Megestrol attenuates the hormonal response to CCK-4-induced panic attacks

Progestational hormones may have anxiolytic properties. CCK-4 (cholecystokinin tetrapeptide) can be used pharmacologically to induce panic attacks both in normal controls and patients suffering from panic disorder. In this study we compared the effects of pretreatment with the progestational hormone megestrol and placebo on CCK-4-induced panic attacks and stress hormone release in healthy male controls. Using a double-blind balanced design, we pretreated 10 medically and psychiatrically healthy male controls with placebo or megestrol 160 mg at 11 p.m. and 8 a.m. (sigma=320 mg) prior to the experiment. Following 1 h of rest, 12 blood samples were drawn between 1,000 h and 1,300 h and analyzed for ACTH and cortisol levels. At 1,100 h, subjects received an intravenous injection of 50 microg CCK-4. Clinical ratings were performed at 1,045 h and 1,110 h, and included the Acute Panic Inventory (API), International Diagnostic Checklist (IDCL), as well as a visual analog scale (VAS) for anxiety and tension. CCK-4 significantly increased anxiety and tension. Pretreatment with megestrol showed no significant effect on clinical ratings. Baseline ACTH and cortisol levels, as well as ACTH and cortisol levels after administration of CCK-4, were significantly reduced after pretreatment with megestrol. In a sample of healthy male controls, pretreatment with megestrol had a profound effect on the hypothalamic-pituitary-adrenal (HPA) axis, whereas the clinical effects on panic attacks were weak. Further studies in a larger sample of subjects, including both females and patients suffering from panic disorder, seem warranted.     

Behavioral,cardiovascular, and neuroendocrine profiles following CCK-4 challenge in healthy volunteers: A comparison of panickers and nonpanickers

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. Depression and Anxiety 8:1–7, 1998. © 1998 Wiley-Liss, Inc.     

The acute antipanic and anxiolytic activity of aerobic exercise in patients with panic disorder and healthy control subjects

Regular physical activity is anxiolytic in both healthy subjects and patients with panic disorder. In contrast, acute exercise may induce acute panic attacks or increase subjective anxiety in patients with panic disorder more than in other people. The effects of quiet rest or an aerobic treadmill exercise (30 min at an intensity of 70% of the maximal oxygen uptake, VO_2max) on cholecystokinin tetrapeptide (CCK-4) induced panic attacks were studied in a crossover design in 12 patients with panic disorder and 12 matched healthy subjects. The effects of CCK-4 (25 μg in patients and 50 μg in control subjects) were measured with the Acute Panic Inventory (API) score, comparing panic attack frequencies, total score, and subscores for anxiety and somatic symptoms. CCK-4-induced panic attacks were less frequent after prior exercise: they occurred in 15 (62.5%) subjects after rest (9 patients and 6 control subjects), but only 5 (20.8%) subjects after exercise (4 patients and 1 control subject). In both conditions, CCK-4 administration induced a significant increase in the total API score and the anxiety and somatic symptoms subsores. However, compared to prior rest, exercise resulted in a significantly reduced CCK-4-induced increase of the total API score and the anxiety subscore. In patients with panic disorder exercise increased the total API score and the somatic symptoms subscale but not the anxiety subscore. Patients with panic disorder showed increased somatic but not anxiety symptoms after an acute bout of exercise. Severity of CCK-4-induced panic and anxiety, on the other hand was reduced by exercise. These findings suggest that in addition to exercise training an acute bout of exercise may be used to reduce anxiety and panic attack frequency and intensity in panic disorder patients.     

Cholecystokinin-tetrapeptide induces panic attacks in patients with panic disorder

Cholecystokinin-tetrapeptide (CCK-4) and placebo were injected to 11 panic disorder patients. CCK-4 induced a panic attack identical to spontaneous panic attacks in all patients; placebo did not induce any attacks. The role of CCK-4 in anxiety disorders is discussed.     

Noradrenergic neuronal dysregulation in panic disorder: the effects of intravenous yohimbine and clonidine in panic disorder patients.

In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 micrograms/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine-induced panic attacks and had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine-induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.     

Anxiolyticlike effects of atrial natriuretic peptide on cholecystokinin tetrapeptide-induced panic attacks: preliminary findings

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers.

Genetic regulation of the function of serotonin (5-HT) may be important for the neurobiology of panic disorder. In order to evaluate the influence of 5-HT-related gene variants on the vulnerability to panic attacks, we genotyped 32 healthy volunteers who participated in the study of the effect of 5-hydroxytryptophan on panic attacks induced with cholecystokinin tetrapeptide (CCK-4). The polymorphisms of interest included those of 5-HT transporter (5-HTTLPR) and monoamine oxidase A (MAO-A promoter region) genes. The results showed significant associations between certain genotypes and panic rate in females but not in male volunteers. Specifically, there was a significantly lower rate of CCK-4-induced panic attacks in female subjects who had MAO-A longer alleles or 5-HTTLPR short allele gene variants. These data suggest that functional genetic polymorphisms of the 5-HT system may influence the vulnerability to panic attacks and add to the growing evidence of inhibitory function of 5-HT in the neuronal circuitry of panic.     

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects

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.     

Effects of CCK-tetrapeptide in patients with social phobia and obsessive-compulsive disorder

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.     

Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Fluoxetine in panic disorder: pharmacologic and tritiated platelet imipramine and paroxetine binding study.

Serotonergic implication in panic disorder has been demonstrated by the efficacy of serotonin reuptake blockers in treatment. Fluoxetine, a potent 5-HT reuptake blocker, has been suggested to have anti-panic efficacy. This open study examines 30 patients (eight males and 22 females) with an average age of 36.9 years, ranging from 18 to 62, who were treated for eight weeks with fluoxetine (mean dose 20 mg per day). All patients fulfilled DSM-III-R criteria of panic disorder with agoraphobia as determined in a SCID interview schedule. Out of 28 patients who started medication, 64% of the patients completed the clinical trial and 36% of the patients dropped out of treatment because of increased anxiety or a lack of efficacy. Thirty-two percent of the patients had zero panic attacks by week 3. By the end of eight weeks of treatment, 48% of the patients had zero panic attacks. There was a significant reduction in anxiety and phobic avoidance and panic attacks. Tritiated platelet imipramine and paroxetine bindings revealed significantly lower maximal binding for patients with panic disorder in comparison with controls. Paroxetine Bmax showed a trend to increase in the direction of control values by the end of the trial.     

Carbon dioxide test as an additional clinical measure of treatment response in panic disorder

OBJECTIVE: We aim to determine if a treatment with a dose of clonazepam--2 mg/day, for 6 weeks, blocks spontaneous panic attacks and the ones induced by the inhalation of 35% carbon dioxide (CO2) in panic disorder (PD) patients. The CO2 challenge-test may be a useful addition tool for measuring the pharmacological response during the initial phase (6 weeks) in the treatment of PD. METHOD: Eighteen PD patients drug free for a week participated in a carbon dioxide challenge test. Fourteen had a panic attack and were openly treated for a 6-week period with clonazepam. At the end of the 6-week period they were submitted again to the CO2 challenge test. RESULTS: After 6 weeks of treatment with clonazepam, 12 of 14 PD patients (85.7%) did not have a panic attack after the CO2 challenge test. Just 2 of 14 patients (14.3%) had a panic attack after the CO2 challenge test. Ten of 14 (71.4%) PD patients had panic free status after clonazepam treatment. The 2 patients who had a panic attack in the sixth week, after the CO2 test, did not have panic free status after the treatment with clonazepam. CONCLUSION: The CO2-test may be a valid tool for testing and predicting the drug response.     

Anxiolytic activity of atrial natriuretic peptide in patients with panic disorder

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: The results support the antipanic activity of atrial natriuretic peptide. Nonpeptidergic atrial natriuretic peptide receptor ligands may be ultimately used to treat anxiety disorders.     

DSM-III personality disorders and the outcome of treated panic disorder

Fifty-two patients with panic disorder who had been receiving active benzodiazepine treatment for 8 weeks were assessed by using the outcome measures of spontaneous and situational panic attacks, scores on the Hamilton scales for anxiety and for depression, and scores on self-rated disability scales. Although spontaneous panic attacks were not affected by the presence of any personality disorder, the remaining outcome measures showed a strong and negative association with DSM-III antisocial, borderline, histrionic, and narcissistic personality disorders. There was also a mild negative association with avoidant personality disorder. A subgroup of patients with both major depression and panic disorder appeared more strongly affected.     

A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder.

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.     

Respiratory variability in panic disorder.

Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.     

Lactate- and isoproterenol-induced panic attacks in panic disorder patients and controls

In a double-blind study using sodium lactate and isoproterenol infusions to provoke panic attacks, 73 of 86 panic disorder patients and 10 of 45 controls panicked with lactate, and 58 of 86 patients and 4 of 45 controls panicked with isoproterenol. We measured baseline and peak anxiety ratings in 10 controls with lactate-induced panic attacks, 31 controls who did not panic during lactate infusions, and 63 panic disorder patients who did panic during lactate infusions. The controls who panicked with lactate had robust increases in their anxiety ratings very similar to the increases experienced by patients who panicked with lactate.     

The effect of personality on placebo response in panic patients

Twenty-eight patients who participated as a placebo group in a treatment study of panic disorder were studied to determine the effect of personality on study completion and outcome. Those subjects who completed only 3 weeks had significantly more pathological personality traits than those who continued in the study. For those continuing beyond 3 weeks, there were negative correlations between the paranoid and borderline personality traits and a global outcome measure. Spontaneous panic attacks were not affected by personality.     

Endocrine, cardiovascular, and behavioral responses to clonidine in patients with panic disorder.

We examined adrenergic regulation in patients with panic disorder by challenging 10 patients and 14 age-matched and sex-matched controls with intravenous infusions of clonidine hydrochloride (2 micrograms/kg), an alpha 2-adrenoreceptor agonist. Growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure, heart rate, and behavioral (anxiety, sedation) responses were monitored. The data replicated the previously reported finding of blunted growth hormone (GH) responses to clonidine in patients with panic disorder. Reported abnormalities in MHPG, cardiovascular, and behavioral responses of panic patients to clonidine infusion were not replicated. The robustly blunted GH response to clonidine in panic patients supports the adrenergic dysregulation hypothesis of panic disorder, but alternative interpretations of this finding are available and further study is needed.