (CCK-4), in healthy volunteers. The study group consisted of 92 men and women with no personal or family history of psychiatric illness. Participants provided blood samples for genotyping of the CCKBR alleles and they received a 25 μg bolus injection of CCK-4. Behavioral, cardiovascular and hormonal responses to the peptide were assessed and analyzed with adjusted linear regression models. Carriers of the CCKBR alleles tended to have higher levels of pre-challenge anxiety and significantly higher levels of anxiety sensitivity and introversion than those without the alleles. However, they did not exhibit an enhanced panicogenic response to CCK-4. Overall, our findings do not demonstrate a role of these alleles in modulating CCK-4's panicogenicity. The significant association between the risk alleles and anxiety-related personality traits is intriguing and further exploration of this association is merited.

Topics: Adult; Central Nervous System Stimulants; Female; Gene Frequency; Genetic Association Studies; Humans; Male; Panic Disorder; Polymorphism, Genetic; Receptor, Cholecystokinin B; Risk Factors; Sequence Analysis, DNA; Tetragastrin; Young Adult

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.. 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).. 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.. 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.

Topics: Adult; Gene Expression Regulation; Humans; Lactoylglutathione Lyase; Male; Panic Disorder; Psychiatric Status Rating Scales; RNA, Messenger; Tetragastrin

In this study we examined how personality disposition may affect the response to cholecystokinin tetrapeptide (CCK-4; 50 microg) challenge in healthy volunteers (n=105). Personality traits were assessed with the Swedish universities Scales of Personality (SSP). Statistical methods employed were correlation analysis 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 the above mentioned 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.

Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Panic Disorder; Personality; Personality Inventory; Predictive Value of Tests; Psychiatric Status Rating Scales; Regression Analysis; Tetragastrin; Young Adult

Recent animal studies consistently confirm the involvement of brain-derived neurotrophic factor (BDNF) in the regulation of anxiety-related behaviours. The role of BDNF in human anxiety has been less investigated. The aim of our study was to examine the association between serum BDNF levels and panic/anxiety responses to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. BDNF concentrations were detected in serum samples of 37 male and female volunteers before and 120 min after CCK-4 injection. The baseline levels of serum BDNF did not predict the occurrence of CCK-4-induced panic attacks or intensity of panic symptoms and did not significantly change 2 h after the challenge. BDNF serum concentrations 120 min after provocation did not differentiate panickers from non-panickers; however, the subjects reporting stronger anxiety response showed higher levels of BDNF than those with mild anxiety. The anxiety net increase on the Visual Analogue Scale, but not severity of panic symptoms, significantly and positively correlated with the change in BDNF concentration from baseline values. This is the first challenge study to demonstrate a possible impact of BDNF on human anxiety. Our findings suggest a general involvement of BDNF in the regulation of anxiety rather than a specific role of BDNF in disposition to panic attacks.

Topics: Adolescent; Adult; Anxiety; Brain-Derived Neurotrophic Factor; Female; Humans; Male; Panic; Panic Disorder; Tetragastrin

Since little is known concerning regulation of immunological parameters in rapid changing psychiatric states like panic attacks, we measured cytokines at different time points in healthy subjects, which underwent experimental panic induction using the CCK-4 paradigm. Apart from a challenge related IL-6 increase, we could not observe any changes of neuroimmunological markers in relation to acute anxiety with regard to time and group. Herein we conducted for the first time a new approach to immunological research in panic disorder, suggesting immune changes are more related to long term disease stress.

Topics: Adult; Biomarkers; Humans; Interleukin-6; Male; Panic Disorder; Tetragastrin

Experimental panic induction with cholecystokinin tetrapeptide (CCK-4) is considered as a suitable model to investigate the pathophysiology of panic attacks. While only a few studies investigated the brain activation patterns following CCK-4, no data are available on the putative involvement of the amygdala in the CCK-4 elicited anxiety response. We studied the functional correlates of CCK-4-induced anxiety in healthy volunteers by means of functional magnetic resonance imaging (fMRI) and region of interest (ROI) analysis of the amygdala. Sixteen healthy volunteers underwent challenge with CCK-4 compared with placebo in a single-blind design. Functional brain activation patterns were determined for the CCK-4-challenge, the placebo response and anticipatory anxiety (AA). CCK-4-induced anxiety was accompanied by a strong and robust activation (random effects analysis, P < 0.00001, uncorrected for multiple testing) in the ventral anterior cingulate cortex (ACC), middle and superior frontal gyrus, precuneus, middle and superior temporal gyrus, occipital lobe, sublobar areas, cerebellum, and brainstem. In contrast, random effects group analysis for placebo and AA using the same level of significance generated no significant results. Using a more liberal level of significance, activations could be observed in some brain regions such as the dorsal part of the ACC during AA (random effects analysis, P < 0.005). Overall functional responses did not differ between panickers and nonpanickers. Only 5 of 11 subjects showed strong amygdala activation. However, ROI analysis pointed towards higher scores in fear items in these subjects. In conclusion, while overall brain activation patterns are not related to the subjective anxiety response to CCK-4, amygdala activation may be involved in the subjective perception of CCK-4-induced fear.

Topics: Adult; Amygdala; Anxiety; Brain; Brain Mapping; Fear; Gyrus Cinguli; Humans; Limbic System; Magnetic Resonance Imaging; Male; Nerve Net; Panic Disorder; Tetragastrin; Young Adult

Despite continuing efforts to determine genetic vulnerability to panic disorder (PD), the studies of candidate genes in this disorder have produced inconsistent or negative, results. Laboratory panic induction may have a potential in testing genetic substrate of PD. In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. The study sample consisted of 110 healthy volunteers (47 males and 63 females, mean age 22.2 +/- 5.2) who participated in CCK-4 challenge test. Nine gene-candidates, including 5-HTTLPR, MAO-A VNTR, TPH2 rs1386494, 5-HTR1A -1019C-G, 5-HTR2A 102T-C, CCKR1 246G-A, CCKR2 -215C-A, DRD1 -94G-A and COMT Val158Met, were selected for genotyping based on previous positive findings from genetic association studies in PD. After CCK-4 challenge, 39 (35.5%) subjects experienced a panic attack, while 71 subjects were defined as non-panickers. We detected significant differences for both genotypic and allelic frequencies of 1386494A/G polymorphism in TPH2 gene between panic and non-panic groups with the frequencies of G/G genotype and G allele significantly higher in panickers. None of the other candidate loci were significantly associated with CCK-4-induced panic attacks in healthy subjects. In line with our previous association study in patients with PD, we detected a possible association between TPH2 rs1386494 polymorphism and susceptibility to panic attacks. Other polymorphisms previously associated with PD were unrelated to CCK-4-induced panic attacks, probably due to the differences between complex nature of PD and laboratory panic model.

Topics: Adult; Brain; Brain Chemistry; Catecholamines; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Male; Mutation; Panic Disorder; Polymorphism, Genetic; Tetragastrin; Tryptophan Hydroxylase; Young Adult

Pharmacological magnetic resonance imaging (phMRI) is a method to study effects of psychopharmacological agents on neural activation. Changes of the blood oxygen level dependent (BOLD), the basis of functional MRI (fMRI), are typically obtained at relatively high sampling frequencies. This has more recently been exploited in the field of fMRI by applying independent component analysis (ICA), an explorative data analysis method decomposing activation into distinct neural networks. While already successfully used to investigate resting network and task-induced activity, its use in phMRI is new. Further extension of this method to tensorial probabilistic ICA (tensor PICA) allows to group similar brain activation across the anatomical, temporal, subject or session domain. This approach is useful for pharmacological experiments when no pharmacokinetic model exists. We exemplify this method using data from a placebo-controlled cholecystokinine-4 (CCK-4) injection experiment performed on 16 neuropsychiatrically and medically healthy males (age 25.6 +/- 4.2 years). Tensor PICA identified strong increases in activity in 12 networks. Comparison with results gained from the standard approach (voxelwise regression analysis) revealed good reproduction of areas previously associated with CCK-4 action, such as the anterior cingulate, orbitofrontal cortex, cerebellum, temporolateral, left parietal and insular areas, striatum, and precuneus. Several other components such as the dorsal anterior cingulate and medial prefrontal cortex were identified, suggesting higher sensitivity of the method. Exploration of the time courses of each activated network revealed differences, that might be lost when a fixed time course is modeled, e. g. neuronal responses to an acoustic warning signal prior to injection. Comparison of placebo and CCK-4 runs further showed that a proportion of networks are newly elicited by CCK-4 whereas other components are significantly active in the placebo conditions but further enhanced by CCK-4. In conclusion, group ICA is a promising tool for phMRI studies that allows quantifying and visualizing the modulation of neural networks by pharmacological interventions.

Topics: Adult; Brain Mapping; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Nerve Net; Panic Disorder; Principal Component Analysis; Tetragastrin

In order to elucidate the impact of psychological factors on panic severity the correlation between baseline anxiety and panic response to cholecystokinin-tetrapeptide (CCK-4), an established model of human anxiety, was investigated in 33 healthy volunteers. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI). Trait and state anxiety did not differ between panickers and nonpanickers nor were they correlated with panic severity. In conclusion, psychological factors are not major determinants for the subjective panic response to CCK-4 thus emphasising the importance of neurobiological factors.

Topics: Adult; Anxiety; Anxiety Disorders; Brain; Causality; Drug Resistance; Fear; Humans; Male; Neuropsychological Tests; Panic Disorder; Predictive Value of Tests; Tetragastrin

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.

Topics: Adrenocorticotropic Hormone; Adult; Alprazolam; Anti-Anxiety Agents; Area Under Curve; Female; Heart Rate; Humans; Hydrocortisone; Male; Panic Disorder; Psychiatric Status Rating Scales; Tetragastrin; Transcranial Magnetic Stimulation

Exercise has an anxiolytic activity and it increases the concentrations of atrial natriuretic peptide (ANP). Because ANP has an anxiolytic activity, this hormone might contribute to the anxiolytic effects of aerobic exercise. Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks were studied in 10 healthy subjects after "quiet rest" or 30 min of aerobic exercise. Plasma ANP concentrations were measured before and after exercise or quiet rest using a commercial IRMA kit. Compared to quiet rest, CCK-4-induced anxiety was reduced and plasma ANP concentrations were increased by prior exercise. This anxiolytic activity of exercise was correlated with the increase in plasma ANP concentrations. Our results suggest that besides other mechanisms, ANP might be a physiologically relevant humoral link between the heart and anxiety-related behavior contributing to the acute anxiolytic effects of exercise.

Topics: Adult; Anxiety; Atrial Natriuretic Factor; Exercise; Female; Humans; Male; Panic Disorder; Reference Values; Tetragastrin

Cholecystokinin (CCK) has been implicated in anxiety disorders. The midbrain periaqueductal gray (PAG), which modulates anxiety and panic reactions, contains CCK-immunoreactive fibers and CCK(2) receptors. The present study investigated the involvement of CCK(2) receptors of the PAG dorsolateral subdivision (dlPAG) in the regulation of inhibitory avoidance and escape, two defensive behaviors that have been related in terms of psychopathology to generalized-anxiety and panic disorders, respectively. Male Wistar rats were microinjected in the dlPAG with the CCK(2) receptor agonist cholecystokinin-tetrapeptide (CCK-4; 0.08-0.32 nmol/0.2 microL), the CCK(2) receptor antagonist LY-225910 (0.05-0.20 nmol/0.2 microL) or LY-225910 prior to CCK-4. Inhibitory avoidance and escape behaviors were evaluated in the elevated T-maze. Whereas CCK-4 facilitated escape, indicating a panic-like action, LY-225910 had the opposite effect. Pretreatment with a non-effective dose of LY-225910 prevented the panic-eliciting action of CCK-4. Neither CCK-4 nor LY-225910 affected inhibitory avoidance acquisition. The present results substantiate the view that dlPAG CCK(2) receptors modulate panic-related behaviors.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Exploratory Behavior; Fear; Male; Maze Learning; Motor Activity; Neural Pathways; Panic Disorder; Periaqueductal Gray; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Tetragastrin

Regular physical activity is anxiolytic for both healthy subjects and patients with panic disorder. However, the acute antipanic activity of exercise has not yet been studied systematically.. The effects of quiet rest or aerobic treadmill exercise (30 minutes at 70% of maximum oxygen consumption) on cholecystokinin tetrapeptide (CCK-4)-induced panic attacks were studied in a crossover design in 15 healthy subjects. The effects were measured with the Acute Panic Inventory.. Panic attacks occurred in 12 subjects after rest but in only six subjects after exercise. In both conditions, CCK-4 administration was followed by a significant increase in Acute Panic Inventory scores; however, prior exercise resulted in significantly lower scores than quiet rest.. Aerobic exercise has an acute antipanic activity in healthy subjects. If the authors' results are confirmed in patients, the optimum intensity and duration of acute exercise for achieving antipanic effects will have to be characterized.

Topics: Adult; Cross-Over Studies; Exercise; Female; Humans; Male; Oxygen Consumption; Panic Disorder; Personality Inventory; Rest; Tetragastrin

Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks.. We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha-THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis.. Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls.. The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well-documented pharmacological properties of these compounds as gamma-aminobutyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorder.

Topics: Adult; Female; Gas Chromatography-Mass Spectrometry; Gonadal Steroid Hormones; Humans; Male; Middle Aged; Panic Disorder; Placebos; Pregnanolone; Receptors, GABA-A; Sodium Lactate; Tetragastrin

The authors report that cholecystokinin (CCK), via its subtype 2 receptor (CCK2R) located presynaptically on cerebral arteries, mediates the release of nitric oxide (NO), which induces vasodilatation. Whereas CCK octapeptide and its fragment CCK tetrapeptide (CCK-4) lack a direct effect on the smooth muscle of pial vessels, the authors showed that both CCK peptides modulate the neurogenic responses in bovine cerebral arteries. The neurogenic vasodilatation induced by CCK-4 was blocked by the CCK2R antagonist, L-365,260, and antagonized by neuronal NO synthase (nNOS) inhibitors, but was independent of the endothelium. In whole-mount arteries, CCK2Rs were detected in nerve fibers and colocalized with nNOS and synaptophysin. The findings provide, for the first time, a neural mechanism by which CCK may increase cerebral blood flow.

Topics: Animals; Cattle; Cerebral Arteries; Cholecystokinin; In Vitro Techniques; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Panic Disorder; Pia Mater; Presynaptic Terminals; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Tetragastrin; Tissue Distribution; Vasodilation

Trait dissociation might influence the response to panicogens in normal controls. The behavioral effects of 25 microg of cholecystokinin tetrapeptide (CCK-4) were studied in 18 healthy men, nine each with high or low trait dissociation. Subjects with high trait dissociation showed a significantly lower increase of acute dissociative, anxiety and panic symptoms compared with subjects with low trait dissociation. Trait dissociation should be assessed in further behavioral challenge studies as a potentially important covariate.

Topics: Adult; Anxiety Disorders; Gastrointestinal Agents; Health Status; Humans; Male; Panic Disorder; Severity of Illness Index; Tetragastrin

Older age is associated with diminished symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). We hypothesized that circulating concentrations of endogenous CCK-4 and/or CCK-8 are increased in later life, possibly due to decreased enzymatic degradation, and that this is associated with desensitization of CCK-B receptors. The study group consisted of 20 healthy subjects aged 18-30 years and 20 healthy subjects aged 65-85 years. The two groups were compared on fasting basal plasma concentrations of CCK-4, sulfated CCK-8 (CCK-8s) and nonsulfated CCK-8 (CCK-8 ns), and on binding capacity of lymphocyte CCK-B receptors. Under single-blind (to subject) conditions, subjects were then administered an intravenous bolus of placebo, followed 50 min later by an intravenous bolus of 50 micro g of CCK-4. Plasma concentrations of total CCK (CCK(T)) were measured 2 min before and 2, 5, 10, and 15 min after each injection. Compared with younger subjects, older subjects had a significantly higher basal plasma concentration of CCK-8s and significantly diminished binding capacity of CCK-B receptors. Following injection of placebo, plasma CCK(T) concentrations did not significantly change from baseline in either age group, but the elderly had significantly higher concentrations than the young at 2, 5, and 10 min. Following injection of CCK-4, the plasma concentration of CCK(T) was highest at 2 min and declined after that. The elderly had significantly higher CCK(T) concentrations (ie. a slower decline in CCK(T)) than the young at 5, 10, and 15 min. These findings are consistent with our hypothesis and suggest that age-related changes in the CCK system could contribute to the diminished panicogenic response to exogenous CCK-4 in older persons.

Topics: Adult; Aged; Aged, 80 and over; Aging; Brain; Cardiovascular Physiological Phenomena; Female; Humans; Lymphocytes; Male; Middle Aged; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Sincalide; Tetragastrin

Topics: Adrenocorticotropic Hormone; Dominance, Cerebral; Electric Stimulation Therapy; Electromagnetic Fields; Female; Humans; Hydrocortisone; Middle Aged; Panic Disorder; Prefrontal Cortex; Tetragastrin; Treatment Outcome

Preclinical findings on the role of corticotropin releasing hormone (CRH) in stress and anxiety, on the interaction of CRH and cholecystokinin (CCK) in modulating anxiety, as well as the blunted corticotropin (ACTH) response to CRH in panic disorder suggest that CRH may play a role in panic disorder. To further characterize the role of the hypothalamic-pituitary-adrenocortical (HPA) system in panic disorder, we compared patients with and without CCK tetrapeptide (CCK-4) induced panic attacks. Twenty-four patients with panic disorder were given injections of CCK-4 (25 micrograms). Panic attacks, psychopathological changes, as well as ACTH and cortisol secretion were recorded. Fifteen of the 24 patients experienced a panic attack after CCK-4. ACTH secretion was significantly higher in the patients with CCK-4-induced panic attacks than in those without such attacks. The patients without CCK-4-induced attacks had a brief but less pronounced increase in ACTH concentrations. Cortisol concentrations were not significantly increased after CCK-4 administration. The increased ACTH concentrations suggest that the activation of the HPA system in CCK-4-induced panic attacks plays a physiological role. CRH may be involved in experimentally-occurring and perhaps in naturally-occurring panic attacks as well.

Topics: Adrenocorticotropic Hormone; Adult; Female; Humans; Hydrocortisone; Male; Panic; Panic Disorder; Tetragastrin

Topics: Adult; Humans; Male; Memory; Panic Disorder; Stress Disorders, Post-Traumatic; Tetragastrin

Topics: Adult; Arousal; Blood-Brain Barrier; Calcium; Depressive Disorder; Female; Humans; Male; Panic Disorder; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Schizophrenia; T-Lymphocytes; Tetragastrin

We investigated the effects of brain cholecystokinin (CCK) receptors on the intracellular calcium concentration and protein kinase C in human T cells. CCK-4 produced a transient increase in calcium in the absence of extracellular calcium. CCK-B agonists stimulated calcium mobilization in a dose-dependent manner in T cells. CCK-B antagonists suppressed CCK-4-induced calcium mobilization more potently than CCK-A antagonist. The recovery of desensitization of the CCK-4-induced response was delayed by phosphoserine/phosphothreonine phosphatase inhibitor, calyculin A. The responsiveness to CCK-4 was also reduced by phorbol 12,13-dibutyrate (PDBu), and this effect of PDBu was abolished completely by preincubation with staurosporine. CCK-4-induced calcium mobilization was too small to attribute the desensitization to the protein kinase C transduction pathway. T cells from patients with untreated panic disorder exhibited significantly higher cholecystokinin-4-induced calcium mobilization than those from healthy controls or patients with treated panic disorder. These results suggest that cholecystokinin-B receptor function in T cells of patients with panic disorder is enhanced. Cholecystokinin-4-induced calcium mobilization in T cells may be state dependent and useful as a biological marker of panic disorder.

Topics: Adult; Alprazolam; Biomarkers; Calcium; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nootropic Agents; Panic Disorder; Pentagastrin; Receptors, Cholecystokinin; Sincalide; T-Lymphocytes; Tetragastrin

The relationship between personality, as measured by selected clinical scales of the Minnesota Multiphasic Personality Inventory (MMPI) (Hypochondriasis, Depression, Hysteria, Psychasthenia, Social Introversion, and Anxiety) and the Anxiety Sensitivity Index (ASI), and behavioral response to the panicogenic agent cholecystokinin-tetrapeptide (CCK-4) was examined in 29 patients with panic disorder with or without agoraphobia. Significant correlations were found between the MMPI Social Introversion scale and somatic, cognitive, and affective response to CCK-4. Both the MMPI Anxiety scale and the ASI correlated significantly with cognitive response to CCK-4, but not with somatic or affective response. None of the other selected MMPI clinical scales correlated with response to CCK-4. Multiple regression analyses identified the MMPI Social Introversion scale as the best predictor of all three indices of panic-anxiety induced by CCK-4. The results suggest that the relationship between neurotic introversion and sensitivity to CCK requires closer scrutiny.

Topics: Adult; Agoraphobia; Arousal; Female; Humans; Introversion, Psychological; Male; Middle Aged; MMPI; Panic Disorder; Personality Inventory; Psychometrics; Tetragastrin

Cholecystokinin tetrapeptide (CCK4) is known to induce panic attacks in patients with panic disorder at a lower dose than in normal controls. Therefore, the cholecystokinin B (CCKB) receptor gene is a candidate gene for panic disorder. We searched for mutations in the CCKB gene in 22 probands of panic disorder pedigrees, using single-strand conformation polymorphism (SSCP) analysis. Two polymorphisms were detected. A polymorphism in an intron (2491 C-->A) between exons 4 and 5 was observed in 10 of 22 probands. A missense mutation in the extracellular loop of exon 2 (1550 G-->A, Val125-->Ile) was found in only one proband. This mutation was also examined in additional 34 unrelated patients with panic disorder and 112 controls. The prevalence rate of this mutation was 8.8% in patients with panic disorder (3/34) and 4.4% in controls (5/112). The mutation did not segregate with panic disorder in two families where this could be tested. These results suggest no pathophysiological significance of this mutation in panic disorder.

Topics: Adult; Amino Acid Sequence; DNA Primers; Exons; Family; Female; Humans; Male; Panic Disorder; Pedigree; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reference Values; Tetragastrin

Topics: Anxiety Disorders; Carbon Dioxide; Comorbidity; Depressive Disorder; Female; Humans; Lactates; Menstrual Cycle; Panic Disorder; Premenstrual Syndrome; Tetragastrin

Topics: Anxiety; Humans; Panic Disorder; Personality Tests; Tetragastrin

Cholecystokinin (CCK) has been implicated in the genesis of panic disorder. In this study we measured the ventilatory response to i.v. injection of CCK-tetrapeptide (CCK-4) in anaesthetized dogs. We found an immediate and transient increase in minute ventilation. The response was large (more than 100% of baseline) and lasted 1-2 min. Repeated CCK-4 injection produced a somewhat reduced response, suggestive of a slight degree of tachyphylaxis. Blood pressure and heart rate changed only slightly (<10%), while respiratory mechanical parameters remained unchanged following CCK-4 administration. We conclude that CCK-4 has a significant effect on ventilation in the anaesthetized dog, which suggests that this species may provide a useful quantitative assay for the anxiogenic effects of CCK.

Topics: Animals; Dogs; Injections, Intravenous; Panic Disorder; Respiration; Tetragastrin; Time Factors

Eleven panic disorder patients who panicked in response to exogenous cholecystokinin tetrapeptide (CCK-4) were rechallenged after chronic treatment with imipramine. In the rechallenge the patients displayed a marked reduction in the number and intensity of panic symptoms, duration of symptoms, frequency of panic attacks, and cardiovascular responsiveness. This study demonstrates that imipramine can antagonize the panicogenic effects of CCK-4.

Topics: Adult; Ambulatory Care; Female; Humans; Imipramine; Male; Panic Disorder; Severity of Illness Index; Tetragastrin

The authors determined whether fear of anxiety symptoms mediates panicogenic responses to cholecystokinin tetrapeptide (CCK-4) in healthy subjects. Individuals with a preexisting high level of anxiety sensitivity (N = 10) experienced significantly more catastrophic cognitions and fear of somatic symptoms than did subjects with low (N = 9) or medium (N = 17) anxiety sensitivity, but they were not more susceptible to experiencing a panic attack. Thus, cognitive factors do not appear to be critical determinants of CCK-4-induced panic attacks.

Topics: Adolescent; Adult; Anxiety; Blood Pressure; Cognition; Fear; Female; Heart Rate; Humans; Male; Panic Disorder; Personality Inventory; Tetragastrin

Since cholecystokinin (CCK) is known to be anxiogenic in experimental animals and to induce panic attacks in humans, lymphocyte CCK-8 concentrations were measured in 15 patients with panic disorder and 15 age- and sex-matched healthy subjects. The patients' levels were measured again after a 30-day course of alprazolam therapy, 1.5 mg/day. The CCK-8 concentrations were significantly lower in the patients than in the control subjects and did not change after alprazolam therapy. There was no correlation between the peptide values and levels of anxiety or frequency and severity of panic attacks.

Topics: Adolescent; Adult; Alprazolam; Child; Female; Humans; Lymphocytes; Male; Panic Disorder; Severity of Illness Index; Sincalide; Tetragastrin

Cholecystokinin concentrations in the CSF of 25 patients with panic disorder and 16 normal comparison subjects were ascertained by radioimmunoassay. The patients with panic disorder had significantly lower CSF concentrations of cholecystokinin, which may reflect increased CNS cholecystokinin receptor sensitivity, reduced numbers of receptors, or a compensatory reduction in cholecystokinin octapeptide secondary to theoretically increased central cholecystokinin tetrapeptide activity.

Topics: Adolescent; Adult; Brain; Cholecystokinin; Female; Humans; Middle Aged; Panic Disorder; Receptors, Cholecystokinin; Sincalide; Tetragastrin

Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the effects of CCK-4 are reproducible in panic patients opens the doors for studies of the effects of drug treatment on CCK-4-induced panic.

Topics: Adult; Female; Humans; Injections, Intravenous; Male; Middle Aged; Panic Disorder; Personality Inventory; Placebos; Reproducibility of Results; Severity of Illness Index; Tetragastrin